Sources of chitin [25].
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
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Wei",slug:"tianxing-wei",email:"weitianxing925@126.com",position:null,institution:{name:"Beijing Forestry University",institutionURL:null,country:{name:"China"}}},{id:"319300",title:"Prof.",name:"Qingke",middleName:null,surname:"Zhu",fullName:"Qingke Zhu",slug:"qingke-zhu",email:"xiangmub@126.com",position:null,institution:{name:"Beijing Forestry University",institutionURL:null,country:{name:"China"}}},{id:"319301",title:"Prof.",name:"Guangquan",middleName:null,surname:"Liu",fullName:"Guangquan Liu",slug:"guangquan-liu",email:"gqliu@iwhr.com",position:null,institution:{name:"China Institute of Water Resources and Hydropower Research",institutionURL:null,country:{name:"China"}}}]},book:{id:"8937",title:"Soil Moisture Importance",subtitle:null,fullTitle:"Soil Moisture Importance",slug:"soil-moisture-importance",publishedDate:"March 24th 2021",bookSignature:"Ram Swaroop Meena and Rahul Datta",coverURL:"https://cdn.intechopen.com/books/images_new/8937.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"313528",title:"Associate Prof.",name:"Ram Swaroop",middleName:null,surname:"Meena",slug:"ram-swaroop-meena",fullName:"Ram Swaroop Meena"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"10878",leadTitle:null,title:"Bioethical Issues in Healthcare",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tThe issues in healthcare today are exploding. Every week we hear about both advances and setbacks in various technologies--CRISPR-Cas- 9, genetic testing, drug-resistant diseases, organ transplantation, brain death, etc. Bioethicists need to work collaboratively with one another globally not only to address these critical issues but also to offer some guidance on how to move forward in the best interests of humanity. Scientists, politicians, public policy advocates, pharmaceutical representatives, business executives are all searching for answers that will address the medical, ethical, and legal issues facing humanity. The role of the Bioethicist is to identify challenges, analyze issues, collaborate with colleagues to coordinate possible positions, and then help to implement changes.
\r\n\r\n\tThis book will challenge those in the medical, legal, and ethical fields to perform these tasks for the common good of humanity. This is an ambitious agenda but one that must be undertaken so that the public is made aware of these issues and what can be done to reach viable conclusions.
\r\n\t
Very commonly used in quantitative analysis, infrared spectrometry FTIR has been exploited in many fields. It has been used in mineralogy in addition to chemical analyzes to determine the structure of a rock and to know the bonds between the atoms, in pharmaceutical for the quantitative measurement of the constituents and the thickness of the coating of the tablets, in dairy industries to determine the moisture of milk powders and butters, in the textile industry for fiber sizing and maturity of cottons, in the chemical industry, in agribusiness, and in several other industries. When a specific absorption of a chemical function of a complex molecule is sufficiently isolated in its spectrum, it is always possible to carry out quantitative measurements. There are several major fields of application for infrared spectrophotometry. First, we can quote functional analysis is probably the main application of infrared spectrometry, at least in industry. Then, the structural analysis, infrared spectrometry allows to obtain even more fine information, concerning the “construction of the molecular edifice.” In organic compounds, it allows for example to differentiate the isomers of position (ortho-, meta-, and para-) aromatic hydrocarbons, as well as the cis- and transisomers of olefins. For mineral compounds, the infrared spectrum depends on the symmetry of molecules; it often allows finding the system in which a chemical compound is crystallized. It is also possible, but only in the case of small molecules, to calculate geometric parameters such as moments of inertia. The analysis is done by comparing with reference spectra of which there are several files. Also, FTIR spectroscopy is the method most used for calculating the degree of DD of chitosan. This polymer was discovered in 1859 by C. Rouget by treating chitin with concentrated KOH at elevated temperature. But it was not until 1894 that Hoppe-Seyler gave the “modified chitin” the name chitosan [1]. Chitosan has some advantageous properties, such as biocompatibility, biodegradable polymer of high molecular weight, nontoxic, and antimicrobial activity, that encourage its applications in many fields including agriculture [2, 3], paper industry, food and textile industries, pharmaceutics [4, 5], biochemistry, biotechnology, cosmetics, biomedical applications [6, 7, 8], environment, and water treatment [9, 10, 11, 12, 13]. The properties of chitin and chitosan depend considerably on the degree of deacetylation (DD), a parameter defined as the mole fraction of deacetylated units in the polymer chain [14, 15]. Therefore, the determination of DD has been one of the interesting parameters to study chitosan preparations. The process of deacetylation involves the removal of acetyl groups from the molecular chain of chitin, leaving behind a complete amino group (-NH2), and chitosan properties are very linked on this high degree of chemical reactive amino groups. Since the degree of deacetylation (DD) depends mainly on the method of purification and reaction conditions, it is therefore essential to characterize chitosan by determining its DD prior to its use. The main parameters involved in the process are temperature, time of reactions, and the concentration of reagents. A simple and nonexpensive chemical treatment of mineral/protein removal from chitin is usually used with HCl/NaOH reagents, respectively, and chitosan is chemically or enzymatically produced. They vary only on the acetyl group container, which is designated by the degree of acetylating (DA) designating the percentage of acetylated units relative to the number of total units. The term chitosan applies to any copolymer whose DD is greater than 50%. Each chitosan is therefore characterized by the fraction of residual N-acetamide groups (DA) or by the relative amount of amino groups of the chitosan molecule (DD = 1-DA) [16]. It is important to distinguish between the degree of acetylation (DA) and the degree of deacetylation (DD). One being the opposite of the other, that is to say that chitosan having an 85% DD, it has 15% of acetyl groups and 85% of amine groups on its chains. The degree of deacetylation (DD) of chitosan is a dominant structural parameter that significantly influences the physicochemical properties of chitosan such as solubility, overall charge, reactivity, and mechanical properties such as elongation, breaking, and tensile strength. This parameter also influences biological properties [17] such as biocompatibility and biodegradability. For determination of the degree of deacetylation (DD), several analytical methods have been employed. Infrared spectroscopy [18, 19] and UV spectrophotometry [20] as analytical tools offer advantage over other traditional techniques which are expensive and destructive to the sample. FTIR spectroscopy is a quick technique for a quantitative evaluation of the DD through the determination of absorption ratios. FTIR analysis is attractive due to its nondestructive character, fastness, sensitivity, and suitability for both soluble and nonsoluble samples. Among the solution methods, first-derivative UV spectrophotometry draws attention owing to its simplicity and effectiveness in providing accurate results for highly deacetylated chitin. It was conceived by Muzzarelli and Rocchetti [20] and relies on simple reagents and instrumentation. In addition, the results obtained from this method are reasonably independent of protein contamination. Alonso et al. [21] established the possibility to determine the acetylation degree with the use of empirical correlations based on the weight losses associated with the main decomposition peaks. A similar approach has been adopted to investigate if there was any relationship between the weight loss of the sample and its DD. According to Yu et al. [22], the conductometric assay is an adequate and accurate method for determining the degree of deacetylation of chitosan, except for some samples that have a high degree of crystallization. The conductometric method can be carried out in basic and acid medium. Other methods have also been used such as SEM and NMR for magnetic properties of certain atomic nuclei and the determination of DD.
The objective of this chapter is to present a bibliographic synthesis on the use of spectroscopy FTIR in order to study and optimize the reaction of deacetylation by calculating the chitosan DD. At the end of the chapter, a simple comparison between IR and other methods of DD determination is presented to find the most reliable formula of DD calculation.
Chitin is the structural polymer of exoskeletons of all arthropods (crustaceans and insects) and endoskeletons of cephalopods (cuttlefish, squid, etc.). The cuticles of various crustaceans, mainly crabs and shrimp, are the main sources of raw material for the production of chitin (Table 1). Chitin is found as part of a complex network of proteins on which calcium carbonate is deposited to form the rigid shell in crustaceans or more specifically in shellfish. The interaction between chitin and proteins is very intimate and there is also a small fraction of proteins involved in a polysaccharide-protein complex [24]. Thus, the preparation of chitin from shellfish requires the elimination of the two main constituents, namely proteins by deproteinization and calcium carbonate by demineralization, as well as small amounts of pigments and lipids generally removed during the two steps. An additional fading step is applied to remove residual pigments. Many methods have been proposed and used over the years to prepare pure chitin; however, no standard method has been adopted. Deproteinization and demineralization can be carried out using chemical or enzymatic treatments. In the case of shrimp, the shell wall is thinner, which facilitates the isolation of chitin compared to other types of shells. The selected shells are then cleaned, dried, and ground into small shell pieces. Shrimp carapaces have the following average mass composition:
75% water
12% protein
9% mineral salts
4% chitin
traces of lipids and organic pigments
We then develop the two essential steps for the preparation of chitin from the carapaces, namely deproteinization and demineralization.
The deproteinization of chitin consists in eliminating proteins; it is difficult because there is a breakdown of the chemical bonds between chitin and proteins. This is done using basic solutions in a heterogeneous way. Complete protein isolation is particularly important for biomedical applications. A wide range of chemicals have been tested as deproteinization reagents, including NaOH, Na2CO3, NaHCO3, KOH, K2CO3, Ca(OH)2, Na2SO3, NaHSO3, CaHSO3, Na3PO4, and Na2S. The reaction conditions vary considerably in each study. NaOH is the preferred reagent and is applied at a concentration ranging from 0.125 to 12 M, at different temperatures (up to 20°C) and a duration of treatment (from a few minutes to a few days). In addition to deproteinization, the use of NaOH results in partial deacetylation of chitin and hydrolysis of the biopolymer, which decreases its molecular weight.
Demineralization is a necessary step to produce chitosan. It consists of dissolving minerals, mainly calcium carbonate bound to chitin. Demineralization is generally carried out by acid treatment using HCl, HNO3, H2SO4, CH3COOH, and HCOOH [26, 27]. Of these acids, the preferred reagent is dilute hydrochloric acid. Demineralization is an acid–base reaction between carbonate ions and acids in water with the release of carbon dioxide, as indicated in the following equation:
All the other minerals present in the crustacean cuticle react in the same way and give soluble salts in the presence of acid. Then, the salts can be easily separated by filtering the solid phase of chitin, followed by washing with distilled water.
Chemically, a kilogram of fresh shells provides about 40 g of dry chitin. After the chemical treatment, the grinding and sieving processes to obtain a homogeneous chitin cause losses of about 40%. The final yield is 2.5%, 25 g of chitin per kilogram of shell. Table 2 summarizes the operating conditions of chitin extraction according to different sources.
Lower plants | Annelid | Mushrooms | Molluscs |
---|---|---|---|
Algae Lichen yeasts | Ascomycetes (Class) Penicillium Blastocladiales (Family) Chytridiaceae (Family) | Earthworm Leech | Cuttlefish Octopus |
Lobsters Crabs Shrimps Scampi Krill | Octopus Scorpions | Spiders Ants Cockroaches Coleoptera (Order) |
Sources of chitin [25].
Deproteinization | Demineralization | |||||||
---|---|---|---|---|---|---|---|---|
Source | CNaOH* | T°C | Number of baths | Duration(h) | CHCL | T°C | DURAT-ION (h) | |
Shrimp | 0.125 M 0.75 M | 100 100 | 1 1 | 0.5 0.5 | 1.25 M | Room | 1 | [28] |
Shrimp | 1.25 M | 100 | 1 | 0.5 | 1.57 M | 20–22 | 1–3 | [29] |
Shrimp | 1% | 65 | 1 | 1 | 0.5 M | Room | — | [30] |
Shrimp | 3% | 100 | 1 | 1 | 1 M | Room | 0.5 | [31] |
Shrimp | 4% | 100 | 1 | 1 | 5% | Room | — | [32] |
Shrimp | 7.5–12.5 M | 1 | 30–180 mn | 0.3–3.5 M | Room | 24 | [23] | |
Shrimp | 1 M | Room | 1 | 24 h | 1 M | Room | 24 | [3] |
Crab | 0.5 M | 65 | 1 | 2 | 1.57 M | Room | 5 | [33] |
Crab | 1 M | 80 | 1 | 3 | 1 M | Room | 12 | [34] |
Crab | 1 M | 100 | 1 | 36 | 2 M | Room | 48 | [28] |
Crab | 1 M | 100 | 3 | 72 | 1 M | Room | — | [35] |
Crab | 1.25 M | 85–90 | 3 | 24 | 1.37 M | Room | 24 | [36] |
Crab | 1 M | 50 | 1 | 6 | 1 M | 20 | 3 | [37] |
Crab/lobster | 2.5 M | Room | 3 | 72 | 11 M | −20 | 4 | [38] |
Lobster | 1 M | 100 | 5 | 12 | 2 M | Room | 5 | [39] |
Lobster | 5% | 80–85 | 2 | 0.5 | 5% | 70 | 4 | [40] |
Lobster | 10% | 100 | 1 | 2.5 | 10% HCl 90% formic | Room | 18 | [41] |
Krill | 0.875 | 90–95 | 1 | 2 | 0.6 M | Room | 2 | [42] |
Krill | 3.5% | 25 | 1 | 2 | 3.5% | 20 | 1.5 | [43] |
Crawfish | Room | [44] |
Chitin extraction conditions.
Chitosan represents a family of polymers obtained at varying degrees after deacetylation of chitin. In fact, the degree of acetylation (DA), which reflects the balance between the two types of residues (Figure 1), differentiates chitin from chitosan. When the DA (expressed as molar percentage) is less than 50 mol%, the product is called chitosan, and it is characterized by its solubility in acidic solutions [45]. During deacetylation, the amides are protonated and the acetyl groups are removed, but a depolymerization reaction, indicated by the changes in the molecular weight of the chitosan, is also produced.
Equation of chitin conversion to chitosan by deacetylation.
Chitin can be converted to chitosan by enzymatic preparations [46, 47, 48, 49] or by a chemical process [50, 51]. Chemical methods are widely used for commercial purposes for the preparation of chitosan because of their low cost and their ability to mass produce [51].
To deacetylate chitin chemically, acids or bases are used. However, glycosidic bonds are very sensitive to acid treatment [51, 52]; therefore, alkaline deacetylation is often used. The deacetylation reaction is heterogeneous [53] or homogeneous [54]. Generally, in the heterogeneous process, chitin is treated with hot concentrated NaOH solution for a few hours and chitosan is produced as an 85–99% deacetylated insoluble residue. According to the homogeneous method, the alkaline chitin is prepared after dispersion of the chitin in concentrated NaOH (30 g NaOH/45 g H2O/3 g Chitin) at 25°C for 3 h or more and then dissolved in crushed ice around 0°C. This method gives a soluble chitosan with an average degree of acetylation of 48–55% [50]. This process produces a deacetylation with acetyl groups uniformly distributed in the chains, for example chitosan with DA = 10% after 580 h at 25°C [54].
The details of the process parameters employed by various researchers that include the number of demineralization, deproteinization, and deacetylation step have been reviewed and summarized in Table 3.
Source | Number of deproteinization baths | Number of demineralization baths | DA | |
---|---|---|---|---|
Cirripedia | Anatife | 4 | 2 | 51 |
Reptantia | Red crab | 3 | 5 | 48 |
Brachyura | Marbled crab | 3 | 3 | 50 |
Reptantia | Spider crab | 3 | 3 | 47 |
Macrura | Lobster | 3 | 3 | — |
Natantia | Crayfish | 7 | 3 | 51 |
Slipper lobster | 3 | 2 | — | |
Freshwater cayfish | 3 | 2 | — | |
Pink shrimp | 3 | 3 | 51 | |
Gray shrimp | 2 | 2 | 51 | |
Stomatopoda | Squilla | 3 | 3 | 51 |
Cephalopoda | Squid | 2 | 2 | 51 |
Comparison of chitosan production from different sources according to Tolaimate et al. [55].
The main disadvantages of chemical deacetylation are energy consumption, waste concentrated alkaline solutions and thus increased environmental pollution. In order to avoid these disadvantages, an alternative enzymatic method exploiting chitin deacetylases has been explored. The use of chitin deacetylase offers the possibility of a nondegradable controlled process, leading to the production of well-defined chitosan [56]. This method is especially used to prepare chitosan oligomers.
Chitin deacetylase catalyzes the hydrolysis of N-acetamido linkages in chitin to produce chitosan. The presence of this enzymatic activity has been reported in several fungi [57, 58] and insect species [59]. The most studied enzymes are those extracted from the mushrooms Mucor rouxii [46, 56, 57], Absidia coerulea [60, 61], and Aspergillus nidulans [62, 63], and two strains of Colletotrichum lindemuthianum [64, 65]. All enzymes are glycoproteins and are secreted either in the periplasmic region or in the culture medium. In addition, all the enzymes exhibit remarkable thermal stability at their optimum temperature (50°C) and a very high specificity for the bound N-acetyl-D-glucosamine polymers.
The determination of average DD for chitosan may be performed by different techniques: infrared spectroscopy, elementary analysis, potentiometric titration, and 1H liquid state and solid state 13C-NMR. But FTIR technique has specifically proved to be useful for the analysis of chitin due to its limited solubility in most of the solvents. Nevertheless, FTIR needs a calibration versus an absolute technique like nuclear magnetic resonance (NMR). Identifying the right combination of bands and baselines required a lot of effort, which led the authors to preface a large number of methods in the literature. In fact, several methods have been tried to determine the degree of deacetylation (DD) by FTIR [18, 66, 67, 68, 69]. Below is a description of the major three types used to calculate DD by FTIR.
El ouahli [70] calculated from the absorption bands at 1320 and 1420 cm−1. The first band is characteristic of the acetylated amine or amide function, while the second band is chosen as the reference band. The following equation is used to determine DD of chitosan:
This IR characterization formula for chitosan is based on the relationship between the absorbance (A) value of the primary amide at 1655 cm−1 and that of the hydroxyl at 3450 cm−1. The degree of deacetylation (DD) was calculated by Eq. (3), [66, 69]:
In our study, a ratio had been already proposed [68, 71, 72]. However, choosing an appropriate calculation procedure was not an easy task since the choice of the baseline on FTIR spectra, reference, and the probe bands was difficult. In our work, the average DD was determined by the following formula:
where A1655 is the absorbance at 1655 cm−1 of the amide I band as a measure of the N-acetyl group content and A3430 is the absorbance at 3430 cm−1 due to hydroxyl group as an internal standard. The value 1.33 represents the ratio of this absorbance for a fully acetylated compound. An appropriate baseline in each spectrum was determined by using origin software.
The baseline problem for reference peaks has been studied and summarized in Table 4 and Figure 2. Table 4 shows that there are other formulas for calculating chitosan DD by FTIR and that these formulas have been approved by other techniques such as NMR.
DA calibration curve | Method for DA standard | Ref. |
---|---|---|
1. DA = (A1655/A3450) × 155 | Titration | [66] |
2. (A1320/A1420) = 0.3822 + 0.03133 × DA | 1H NMR, 13C NMR | [67] |
3. (A1320/A3450) = 0.03146 + 0.00226 × DA | 1H NMR, 13C NMR | [67] |
4. (A1560/A2875) = 0.2 + 0.0125 × DA | Elemental analysis | [71] |
Calibration curves from absorption ratios versus standard DA values [73].
FTIR spectrum of chitin and the baseline [
A synthesis of the study on the effect of the operating conditions to know temperature concentration of the base and the time on the reaction of deacetylation will be presented using IR.
In this deacetylation reaction, it is an interrelation between the following variables: the concentration of the basic solution, the temperature, and the reaction time. The deacetylation reaction in basic medium is summarized in Eq. (5):
For CNaOH = 12 N, the DD values calculated from the FTIR shown in Table 5 do not exceed 55% and stabilize after a critical time t < 60 min. At a low concentration of NaOH, the equilibrium time became higher, which shows that the chitosan DD is low, which means that the deacetylation reaction is highly dependent on the concentration of NaOH, due to the inaccessibility of acetamide groups in the polymer chain. This type of behavior, observed by other authors, is explained firstly by the fact that the N-deacetylation occurs preferably at the level of the amorphous region of chitin and then passes from the edge to the interior of the crystalline region [26, 27]. The second reason concerns the equilibrium of the reaction and the degradation of chitosan. Other authors [10, 22, 28] have assumed that it can be controlled by both reaction and diffusion. The low deacetylation of chitin has also been attributed to the rearrangement of acetyl groups in the monomer unit with respect to the OH hydroxyl group [9]. Analysis of the results of the measurement of the DD (Table 5) shows that this increased by approximately 8% (66–74% DD), at a high concentration of NaOH (10 M) and with a thermal increase of 20°C (100–120°C). This variation of DD seems less important, only +2% (26–28% DD) at low concentration of NaOH (7.5 M). This increase in DD is particularly significant (13%) with a base concentration increase of 2.5 M (10 M to 12.5 M). Thus, the variation in NaOH concentration more significantly influences the reaction rate of DD than temperature.
Temperature of DD | Concentration of the base (M) | Time (mn) | DD |
---|---|---|---|
25°C | 8 | 180 | 38 |
10 | 120 | 45 | |
12 | 60 | 55 | |
80°C | 4 | 38 | 35 |
8 | 38 | 52 | |
10 | 38 | 55 | |
12 | 38 | 63 | |
120°C | 8 | 50 min | 40 |
12 | 50 min | 50 | |
8 | 300max | 65 | |
12 | 300max | 70 |
Evolution of DD as a function of the concentration of the base at different temperatures [3].
Table 6 shows the effect of temperature on deacetylation; the more the temperature increases, the more the deacetylation increases, but the total conversion of chitin to chitosan is only carried out at the temperature of 80°C and for high concentrations of the base [23]. Analysis of the results of the measurement of DD shows that it has increased approximately 8% (66–74% DD), at high concentration of NaOH (10 M) and a thermal increase of 20°C (100–120°C). This variation of DD seems less important, only +2% (26–28% DD) at low concentration of NaOH (7.5 M). This discrepancy can be considered as an error of analysis. However, this increase in DD is particularly significant (13%) with a base concentration increase of 2.5 M (10–12.5 M). The temperature in this step is a factor that weakens the binding of the acetyl groups and accelerates the deacetylation reaction. Ahlafi and al [3] also found that the DDs increase as the NaOH concentration and temperature increase as the time of reaction increases. These reached a maximum of 63% and 71% for CNaOH = 12 N at T = 80 and 120°C, respectively. On the other hand, it can be observed that the critical time decreases when the temperature and the concentration of NaOH increase. It can be seen in the case of CNaOH = 12 N and T = 120°C. The increase of DD values with these parameters can be attributed to the change of the structure during deacetylation of chitin at height temperature, as confirmed by FTIR studies. These results confirm the hypothesis that the interaction of concentration and thermal energy are the main criteria to be taken into account for the deacetylation reaction.
The analysis of the results (Table 7) shows that the best deacetylation started after 60 min, for the three concentrations of NaOH studied. At this time, the activation energy for deacetylation can be reached and the chemical bond break occurs. However, this breakdown of the acetyl groups is significant only at the level of the high alkaline concentration (> 10 M). Diffusion of the alkaline solution on the shell substrate increases with time. These results confirm the hypothesis that there is an interaction between the concentration of NaOH and the reaction time on DD.
At the lowest NaOH concentration (7.5 M), the percentage of deacetylation increases from about 60°C but remains low even at 120°C (Table 7). The extracted product remains predominantly in the form of chitin. The deacetylation is terminated after a period ranging from 90 to 120min depending on the concentration of NaOH. Moreover, for a lower concentration of NaOH (8.75 M), this reaction is incomplete even after 3 h for different authors [74]. Therefore, in the case of a low concentration of NaOH (less than 10 M), the deacetylation does not occur completely. Thus, to obtain a good-quality chitosan, it is necessary to resume the treatment several times using NaOH solution [75, 76]. This reprocessing scheme is technically not easy and economically unviable on a large scale. So, for better deacetylation, 1 h is sufficient for concentrations greater than 10 M.
The rate of deacetylation therefore depends not only on the concentration of NaOH used but also on the temperature for a breakdown of the acetyl bonds. However, a high temperature leads to a degradation of chitosan, which causes the viscosity η to drop and the molecular weight M (η = kM a) to drop, which affects the solubility of chitosan. The variation of the concentration of NaOH does not affect its molecular weight [76].
The chitin deacetylation process followed the pseudo–first-order kinetics for all the temperatures studied (25, 80, and 120°C) and at the same alkaline concentration (12 N) [3]. The Table 8 showed that the values decreased as a function of temperature. This indicates that the speed of the deacetylation reaction is faster at the beginning of the reaction t < 60 min, but it was very slow at the end of reaction.
T(°C) | 25 | 80 | 120 |
---|---|---|---|
k2 (min−1) 2nd step | 1.70 × 10−5 | 2.23 × 10−4 | 22 × 10−4 |
Apparent rate constant [3].
The apparent activation energy was estimated at about 48.76 kJ/mol from the straight line of the Arrhenius plot (in k vs. (1/T)) [3]. This value is in the same order of magnitude as that found by other authors for heterogeneous N-deacetylation performed between 80 and 120°C [10, 12, 22, 26]. The concentration of NaOH significantly influences the variation of the reaction temperature. Rinaud and al. [14] mention that at a NaOH concentration of 10–15 M, the energetic activation (Ea) of the deacetylation is, respectively, about 22–50 kJ/mol, which makes it possible to increase the degree of deacetylation. The results indicated that the reaction at higher concentration and temperature proceeded easier than that at their lower values.
The reagent diffusion mechanism represents the second step in deacetylation of chitin. Recently, Sarhan et al. [28] have proposed a mechanism in which heterogeneous N-deacetylation is controlled by both reaction and diffusion: the first step involves the reaction of the onium salt, designated (Q+ X−), with NaOH to give the corresponding onium hydroxide (Q+ OH−) capable of diffusing from the aqueous phase to the organic phase to start the deacetylation process by attacking the C = O of the acetyl group and then at the end of the reaction of hydrolysis, the resulting onium acetate (CH3COO−Q+) will diffuse into the aqueous phase to be regenerated to a new onium hydroxide by the reaction with NaOH. From our results, the DD/CNaOH ratios remain constant at each temperature at longer deacetylation times, which means that the deacetylation reaction is complete.
The results obtained under various conditions were analyzed statistically using multilinear regression analysis (uncertainty value =0.05) [23]. The NaOH concentration, temperature, and reaction time were chosen as independent parameters for the three-variable and three-level (maximum, mean, and minimum) factorial design. The best equation obtained for the chitosan extraction process in this study is Eq. (6). Shrimp at a higher temperature is not reliable. In addition, the production of chitosan at high temperature causes degradation of the container and therefore involves manipulations more difficult to adapt for industry. To ensure the quality of the chitosan product, the digestion temperature must be kept constant at 110°C.
The values of this equation indicate that the effect of three factors studied influences DD in the following order: reaction time (24.86) > NaOH concentration (5.6) > reaction temperature (3.78). Further, a reaction time of 152 min (≈2.5 h) is predicted from Eq. (5) to reach 90% DD using a NaOH concentration of 12.5 M and a temperature set at 110°C. This time predicted by the factorial plane seems consistent with the actual deacetylation reaction time (120 min) with an error of 27%.
The production of chitosan from dried shrimp exoskeletons can be done in 1 day instead of the 3 days required by the conventional method. The results obtained show that the extracted chitosan has a DD greater than 90% under optimal conditions by the hydrothermal-chemical technique in two stages at 110°C, that is, 11.25 M NaOH for 3 h or 12.5 M NaOH during 2 h. For the extraction of chitosan at an SD of 85% in the context of water treatment, the transformation procedure must be carried out under the following optimal conditions:
Demineralization at 50°C for 2.5 h in 2 M HCl
Deproteinization and deacetylation at 110°C with 11.25 M NaOH for 2 h
A new method of producing very high DD content chitosan under low concentration alkaline conditions has been introduced by Xiaofei et al. [79]. The synthesis was produced at high temperatures and pressures. The results in Table 9 were deduced from IR spectra. Compared to traditional methods, low concentration alkaline and short reaction time are excellent benefits. In addition, compared to the enzymatic and organic solvent treatment method, the pressure method was inexpensive and convenient without further purification. Excellent repeatability and simplified operation increased its availability in production and large application chitosan scale with large quantity production. In order to produce chitosan with a very high content of DD by chitin in a more efficient and more environmentally friendly way, Xiaofei et al. [79] have changed the pressure and have used the multistep method for the deacetylation of chitin in alkaline at low concentration. They adopted the alkaline recycling model using alkaline waste in the next deacetylated step. In this model, they added an alkali according to the different demands of each phase and eliminated acetyl in a timely manner, in case the high concentration of the acetyl group would inhibit the deacetylation. In addition, the use of the base in several steps will be effective not only to control the degree of deacetylation but also to control the molecular weight of the resulting product.
C/% | CT:NaOH | RT/min | T/C | Productivity/% | DD/% |
---|---|---|---|---|---|
5 | 1:20 | 120 | 120 | 88.95 | A |
5 | 1:20 | 240 | 120 | 90.48 | A |
10 | 1:20 | 120 | 120 | 88.41 | A |
10 | 1:20 | 240 | 120 | 90.88 | A |
15 | 1:20 | 120 | 120 | 86.76 | A |
15 | 1:20 | 240 | 120 | 88.73 | A |
20 | 1:20 | 120 | 120 | 87.66 | A |
20 | 1:20 | 240 | 120 | 86.94 | A |
25 | 1:20 | 120 | 120 | 85.69 | A |
25 | 1:20 | 240 | 120 | 85.88 | A |
30 | 1:20 | 120 | 120 | 85.19 | A |
30 | 1:20 | 240 | 120 | 86.53 | A |
30 | 1:20 | 360 | 120 | 85.44 | A |
35 | 1:20 | 120 | 120 | 84.17 | 85.05 |
40 | 1:20 | 120 | 120 | 82.00 | 90.13 |
40 | 1:20 | 120 | 120 | 81.27 | 94.26 |
40 | 1:20 | 120 | 120 | 81.93 | 89.19 |
The effect of different reaction conditions on DD value of chitosan [79].
A: Undissolved in HCl.
Working under high pressure and with low concentrations of the base, they were able to extract chitosan with DD of 100%. In fact, only 15% of alkali solution and a ratio of 1:10 chitosan powder to NaOH solution and to a pressure of less than 0.11–0.12 MPa for 120 min lead to 100% DD. When the alkali concentration varies from 5–15%, the very high value DD chitosan (up to 95%) is produced. The method under pressure to prepare 100% deacetylated chitosan with less environmental pollution is very interesting.
To extract a large quantity of chitosan, industrialists need high temperatures and chemicals in large quantities. In addition, the conventional process requires a lot of time and consumes a lot of energy, which would harm the environment. Recently, microwave irradiation has been used as an unconventional energy source in chemical reactions. The objective of this study is to synthesis chitosan under microwave irradiation in order to reduce the impact of environmental pollution due to excessive use of chemical treatments [80, 81, 82]. The study will examine the effect of chemical addition, reaction time, operating temperature on manufacturing, and chitosan DD under microwave irradiation. These results will be compared to those from conventional heating methods to compare results. As part of this research, they developed the design and manufacture of a proton prototype for the production of chitosan from shrimp shell waste. Research has concluded that microwaves will accelerate reaction time.
The results showed that the demineralization condition of shrimp waste was achieved at the concentration of HCl 3,5 N solution with the weight ratio of shrimp shell waste and HCl solution of 1: 5 (w/v), at a temperature of 50°C during 1 h heating. In those conditions, the ash content was 8.06%. Ash content decreases to 5.4% if the demineralization reaction is carried out under microwave irradiation with 130 watts for 10 min. The optimum condition of the deproteinization process was achieved by heating at a temperature of 70°C for 2 h and at 4% NaOH concentration for shrimp waste ratio: a NaOH solution of 1:5 (w/v). In this condition, they obtained nitrogen levels of 1.882% (11.763% protein content). If the deproteinization reaction was performed under microwave irradiation with 130 W of power for 15 min, the nitrogen content obtained was 1.833% (11.461% protein content) (Table 10
Chitin treatment | NaOH conc. (%) | DD% | Mw (k Daltons) | Solubility (%) |
---|---|---|---|---|
20 mesh | 30 | 67.58F ± 0.92 | 2415.09 | 66.31H ± 0.35 |
40 | 75.77E ± 3.54 | 1476.21 | 74.94G ± 0.79 | |
50 | 78.83D ± 1.05 | 1267.11 | 96.77BC ± 0.17 | |
40 mesh | 30 | 76.89DE ± 0.89 | 866.03 | 99.05A ± 0.05 |
40 | 78.64D ± 0.86 | 1107.50 | 92.79D ± 0.01 | |
50 | 83.05C ± 0.29 | 2160.88 | 95.60C ± 0.87 | |
60 mesh | 30 | 88.39B ± 0.49 | 949.95 | 83.28F ± 0.87 |
40 | 89.17B ± 0.28 | 1274.85 | 85.57E ± 1.37 | |
50 | 95.19A ± 0.74 | 4467.05 | 97.73AB ± 0.95 | |
Commercial chitosan | ||||
85.00C ± 0.66 | 300 | 99.00A ± 0.72 |
Degree of deacetylation (DD), molecular weight (mw), and solubility of chitosan samples extracted from shrimp wastes using microwave technique [81].
Data are the mean.
Mean values in the same column bearing the same superscript do not differ significantly.
To differentiate chitin from chitosan, it is necessary to define the degree of acetylation (DA), that is to say the ratio of the number of units comprising an acetyl group on the number of units in the molecule. We can also speak of degree of deacetylation (DD) such that: DD = 100 - DA in%.
The calculation of DD was made according to several methods described in the literature: acid and basic conductometric method, pH-metric method, UV method, and IR spectroscopy method. In a recent study [70], an attempt was made to compare IR and other analytical methods to compute DD. The analysis was performed by acidic conductometric assay. Basic conductometric dosing and pH-metric dosing techniques will be compared to IR.
According to Yu et al. [22], the conductometric assay is an adequate and accurate method to determine the degree of deacetylation of chitosan. It was carried out in basic and acid medium.
A solution of chitosan was prepared by dissolving a mass of 150 mg of chitosan in 10 ml of hydrochloric acid (0.1 N) and then the volume was adjusted to 200 ml by addition of distilled water. The prepared solution is titrated with stirring with sodium hydroxide solution (0.1 N). Figure 3A shows the change in the volume of sodium hydroxide as a function of the conductivity of the chitosan solution. The curve has two points of inflection. The difference in the volume of NaOH between these two points corresponds to the amount of HCl required to dissolve the chitosan, which is to say to transform the -NH2 groups into -NH3+.
(A) Variation of the conductivity of the chitosan solution as a function of the volume of the base (B) variation of the conductivity of the chitosan solution as a function of the volume of the acid solution.
The degree of deacetylation (DD) of chitosan is then determined from the following relationship [70]:
where N is the normality of the NaOH solution (mol/l); V2 and V1 are the equivalent volumes of NaOH representing two inflection points, respectively; M is the mass of chitosan; 203 (g/mol) is the molar mass of the acetyl monomer; and 42 (g/mol) is the difference between the molecular weight of the acetyl monomer and the molecular weight of the deacetylated monomer.
The degree of deacetylation according to the conductometric method is:
The determination of the DD by acid conductometric assay is carried out as follows: a mass of 150 mg of chitosan is dispersed in 200 ml of distilled water; while stirring, the mixture is titrated with 0.1 N HCl solution. Figure 3B shows the evolution of the conductivity of the chitosan solution as a function of the volume of HCl poured. The point of inflection corresponds to the amount of HCl consumed by the amine groups of chitosan. The DD will be calculated from the following equation:
where N is the normality of the HCI solution (mol/l), V is the volume corresponding to the inflection point as shown in Figure 3B, m is the mass of chitosan (g), and 42 (g/mol) is the difference between the molecular weight of the acetylated monomer and the molecular weight of the deacetylated monomer.
DDA calculation gives:
The determination of the DD by pH-metric assay was carried out according to the method described in the literature [77, 78].
A solution of chitosan was prepared by dissolving a mass of 125 mg of chitosan in a solution of excess HCl (0.1 N) and then neutralizing this solution with sodium hydroxide solution (0.05 N). Figure 4A shows the titration curve of chitosan, and Figure 4B shows the corresponding secondary derivative. From this last curve, the amount of hydrochloric acid necessary to protonate the amine groups is determined. The degree of deacetylation calculated from this method is 77.10%.
(A) Variation of the pH according to the volume of soda poured for the solution of the chitosan and the solution of the hydrochloric acid, (B) secondary derivative curve corresponding to the assay.
The results of the DDA obtained by the different assay methods are shown in Table 11.
Dosing method | DDA (%) |
---|---|
Basic conductivity meter | 76.35 |
Conductometric acid | 77.30 |
pH-metric | 77.10 |
Infrared spectroscopy | 78.50 |
Calculated average | 77.32 |
DD values obtained with different assay methods [70].
The average value of DD calculated for the chitosan prepared during this work is 77.32%. So, IR spectroscopy remains the simplest and most economical technique for calculating DD.
Another study presented by Xiaofei and al [79] gave a comparison between IR spectroscopy and other techniques and showed the importance of FTIR for calculating DD (Table 12). They have been measured for 3 or 2 times.
Method | 1 (%) | 2 (%) | 3 (%) | 4 (%) | 5 (%) |
---|---|---|---|---|---|
Part-I | |||||
DDTitration1 | 90.82 | 90.57 | 94.93 | 93.04 | 92.48 |
DDTitration2 | 92.85 | 94.62 | 93.97 | 95.40 | 94.99 |
DDTitration3 | 93.10 | 94.45 | 94.86 | 94.35 | 94.66 |
DD-UV1 | 95.97 | 95.96 | 99.42 | 98.18 | 99.34 |
DD-UV2 | 94.44 | 94.87 | 97.72 | 97.07 | 97.00 |
DD-UV3 | 95.02 | 95.36 | 98.07 | 97.42 | 97.99 |
Part-II | |||||
DD-UV1 | 82.00 | 95.96 | 97.68 | 100.00 | 100.00 |
DD-UV2 | 82.27 | 95.86 | 97.73 | 100.00 | 100.00 |
DD-IR1658/3450 | 80.43 | 94.50 | 94.60 | 95.37 | 96.33 |
DD-IR1320/1420 | 87.64 | 100.00 | 100.00 | 100.00 | 100.00 |
Comparison of DD value measured by different methods [79].
The calculation of DD and the number of amine present in chitosan by FTIR allows first to follow the transformation reaction of chitin into chitosan and others by finding the optimal conditions for the synthesis of chitosan by studying the effect of different parameters, namely the concentration of the base, the temperature, and the duration of the reaction. The valorization of shrimp exoskeletons by extraction of chitosan according to the hydrothermal-chemical technique proposed in two stages makes it possible to reduce the production time by at least four times compared to the conventional technique in three stages (3–4 days). In addition, the consumption of digestion and energy chemicals is also significantly reduced. The chitosan obtained by the two-step technique is of good quality. Indeed, the degree of deacetylation is greater than 90% under the optimal conditions for the simultaneous deproteinization and deacetylation.
The compression method for preparing 100% deacetylated chitosan with less environmental pollution was studied by FTIR. The 100% fully deacetylated chitosan was produced in low-concentration alkali and high-pressure conditions, which only requires 15% alkali solution and 1:10 chitosan powder to NaOH solution ratio under 0.11–0.12 MPa for 120 min. When the alkali concentration varied from 5–15%, the chitosan with ultra-high DD value (up to 95%) is produced.
In parallel, the FTIR calculation was also used to show that the microwave could be used in the extraction step of chitosan from chitin. From these results, it could be concluded that shrimp waste is an excellent source for chitin, and the yields of chitosan increased with decreasing the chitin particle size and increasing the concentration of NaOH solution used in deacetylation step. The highest degree of deacetylation was obtained from chitin samples at particle size of 60 mesh deacetylated by 50% NaOH solution, and it was 95.19% compared with 85% for commercial chitosan. Based on this synthesis, it is concluded that FTIR is an effective and reliable technique for the determination of DD and the study of the deacetylation reaction of chitin. All the formulas quoted are valid for calculating DD of chitosan, but the most reliable formula and the formula most approved by other techniques is formula 3 quoted in our works.
A certain minimal level of progesterone must be maintained from ovulation until delivery to allow the birth of a full-term live baby [1]. Progesterone (P), acting in conjunction with the P receptor, causes the production of a large number of various molecules needed for the development of an appropriate secretory endometrium to allow attachment of the blastocyst to the endometrium and adequate invasion to the proper depth of the fetal placental unit [1].
Some of the molecules induced are also needed to suppress rejection of the fetal semi-allograft. One of these immunomodulatory proteins has been termed the progesterone induced blocking factor (PIBF) [2]. There is evidence that PIBF is one of the most important immunomodulatory factors produced during pregnancy to inhibit immune rejection of the fetal semi-allograft [3, 4].
Progesterone-induced blocking factor is an immunomodulatory protein that can suppress or block various aspects of the immune system, especially, but not limited to, natural killer (NK) cells [5, 6]. The blocking effect on cellular immunity, especially NK cell cytolytic activity, may be related, at least in part, to a shift from thymic helper (TH)-1 to TH2 cytokine dominance [7]. One mechanism by which PIBF can suppress NK cell cytolytic activity is by inhibiting degranulation of perforin granules, one mechanism used by NK cells to kill other cells [8].
The “parent” form has a molecular mass of 90 kDa and is localized in the centrosome [9]. Various splice variants of this nuclear protein lead to smaller intracytoplasmic molecules that have immunosuppressive activity [9]. The actual full-length protein contains 757 amino acids, and the 48 kDa N terminal part is biologically active [10]. The PIBF gene has been identified on chromosome 13 in the vicinity of breast cancer 1 (BRCA1) or BRCA2 or p53 [11, 12].
Progesterone-induced blocking factor rises precipitously in the serum after exposure to P (even in males injected with progesterone) and the source seems to be circulating gamma/delta T cells [2]. However, it seems that the main source of PIBF that allows the early feta-placental to escape immune surveillance are actually cells of the fetal placental unit namely embryonic cells, mesenchymal cells, and trophoblast cells [1, 9].
In 2001, Check et al. hypothesized that it is likely that cancer cells might “borrow” some of the same mechanisms to escape immune surveillance as the fetal-placental unit [13]. Based on their previous research with the PIBF protein, they considered that, whereas treatment for infertility or recurrent miscarriage should be aimed at increasing the production of the PIBF protein, theoretical treatment for cancer could be therapy aimed at suppressing the PIBF protein [13].
Support for this concept was provided by Lachman et al., who showed that many different types of cancer cells express this PIBF protein [9]. Though one may think that highly proliferating cancer cells may be the ones that have the classic nuclear progesterone present, the study by Lachman et al., found many of the cancers associated with PIBF were not known to be positive for the nuclear P receptor [9].
Based on this hypothesis, it was considered that a P receptor antagonist/modulator should cause suppression of PIBF production in rapidly growing cancer cells which could overcome the theoretical block of immune function of cellular immune cells in the tumor microenvironment.
Mifepristone was the first P receptor antagonist developed [14]. It was a derivative of the synthetic progestin norethindrone [14]. It was purposely developed to be an abortifacient to alter the endometrium and cause decidual necrosis and cause the trophoblast to separate from the decidua [14, 15, 16]. Mifepristone sensitizes the pregnant uterus and cervix to endogenous and exogenous prostaglandins increasing uterine contractility and helps to induce cervical softening [14, 15, 16].
Over the years other benefits of mifepristone, related to its anti-progesterone effect, have been developed, including treating uterine leiomyomata and endometriosis [17]. The anti-abortifacient drug comes in 200 mg tablets. Since mifepristone in higher dosages blocks the glucocorticoid receptor, it has been approved as a 300 mg tablet to treat Cushing’s syndrome [18].
Thus, we set up a study to determine if we could detect PIBF in various leukemia cell lines, and, if so, determine if adding mifepristone to the medium could reduce PIBF secretion. To do so we collaborated with Dr. Srivastava from the Roswell Park Cancer Institute, who for many years studied protein production by leukemia cell lines. Twenty-nine cell lines of diverse lineage were all found to express messenger (m) RNA for PIBF [19]. In fact, there was more mRNA dedicated to the production of the PIBF protein, by far, than any mRNA for any other protein previously studied in these leukemia cell lines [19]. Ten cell lines positive for mRNA for PIBF were tested for the PIBF protein using a much less sensitive assay for PIBF than is presently available. Four tested positive for the PIBF protein. Addition of progesterone to the media of the cell lines up-regulated mRNA for PIBF and also the PIBF protein [19]. In contrast, the addition of mifepristone to the media down-regulated both mRNA for PIBF and the 35 kDa PIBF intracytoplasmic splice variant protein (similar in size to the PIBF splice variant in fetal-placental cells) [19].
Subsequently studies using other cancer cell lines supported the conclusions from the leukemia cell line studies. Kyurkchiev et al. found that glioblastoma multiforme also express the intracytoplasmic PIBF protein, but in this case the splice variant measured 57 kDa [20]. Gonzalez-Arenas et al. found, similar to the aforementioned leukemia cell line studies, adding P to the media up-regulates the 57 kDa intracytoplasmic splice variant of PIBF in glioblastoma multiforme cell lines [21]. Interestingly, in addition they added PIBF protein to the media and found that PIBF increased the number of U87 cancer cells on days 4 and 5 of treatment. This suggests that PIBF promotes proliferation of human glioblastoma cancer cells independent of an intact immune system, which would require a whole intact animal or human [21].
Mifepristone has been also found to inhibit the growth of cell lines or murine tumor transplantation from endometrial cancer, breast cancer, prostate cancer, gastric cancer, ovarian cancer, and lung cancer [22, 23, 24, 25, 26, 27].
Goyeneche’s group published some interesting findings concerning mifepristone and ovarian cancer cell lines. They have found that mifepristone inhibits ovarian cancer cell growth in vitro and in vivo [28]. They have published several studies showing the benefit of the combination of mifepristone and chemotherapy with cisplatin therapy or cisplatin-paclitaxel treatment of ovarian cell lines [29, 30, 31].
Based on these cell line studies, more support was provided that cancer cells may borrow some of the same escape mechanisms as the fetal-maternal unit to escape immune surveillance. Thus, therapy aimed to suppress these immune factors could lead to novel effective anticancer therapies [32]. Dr. Szekeres-Bartho, another pioneer in determining that the immunomodulatory protein, PIBF, plays a major role in allowing the fetus to avoid immune surveillance, in 2010 wrote a treatise entitled “PIBF: the double-edged sword. Pregnancy and tumor” [33].
In an opinion entitled “Pregnancy is a model for tumors, not transplantation,” the renowned immunologist Kenneth Beaman, and his group, in 2016, stated “Nearly 65 years have passed since Peter Medawar posed the following question: “How does the pregnant mother contrive to nourish within itself for many weeks or months, a fetus that is an antigenic foreign body.” Now, understanding of reproductive immunology has demonstrated that the HLA antigens in the placenta are non-classical and do not induce rejection. In the placenta and in tumors, 50% or more of the cells are cells of the immune system and were once thought to be primed and ready for killing tumors or “the fetal transplant” but these cells are not potential killers but abet the growth of either the tumor or the placenta. By examining the similarities of the placenta’s and tumor’s immune cells, novel mechanisms to cause tumors to be eliminated can be designed. Thus, 15 years later, the concept we published in 2001 is starting to be accepted by top immunologists in the field [34]. Though Beaman et al. do not refer at all to the PIBF protein, I recommend an article in gynecologic oncology to those readers wanting further knowledge into the immune similarities between pregnancy and cancer to open the door for other novel treatments of malignant tumors other than blocking the progesterone receptor [35].
In humans, the progesterone receptor (PR) is expressed in prostate stroma. Reduced PR expression in cancer-associated stroma can be conducive to a tumor microenvironment favorable for cancer cell invasion and tumor metastases [36]. Thus, if the presence of the PR somehow inhibits tumor invasion and metastases, treating with a PR antagonist may worsen the condition.
However, it may be that the loss of the PR receptor merely suggests a higher percentage of more aggressive cells, and thus, mifepristone, by suppressing PIBF, may inhibit prostate cancer proliferation. Indeed, gavaging mice with spontaneous prostate cancer with mifepristone (which on a weight basis was equivalent to 200 mg daily in humans) improved longevity of survival and body condition scores compared to placebo gavaged C57BL/6 mice [37].
Controlled studies were also performed in mice where there was no knowledge of the presence of the classic nuclear PR. Beneficial effect on longevity and quality of life (body conditioning score) were observed in 129 Pd/J mice with a strong predisposition for testicular cancer, in aldo-keto reductase/J mice with spontaneous lymphocytic leukemia and A/J mice with spontaneous lung cancer [37, 38, 39]. As an example, in A/J mice with spontaneous lung cancer, 67.4% treated with mifepristone survived 1 year vs. 27% of the controls [39]. Even more important, there were 66.7% of mice gavaged with the equivalent of 200 mg/day in humans with mifepristone who had no sick days (body conditioning score less than 4) vs. zero % for controls [39]. These murine carcinoma studies supported the concept that the benefit of mifepristone is not merely for cancers positive for the classic nuclear PR. If the mechanism of improvement did operate through the PIBF mechanism, the presence of the classic nuclear PR is not needed for production of PIBF expression by the tumor cells.
Based on cell line studies and controlled animal studies, we wanted to determine if the mifepristone could provide increased longevity and/or improved quality of life in human patients with advanced cancer. Unfortunately, though physicians generally have the right to use drugs off-label, there was a restriction for mifepristone. This was not related to risk of the drug, but related to appeasing antiabortion groups who feared that the drug could find easy use to cause abortions. Thus, to use mifepristone as an anticancer drug, one needs to obtain from the Food and Drug Administration a compassionate use investigational new drug (IND) approval to use mifepristone to treat cancer.
The first patient we treated with oral daily mifepristone 200 mg/day was a 46-year-old woman diagnosed with a rare thymic epithelial cell cancer. Over a one-year period following initial surgery and radiotherapy more cancerous lesions developed in the lung. There was no standard chemotherapy, but she was approved for experimental octreotide. However, the cancer still progressed. After starting mifepristone 200 mg/daily, though, her lung and mediastinum lesions did not regress, they remained stable. Clinically, she was feeling much better in that she had much less shortness of breath, much less cough and, marked improvement in fatigue. This clinical improvement persisted for over 2 years. Her oncologist decided that since the lesions were stable, this could be the opportunity to attempt a “cure” by a second course of radiotherapy to the mediastinum. She developed pulmonary fibrosis from this second course of radiotherapy. According to the thymic Cancer Carcinoma Society, she had survived the second longest time of any patient with this type of cancer [40]. Now, with more clinical experience, she would have been advised against more radiotherapy and just continue the mifepristone. Most metastatic cancers will not be “cured.” The end point of treatment with mifepristone should be quality of life and increased longevity. This first case of our series of anecdotal cases treated with mifepristone first started treatment in 2004. It is important to note that thyroid epithelial cell cancer is not known to be associated with the classic nuclear P receptor.
The second case of advanced cancer that we obtained a compassionate use IND to treat was a 61-year-old woman with a 6.5 cm invasive moderately differentiated adenocarcinoma of the transverse colon with extensive metastasis to the liver, peritoneum, ovary and uterus. She had marked ascites. The two largest liver metastases measured 3.1 × 1.3 cm and 2.3 × 1.9 cm. She was advised by her oncologist that even with chemotherapy she would only have a 15% chance of living 6 months.
After 1 year of mifepristone therapy 200 mg orally per day her carcinoembryonic antigen level had dropped all the way down to 1.6 ng/mL. After 18 months, there had not been any growth of her metastatic lesions nor did any new ones appear. She had no pain, no vomiting, and she stated her energy was great.
A CT-scan at 22 months showed some growth of the lesions. Nevertheless, she was pain free with good energy even at 27 months when ascites began to return (it had completely disappeared). She was still ambulatory at 30 months when she died.
Several years later talking to her sister we found out that at 18 months, to save money, she started taking the mifepristone every other day. Thus, this case helps to establish that the daily dosage should not be less than 200 mg/day. The case also supports the concept that mifepristone can prolong life and provide palliation for cancers not known to be associated with the classic P nuclear receptor [41].
Another 43-year-old woman with stage IV metastatic colon cancer, who had progressed despite standard chemotherapy, began single agent mifepristone therapy. Similar to the aforementioned case, there was a halt to cancer progression, her energy markedly improved, and she had great relief of pain. After 18 months some of her metastatic lesions began to grow. She assumed that this was the end of her remission, so she stopped the mifepristone, and decided to try a new experimental drug. She died 3 months later [40]. Based on subsequent clinical experience, we would have advised her that even though the lesions are starting to grow again, mifepristone will still prolong a high quality of life, and will prevent rapid spread, thus advising her not to stop mifepristone.
An 83-year-old man with rapidly growing stage IV colon cancer with metastases to his lungs, liver, peritoneum, and lymph nodes showed no improvement to either capecitabine or cetuximab. He was so weak that he could not get out of bed. Within 2 weeks of 200 mg mifepristone tablets daily obtained with compassionate use his energy returned, and he was able to resume normal function and go to restaurants and other social events and completely take care of himself (ECOG 0 now). His appetite also returned, and he was pain free.
After 4 ½ months of therapy none of his previously rapidly growing metastatic lesions grew with the exception of 1 lung lesion that grew 0.3 cm. He had no side effects from treatment. Though he had no kidney metastases, he had pre-existing marked renal impairment. He became uremic. His wife was deciding on dialysis or not when he died of a sudden myocardial infarction [41].
Sometimes, instead of the mifepristone therapy causing stable disease, or changing the pattern from rapid progression to slow progression, the lesions may show marked regression. This is evidenced by a 45-year-old woman who had widely metastatic leiomyosarcoma despite previous treatment with total abdominal hysterectomy and bilateral oophorectomy, letrozole (the tumor was estrogen receptor positive), and gemcitabine/docetaxel, and resection of lung metastases [40].
She was started on mifepristone 200 mg/day orally. This caused an almost total remission, with disappearance of almost all lesions, and those remaining had shown marked decrease in size. After 6 months, some lesions began to appear, but they were still very small. Nevertheless, without experience with the nature of this drug, the oncologist opted to stop mifepristone and place her in an experimental trial. She died within 1 month from complications of this new drug [40].
Another case of very rapidly growing advanced cancer showing complete remission following ingestion of 200 mg/day oral mifepristone was an 80-year-old woman with a history of chronic lymphocytic leukemia who developed sudden onset respiratory failure with a po2 of 72 mmHg. Chest X-ray revealed many lung lesions with a radiographic diagnosis of probable advanced lung cancer with multiple metastatic lesions. Her serum sodium was 118 mmol/L. She refused a surgical diagnosis or chemotherapy based on the presumptive clinical diagnosis of small cell lung cancer with the syndrome of inappropriate anti-diuretic hormone (SIADH) and the bleak prognosis, even with chemotherapy [42].
She sought an alternative treatment and agreed to mifepristone therapy 200 mg orally daily. Within 1 month her po2 returned to 99-100 mmHg without supplemental oxygen. Her serum sodium increased to normal at 145 mmol/L. Her CT-scans showed complete disappearance of all lung lesions even 5 years after initial diagnosis. There did remain, however, a ground glass appearance in the lungs. She died 5½ years later at the age of 85.5 from an acute myocardial infarction, not from lung cancer [42].
Interestingly, though we know that PIBF is secreted by leukemia cell lines and is suppressed by mifepristone, this woman’s CLL slowly progressed while her rapidly growing presumed small cell lung cancer had a complete remission [19]. This could suggest that mifepristone acts better on rapidly growing cells than slowly growing cancers. Of course, it is possible that the mifepristone helped keep the CLL slow growing, but that could simply be related to the normal situation of slow progression with CLL even without treatment. It should be noted that lung cancer, whether small cell or non-small cell (which is still possibly the type of cancer this woman had though small cell was more likely because of the clinical picture) is not known to be associated with nuclear P receptors.
Many cancer therapies are ineffective for brain metastases or primary brain cancers because they cannot cross the blood-brain barrier. There is anecdotal evidence that mifepristone can cross the blood brain barrier and provide palliative benefits for primary brain cancer and brain metastases.
A 43-year-old male with a 3-week history of severe protracted headaches was found to have a large glioblastoma multiforme grade IV that originated in the temporal lobe but involved also the frontal, parietal and temporal lobes and metastases to the spinal cord. Despite surgery, radio and chemotherapy, the tumor rapidly progressed. He was not considered a candidate for any other therapy. At the time of starting mifepristone therapy, he was paralyzed from the neck down and his hands were fixed in the clenched position. He slept most of the day, and when awake, was not able to carry out conversations [43].
Within 2 weeks of treatment with 200 mg oral mifepristone daily, he became much more alert and was able to carry out intelligent conversations. He was now able to open his clenched fists and move his hands. He continued treatment for 3 months and remained alert. However, his paralysis slowly progressed to the point where he was having trouble breathing and swallowing. The mifepristone was stopped, and he died 2 weeks later [43].
Another case demonstrating that mifepristone can cross the blood brain barrier to thwart brain metastases from progressing is a case of a 68 year old male with stage IV metastatic non-small cell adenocarcinoma lung cancer with brain metastases who was referred by his oncologist for mifepristone therapy [44]. Based on the experimental data with efficacy of mifepristone inhibiting growth of cancer cell lines, the beneficial effect in controlled various murine carcinomas, and the anecdotal benefits in individual causes with various advanced cancers following single agent mifepristone therapy the FDA approved our investigator imitated study entitled “A phase II study of treatment with oral mifepristone as salvage therapy in patients who have failed two or more previous chemotherapy regimens” (www.clinicaltrials.gov).
He had no tumor markers that could provide him targeted therapy. His cancer progressed despite 3 rounds of multi-agent chemotherapy including carboplatin/avastin/docetaxel, pemetrexed, and gemcitabine. In October of 2015 he had a seizure and magnetic resonance imaging indicated a 1 cm right frontal lobe metastatic lesion. He received palliative stereotactic radiotherapy to the brain lesion which was completed in November 2015.
With deteriorating symptoms, for example, dyspnea on exertion and fatigue and with no other treatment options available (PD-L1 marker was negative and check-point inhibitors were not approved for PD-L1 negative patients at this time), he was referred for our FDA study.
In all previous cases, the 200 mg mifepristone tablets were obtained from Danco Inc. at a cost of about $500 per month. For the FDA approved investigator-initiated study, we decided to use mifepristone 300 mg tablets daily because the company Corcept, Inc. which manufactures the 300 mg tablet for treatment of Cushing’s syndrome (though the dosage is generally much higher than 300 mg to block the glucocorticoid receptor) was willing to provide the drug free to approved patients.
His clinical symptoms improved significantly within 1 month of treatment with single agent oral mifepristone 300 mg daily. He was ECOG 1 at the start of therapy and after 1 month was ECOG zero. He remains ECOG zero after 4.8 years of treatment, and for the majority of visits, he answers his 43 questions on the quality of life evaluation as “not at all” (the best answer that could be given). There has been no evidence of growth of his previous brain metastases or any new lesions by MRI testing.
One additional important piece of information that his case provides. His metastatic lesions remained stable for 1.5 years. But after 1½ years, some lesions began to grow slowly. His oncologist, based on his experience with other anticancer agents, thought that once disease progression began, it usually accelerates rapidly. He thus suggested to the patient that he stop the mifepristone, and consider nivolumab or pembrolizumab, which had at this time been tried on some patients who were PD-L1 negative, or consider another biopsy to determine if a new tumor marker could be found that would allow targeted therapy. The patient feeling so good on mifepristone therapy and feeling so poorly on all of his previous chemotherapy regimens, opted to take our advice and continue on the mifepristone therapy. Now 3.5 years later and still feeling great, he is very satisfied with his decision not to stop mifepristone therapy [44].
This case exemplifies the mistakes, from lack of experience, that we alluded to in some of the previous case reports, that is, one should not stop the drug if there is the start of tumor progression. There is still a good chance the drug will provide continued extension of a good quality life. Naturally, if a new therapy is likely to be more effective than the mifepristone therapy, then it would make sense to try the new agent. But it makes no sense to try a completely new experimental drug with unknown side effects, as tried by some of the previous described cases. Furthermore, experience suggests that mifepristone inhibits metastases, but cessation of therapy results in rapid spread. This progression can be so rapid that it could be too late to resume mifepristone therapy if the new anticancer therapy is not working.
Therapy with mifepristone could be considered hormonal therapy, but because its hypothesized mechanism is that it removed a block (i.e., PIBF), and thus allows the cellular immune system (especially NK cells) to attack cancer cells, it could also be considered a form of immunotherapy. The question arises as to whether the drug would be effective in cancers positive for the programmed cell death protein ligand 1 (PD-L1) marker where there was initial response to immunotherapy with a check-point inhibitor but where the tumor was now showing resistance.
We did describe a case of a 66-year-old woman with stage IV non-small cell lung cancer, who not only had the PD-L1 marker, but also her cancer was positive for the epidermal growth factor receptor (EGFR). When her cancer began progressing following chemotherapy with carboplatin, pemetrexed and bevacizumab regimen and the carboplatin and docetaxel regimen, she was started on a targeted therapy for the EGFR marker, erlotinib [45]. At that time, there was only first-generation tyrosine kinase inhibitors.
When her cancer progressed despite erlotinib, she was treated with 11 cycles of the check-point inhibitor nivolumab. It was stopped after 11 months because it was apparent the drug was no longer inhibiting her cancer progression. She qualified for the investigator-initiated study, and thus she was treated with the 300 mg oral daily dose of mifepristone [45].
After 18 months of oral 300 mg single agent mifepristone therapy, there had been no cancer progression based on lung CT scans performed every 2 months. In fact, some lesions were actually smaller. She was considered ECOG 1 at the start of mifepristone therapy. At the end of 1 year, she was still ECOG 1 with a good quality of life and normal physical activity.
After 1 year, her pre-existing severe chronic obstructive pulmonary disease (COPD) worsened and she required supplemental oxygen to keep her po2 above 80 mmHg. Based on her COPD, but not her cancer which still had not progressed, at 18 months from initiation of treatment, she was an ECOG 3. She died 2 months later from pneumonia.
Thus, this patient not only showed that mifepristone can prolong life and provide a good quality of life not only in a patient whose lung cancer is positive for the PD-L1 marker, but a person who also has the EGFR mutation [45].
Anecdotal cases are important, but more influential to other physicians would be a larger series. Even better would be a controlled trial with sufficient power, and the very best, a study that has all these qualifications, but is also multi-centered. The FDA approved the aforementioned investigator-initiated study for 40 patients. It is not considered ethical to have patients with such severe disease and subject them to placebo controls. Thus, the study was to evaluate in a larger series the efficacy of mifepristone therapy for advanced lung cancer and compare outcome to historical controls, that is, from quality of life to life expectancy, when dealing with a similar group of patients with lung cancer that has stage IV and failed at least two chemo or immunotherapy regimens.
We were allowed two principal investigators. However, as an investigator-initiated study with no funds provided to the principal investigator by a pharmacological company or a grant, we could not find a principal investigator who treats a larger population of patients with lung cancer. Thus, we became, by default, the only principal investigator. Unfortunately, it is not totally clear to us as to the reasons, but despite our efforts we have only recruited the two aforementioned patients that were treated in this investigator-initiated study. Perhaps some of the fault lies in making the criteria for registering too harsh, but most of the problem is that we have not been referred very many patients to even screen for the study. Even the physician who referred us our first case who still is doing so well after almost 5 years of single agent mifepristone therapy, plus years with no side effects, has not referred us another patient [44]. We asked him if he had more patients and he stated that he could send us 40 patients in 1 year, but patients do not want to travel 100 miles every month to receive the medication. This seem unbelievable but this was also related to us by an oncologist whose research with us involving PIBF helped him get into medical school, where the patients would only have to travel only 15 miles. He was supposed to be our first principal investigator, but his associates objected. Even our own well renowned cancer facility at our institution turned down the opportunity to be a principal investigator and has never referred one patient for treating cancer whether they had lung cancer for this investigator-initiated study, or for compassionate use for other cancers. From what we have ascertained, they refer the patients to hospice when they are at the stage eligible for our study. Yet they kindly refer to us many patients to consider oocyte freezing or embryo banking before potential ovary damaging therapy.
Actually, there were two patients with lung cancer that we screened that would have qualified for the investigator-initiated study. They both had stage IV non-small cell lung cancer positive for the EGFR mutation that were at the end of targeted therapy (erlotinib, afatinib, and osimertinib) because the lesions were progressing. They both responded very well to single agent mifepristone. Their case reports were accepted for presentation at the 2020 American Association for Cancer Research (“Improvement in quality and length of life following treatment with mifepristone in women with stage IV non-small cell lung cancer positive for the EGFR mutation that previously progressed on targeted therapy”). Because our study was not recruiting very well, we advised these two patients to try compassionate use 200 mg mifepristone, where the drug can be shipped to their homes, rather than travel thousands of miles monthly to receive the medication gratis as required by the study design.
There were two other abstracts accepted by the annual 2020 AACR meeting. The title of one tells it all – “Treatment with oral mifepristone enables a patient with end-stage pancreatic cancer, in hospice, on a morphine drip, to restore a decent quality of life.” The only other patient who we treated with mifepristone from pancreatic cancer, similar to the aforementioned patient, demonstrated a marked relief of her severe pain that had been present despite opiates. However, her husband, a physician, was informed by a major oncologic center of a new phase I research study. He quickly brought his wife there for treatment and she died 2 days later from cardiac complications of the new drug [40].
A third abstract accepted for the 2020 annual AACR meeting is entitled “Palliative benefits of oral mifepristone for metastatic osteosarcoma.” This shows the wide diversity of different advanced cancers that have responded to extremely well tolerated oral mifepristone, frequently providing the patients their best quality of life even when their cancers had not been as advanced. The reason is that even in less advanced stages, many of these patients suffered from side effects of chemotherapy or even immunotherapy.
Pancreatic cancer and fibrous osteosarcoma are not known to be associated with the nuclear P receptor. Other patients with some rare advanced cancers have demonstrated significant palliative benefit following mifepristone therapy include a malignant fibrous histiocytoma in a 23-year-old male and an extremely aggressive transitional cell carcinoma of the renal pelvis [40].
The presence of the classic nuclear P receptor in breast cancer tumors has been known for at least 40 years [26]. The thinking in those days was that the presence of the hormone receptor may be needed for the tumor to proliferate. Thus, intervening with the hormone receptor interaction may inhibit cancer growth while not creating serious adverse effects in the patient as long as the hormone-receptor interaction was not essential to life or well-being.
Based on the beneficial effects of blocking the estrogen receptor with selective estrogen receptors, that is, tamoxifen, it is not surprising that mifepristone was evaluated for treating advanced breast cancer with the thought that the interaction of progesterone with the classic nuclear progesterone receptor could somehow allow tumors, for example, breast and ovarian cancer to proliferate.
Mifepristone is a type II progesterone receptor antagonist which promotes DNA binding and also promotes progesterone receptor phosphorylation [46]. Mifepristone was given to advanced stage tamoxifen resistant women (second line setting) and the authors reported a complete or partial response in about 10% [47]. However, 6 of the 11 showed stable disease [47]. Another small study found an objective response rate of 18% [48]. For first line, mifepristone for untreated metastatic breast cancer, a 10% objective response rate was observed [49].
The main method of evaluating efficacy of anticancer treatments 25–40 years ago, and even today, is inhibition of disease progression. Thus, the improvement did not seem adequate enough compared to other “more encouraging therapies”. Thus, interest waned in treating advanced breast cancer with mifepristone. Subsequently, more experience with mifepristone therapy for a variety of advanced cancers will show that although sometimes the treatment will cause a very good objective remission, the majority of the time the drug provides significant palliation and extension of a higher quality life while it slows disease progression.
For ovarian cancer not only is the classic nuclear progesterone receptor present but it also predicts a favorable outcome [50]. For similar reasoning as with breast cancer, mifepristone was given about 20 years ago to patients with ovarian cancer who had persistent lesions or recurrent lesions despite one round of chemotherapy [51]. Mifepristone 200 mg/day was given daily and continued until disease progression was found. They were treated for a mean of only 2 months. For 34 patients there was a response in 26.5% (9% complete and 17.5% partial) [51]. A second study of this drug conducted 10 years later showed a partial response in 42% of patients [52]. Again, the drug was stopped if there was any evidence of progression. The median time of treatment was 2 months [52]. From what we know today, if they would have continued the drug, the ovarian cancer may have progressed slowly while the patient maintained a high-quality extension of life [53].
Should biopsy specimens be tested for PIBF to see if a given patient should be treated with mifepristone?
We do not think it would be unreasonable to see if a given specimen produces PIBF, but can we be sure that the tests are sensitive enough to deprive a patient the potential great benefit of treatment with mifepristone?
Can measurement of serum PIBF be helpful in determining if the cancer is responding to mifepristone or if mifepristone therapy is no longer working?
There have been developed more sensitive and specific serum PIBF assays [2]. However, based on measurement of serum PIBF in patients with gynecologic cancers or breast cancers that are P receptor positive, or even associated with breast cancer antigen 1 or 2, the serum level of PIBF may not be helpful for these purposes [54, 55]. It is the PIBF in the tumor microenvironment that seems to be most important, and this, of course, would be difficult to measure.
The 200 mg daily dosage of mifepristone does not appear high enough to block the glucocorticoid receptor. So, another important question, is if it is the action of mifepristone on blocking the P receptor that leads to its efficacy in treating cancer why does it seem to work in cancers that are not associated with the classic nuclear P receptor?
The evidence supports the fact that it acts on membrane P receptors. Activation of the nuclear P receptor initiates transcription, which is a slower process, whereas rapid activation of the membrane P receptor is a more rapid signaling action [46].
Do cancers need to secrete P to activate the membrane P receptor?
It is possible that at a certain stage cancer cells can make P or a P-like substance sufficient to interact with membrane P receptors. There is evidence that a large variety of cancer cells express the human chorionic gonadotropin (hCG)-beta subunit gene [56]. Activation of the hCG beta subunit gene to produce hCG could lead to local P production by the cancer cells. Alternatively, there may be some other mechanism to activate the membrane P receptor to make PIBF. Even with this scenario, mifepristone could still block the effect of this theoretical non-P membrane P receptor agonist.
Does mifepristone only works when the cancer is at the stage of rapid metastasis?
It is possible that all cancers have mRNA to produce PIBF, but only at a certain level, that is, perhaps stem cell level is the membrane progesterone receptor is activated and PIBF is manufactured. Thus, it is possible that activation of tumor secretion of PIBF only occurs at the stage when it is ready to rapidly metastasize. About 20% of meningiomas are associated with the classic nuclear P receptor. However, a large study comparing mifepristone vs. placebo for unresectable tumors did not find any therapeutic benefit for mifepristone vs. placebo [57]. This could be because meningiomas are slow growing tumors and the PIBF mechanism is only seen with rapidly growing tumors. However, it is also possible that some meningiomas are considered benign. Thus, maybe it is the ability to make PIBF that is one factor allowing the tumor to follow a benign vs. malignant course. One benefit of this large study was to demonstrate a very good safely profile for mifepristone with few side effects [57].
Since a compassionate use IND is required by the FDA, that organization is reluctant to grant an off-label use unless all “standard” treatments have been exhausted. Thus, most of the study subjects in our center have been patients with very advanced cancers where there are few, if any, reasonable treatment options.
One exception is a man, who at the age of 58 was found to have bilateral renal cell carcinoma with metastases to local lymph nodes [42]. Renal cell carcinoma can be multifocal, and even when several lesions are present, the tumor is generally not extremely aggressive. Today the recommendation is renal sparing surgery and to remove the tumors every time one reaches a certain critical size [58, 59, 60]. But 16 years ago, the recommendation was bilateral nephrectomy.
Since there were no chemotherapy or immunotherapy agents16 years ago for renal cell carcinoma, and the patient did not want to become a dialysis cripple, the FDA approved a compassionate use IND for oral mifepristone following a laparoscopic hemi-nephrectomy with retention of a kidney with three lesions left untreated.
After 10 years of single agent treatment, there were no new tumors. The three lesions previously noted on the left kidney remained stable [42]. After 10 years his diabetes caused kidney failure and the start of dialysis. Thus, he had the 1½ kidneys removed. After 2 years of hemo-dialysis, he was approved for a kidney transplant. He is still doing well 16 years from initial diagnosis [42].
This case showed that mifepristone can also work to inhibit tumor growth even when not at the rapidly growing cell stage. Whether this is specific only for renal cell carcinoma, or applies to other malignancies, needs to be determined. Thus, perhaps one should consider using mifepristone in earlier stage metastatic cancers following tumor remission following treatment with chemotherapy or immunotherapy to possibly inhibit recurrence or negate the need to treat with another chemotherapy or immunotherapy regimen with morbid side effects.
One final thought. Frequently, once a tumor has widely metastasized chemotherapy or even immunotherapy may frequently extend life somewhat at the expense of significant side effects from treatment. Mifepristone therapy is devoid of major side effects, and thus may provide possibly a longer higher quality life than “approved therapy.” The treatment of patients with cancer has provided huge profits both for the pharmaceutical companies and the treating institutions. So realistically it is unlikely that mifepristone therapy will become popular in capitalistic societies.
However, in some countries needed to provide effective, yet inexpensive treatment, one could consider offering patients oral government provided mifepristone rather than expensive chemo or immunotherapy agents. The cost of a mifepristone pill in China is 50 cents. In fact, since growth of tumors is still consistent with a prolonged good quality life, one could save money on expensive diagnostic tests to monitor progression. Possibly mifepristone could be considered first line therapy for metastatic disease with consideration of other therapeutic modalities only if health deteriorates despite mifepristone therapy.
Since the drug is available as a generic already, it is unlikely any pharmaceutical company will invest in larger studies to prove its efficacy. Hopefully, the published anecdotal cases, and the easing of the requirements for compassionate use, will encourage other clinicians treating patients with advanced cancer to try the drug and publish their findings. If enough treating physicians request compassionate use IND for mifepristone use, perhaps the FDA will eventually drop the requirement of compassionate use IND, facilitating the use for treating physicians around the world. Many countries, similar to the United States, at this time also restrict the use of mifepristone solely for the purpose of therapeutic abortions, and in some countries, it is completely illegal, at least at the relatively inexpensive price for the 200 mg dosage to use this drug. The use of the 300 mg dosage that does not require a compassionate use IND is cost prohibitive. Possibly the manufactures may one day reduce the price considerably or it will be manufactured by a generic company at a much lower price when the patent expires. Perhaps at a lower cost, insurance companies will be happy to pay for off-label use of mifepristone realizing how much cheaper it is for cancer therapy than conventional chemo or immunotherapy regimens.
As previously mentioned, clinical trials with mifepristone for cancers associated with the classic nuclear P receptor were “disappointing” and thus clinical trails were not pursued. When these studies were initiated 20–30 years ago, the hope was that metastatic cancer can be “cured.” It is now realized that the best hope for advanced cancer is a truce with extension of a better quality of life. Also, at that time the goal of therapy was to induce a tumor response as evidenced by complete or partial tumor regression. We think if they had used the endpoints of quality and length of life, they would have had the satisfaction of treatment as we have had in these anecdotal cases. The majority of cases do not show tumor regression but stable disease and improved quality and length of life.
As far as side effects, the drug has been well tolerated. In higher dosages mifepristone can, by blocking the glucocorticoid receptor, lead to higher serum cortisol levels which acts on the mineralocorticoid receptor leading to hypokalemia. One has to be careful when using other drugs that can interfere with the metabolism of mifepristone leading to hypokalemia. We had one unreported case of a woman adding mifepristone to her ongoing treatment with alpelisib, which in itself can cause hypokalemia. Whereas the combination led to hypokalemia, neither drug by itself caused it. She was taking just the 200 mg dosage of mifepristone.
Similarly, case number 9, who was taking the 300 mg dosage, did develop hypokalemia when she was switched to another bronchodilator for her COPD, but reverted back to normal when it was stopped. She was taking the 300 mg dosage of mifepristone [45].
One man with stage IV non-small cell lung cancer became more somnolent when adding mifepristone to his fentanyl that he was using for pain. Though we advised him to reduce the dosage of fentanyl, he chose to just stop the mifepristone and died 2 weeks later. He had only taken the mifepristone for 2 days.
The authors declare no conflict of interest.
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