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Cellular Cancer Therapy, part 10
CHAPTER 10: CHEMOTHERAPEUTIC PHARMACOLOGY
Due to the lack of adequate reference work, questions about cancer are often very difficult or impossible to answer. What form of chemotherapy is best for some of the rarer tumors? Will nitrogenous mustard yield as good results as cyclophosphamide in treating ovarian carcinomas? Questions like these could not be answered by any book. The best sources of material for making decisions like these, based on the latest advances in cancer research, are journals such as Cancer Chemotherapy Reports, Cancer Research, and Proceedings of the American Association for Cancer Research, even though they are not available in many major hospitals. The Deutsche Medizinische Wochenschrift publishes, on a weekly basis, the results of the oncological treatments the world over that have been shown to be beneficial or yield survival of 5 or more years. Even if these journals were available, very many articles would have to be read to be able to find the precise answers to what are generally very complicated questions.
This chapter is to serve as a complement to our book on Donatian Therapy. It is included as an appendix for the clinician, the oncologist and for all those specialists who dedicate their work to the treatment of patients with malignant neoplasias. Here you will find summarized the therapeutic resources used over the last 18 years for the treatment of malignant neoplasias.
Cell Kinetics. There are two faces to understanding the theoretical basis of the chemotherapy for cancer. The first is its mechanism of action, and the second is the development of cell kinetics, i.e. the velocity of cell reproduction in normal and malignant tissues.
To understand cell kinetics, the cell’s cycles need to be described. All of the cells that are reproducing follow a pattern of activity that is called the cell cycle, which is usually described from mitosis to mitosis.
There are four phases:
a) Mitosis
b) C1
c) S (DNA synthesis)
d) C2
Mitosis. Mitosis is also divided into 4 phases:
a) Prophase, when the chromosomal material is condensed and each chromosome divides into two daughter chromatids, each of which receives half of the new DNA that has been synthesized during the cell cycle.
b) Metaphase. When the chromosomes separate, protoplasmic fibrils develop connecting the centrioles of the cells.
c) Anaphase. When the chromatids separate.
d) Telophase. When the cells themselves separate.
C1. This is the phase of the cell cycle that shows maximal longitudinal variation from one type of cell to the next. It is also the phase in which those cells that are not dividing are found to he at rest, For example, the hepatic cells do not divide unless there is some stimulus such as a partial hepatectomy. The normal hepatic cells that are not dividing stay in C1. When the cells of some tissue have been in C1 for a prolonged period, this is called C0. The concept of C0 has become very important for the development of chemotherapeutic treatments for cancer. There are some exceptions to the cells that remain fixed in C1, since some cells remain in C2. The development (in size) of the cell occurs primarily during C1, which has also been called the post—mitotic stage.
S. The S phase, when the synthesis of DNA is carried out, is of a constant duration in the cells of mammals (6—8 hours).
C2. The duration of C2, the pre—mitotic chase, is relatively constant at about 2 hours.
The time that the cell requires to complete the cell cycle has been called the generation time.
The generation time of the epithelial cells of the small intestine or those of the bone marrow is less than 24 hours. Cell kinetics, then, is the quantitative study of cell proliferation. For this study, two new terms have been introduced: cycle-specific and cycle non-specific medications. By cycle specific medications one understands those that only act in cells that are in some phase of the cell cycle. Bruce uses these terms. This information has led to the practice of spacing the application of antineoplastic medications as in Bergsagel’s intermittent cyclophosphamide treatment.
The concept of cycle specific and non—specific medications is crucial to the understanding of modern cancer chemotherapy. The basic idea is simple.
If certain antineoplastic substances only attack the cells that are dividing and producing more tumoral cells than the normal cells of the bone marrow or some other vulnerable vital tissue of the organism, then through the appropriate spacing of the chemotherapeutic agents, this difference can be exploited to the patient's benefit.
The expression "duplication time" refers to the period necessary for the duplication of the number of viable leukemic cells, while the term "generation time" refers to the period in which individual cells complete one generation of one cycle. Deviance from the logarithmic development is due to the lengthening of the duplication time in leukemic cells.
Pharmacology of cancer chemotherapy
Before describing the mechanism of action of anti-neoplastic medications it is necessary to bring up a few aspects of the biochemistry of the human body. The most important factor’ that differentiates the cells of an organism is the type of protein that they synthesize. These may be enzymes, structural proteins or some other type of protein with a specialized function. The structure of this protein is determined by the genes operating in the cell at a given moment. Though each cell in all organisms, including mammals, has the same genetic make us, it is thought nowadays that the majority of the genes in each differentiated cell are suppressed and therefore do not function.
Let us make a lightning review of how genes control protein synthesis. The gene is a packet of DNA which is a double helix; two chains, one rolled around the other, The skeleton of each chain is a succession of a sugar, deoxyribose, and a phosphate group. The two chains are linked by the specific pairing of the bases by bonds that, though individually are very weak, taken together make this double chain more stable than the majority of proteins before denaturation. Each sugar has a purine or pyrimidine base inserted in it. that directs itself towards a purine or pyrimidine in a sugar in the other chain. Therefore, a double helix looks like a spiral staircase; the "steps" of the stairs are made up of a purine linked to a pyrimidine by hydrogen bonding. These bases are found universally in nature. There are four bases that predominate in DNA, though other bases appear occasionally as minor components. These other bases probably take on the roles of the major bases.
The purines and pyrimidines are cyclic compounds of carbon and nitrogen atoms. Adenine and guanine are purines and cytosine and thymine are the pyrimidines. Cytosine is always linked to guanine and adenine to thymine. According to the theory of cell self—duplication, when the cell divides, the double helix unwinds and the chains separate. Then each chain contains the structure for the synthesis of its pair, since every time there is a cytosine, it should be linked to a guanine, and each time there is an adenine, it should to linked to a thymine.
How does DNA control protein synthesis? This leads to the consideration of the following cell component, RNA, since it is from RNA molecules that proteins are synthesized. RNA is identical in strucure to a chain of DNA, except that the sugar in the skeleton of the chain is a ribose instead of a deoxyribose and in the place of thymine it has a differcnt pyrimidinic base: uracil.
Obviously, if each chain of DNA can synthesize its pair, then the DNA contains enough information to synthesize an RNA molecule. The pairing of bases according to a predetermined pattern is the key. It should be pointed out that the adenine in the DNA will, produce a uracil in the RNA. Therefore, the first step in protein synthesis is the production of an RNA chain by the DNA. This is called messenger RNA. The sequence of bases in this RNA will determine the structure of the protein produced.
Proteins are made up of long chains of amino acids that are called polypeptides, and which can consist of approximately 20 different amino acids. One important discovery was that the sequence of three adjacent bases in the RNA can act as a code for an amino acid. For example, 3 uracils would correspond roughly to the amino acid phenylalanine.
The actual synthesis of proteins involves a structure that contains the messenger RNA (mRNA), transfer RNA (tRNA), amino acids, polypeptide chains that are to be completed, and possibly DNA. Different amino acids are inserted in the tRNA through the action of specific enzymes. The molecules of RNA that contain amino acids transfer their amino acid residues to the polypeptide chains at a specific moment. The order in which the amino acids are inserted is determined by the mRNA which itself is produced by one of the chains of the DNA. Though the role of the ribosomes, which contain ribosomic RNA and proteins, is still unknown, it is thought that they situate the mRNA, the tRNA and the polypeptide chains to facilitate the formation of the subsequent peptide bond.
The biochemical reactions that involve DNA synthesis are especially important for cancer chemotherapy. DNA is a polynucleotide and the nucleotides can be made up of prepaired pyrimidines and purines, hut the majority of nucleotides are produced through spontaneous synthesis. The purine pyrimidine ring is closed after the sugar and the phosphate are inserted. Then the nucleotides link up to form the DNA molecule; this reaction is catalyzed by the enzyme called DNA polymerase.
The final stage in the synthesis of one of the nucleotides, thymidyllic acid (thymine-deoxyribose-phosphate) is the insertion of a methyl group into the 5th position of the uracil in uracilic acid (uracil-deoxyribose-phosphate). This methyl group is donated by the tetra-hydrofolic derivatives, formaminotetrahydrofolic acid and methylation is catalyzed by an enzyme called thymidilic acid synthesase.
There has been a considerable amount of investigation done in the last three years on the molecular biology of repairing enzymes. These enzymes are used for repairing the damage done to DNA by ultraviolet light, radiation or by alkylating agents. There is evidence that they might be involved in the reduplication of DNA. The importance of these enzymes for the protection of the cells of the epidermis against sunlight has been shown by Cleaver, who studied fibroblasts of normal skin and those of patients with xeroderma pigmentosa, a rare hereditary disease in which the skin is extremely sensitive to sunlight or ultraviolet light. These patients develop cancer from an early age and the study of their skin fibroblasts in cell culture revealed that they do not repair the damage done by ultraviolet radiation to the cell DNA, while in the fibroblasts of normal skin, the damage done is repaired by the insertion of new bases in the DNA, in the form of little pieces of cloth. This process is called repair reduplication and each extirpated region involves about 70 nucleotides. One group of investigators that has studied the epithelial cells of human skin affected with cancer have found defective photochemical repair in these cells, in comparison with cells taken from normal people. This suggests that the repair mechanisms are important for preventing normal cells from becoming cancerous, even when the carcinogenic agent is not sunlight.
The word "alkylating" is derived from "alkane" which denotes a hydrocarbon chain with the general formula of CNH2N-2. Warwick, in his classic review, defined alkylating agents as "those compounds capable of replacing a hydrogen atom in another molecule with an alkyl radical."
There have been many review articles on alkylating agents, especially about their biochemistry and pharmacology. The list is headed by the publications of the Chester Beatty Institute, and Ross’s book about biological alkylating agents, published in 1962 is one of the classics. Boeson and Davis published in 1969 a book about cancer chemotherapy which contains an excellent review of the mechanisms of alkylating agents.
Alkylating medications are chemical compounds that are very reactive, capable of combining with nucleophilic groups such as amino and sulfhydrile groups. There are two kinds of alkylating agents: monofunctional and polyfunctional. The monofunctional type only have one active alkyl group, whereas the polyfunctional ones have two or more functional alkyl radicals.
The monofunctional alkylating agents have less anti-tumoral activity than the polyfunctional ones.
There are two types of alkylatlon. One is called first order alkylation, or nucleophilic substitution NS1, which involves the formations of a carbon ion and occurs rapidly, as a function of the concentration of the alkylating agent. The second order substitution or nucleophilic substitution NS2 involves the formation of a transition complex that includes the alkylating agent and the substance with which it reacts; reaction time will depend on the concentration of both substances.
There is no strict separation between NS1 and NS2 alkylating agents, because many medications can react in both ways, depending on the pH and other factors. Those that tend to be NS1 reactants, like mecholorethamine, are very unstable after their administration and react rapidly in the tissues. The NS2 reactants like busulfan and triethylenthiophos phoramide react more slowly. Some NS1 reactants such as chlorambucil are also slower, due to the slower formation of carbon ions because of the borrowing capacity of their aromatic rings.
As has already been stressed, alkylating agents are very highly reactive compounds. It has been shown that they react with so many body substances that for many years there was a controversy as to which of these reactions was important for their effects.
Recently Brooks, Lawley and Roberts, and Warwick have shown that alkylating agents act through DNA fixation, as evinced by the following facts:
1. Alkylating agents are mutagens and carcinogens.
2. In vivo and in vitro, they produce fragmentation and bunching of chromosomes.
3. They inactivate DNA viruses more rapidly than RNA viruses.
4. They are relatively inefficient inhibitors of protein function’.
The very recent experimental evidence has shown that alkylating agents produce their effects through the inter-chain bonding of the N7 atom of guanine on one strand of DNA and the N7 of the guanine on the opposite strand. The studies by Pullman and Pullman on the electronic structure of the purine-pyrimidine pairs in DNA led to the conclusion that the guanine N7 would be the most nucleophilic site. The inter—strand bonding of the DNA of the bifunctional alkylating agent prevents the separation of the two strands of DNA, which is necessary for cell reduplication.
The fact that alkylating agents do not inhibit the bacteriophage that contains only one strand of DNA is interesting evidence corroborating interstrand bonding. The formation of genes (geles?) is a good measure in vitro of interstrand bonding, and it has been demonstrated that the majority of alkylating agents cause the formation of genes (geles?) at a functional concentration. The only exception is busulfan which only causes the formation of genes (geles???) to a concentration many hundreds of times greater than that required for its biological action.
The greater part of the alkylating agents in clinical use today are variants on the basic structure of mustard gas. The basic structure of nitrogenated mustard below differs from sufurated mustard in that the sulfur atom is replaced by a nitrogen atom. The nitrogen atom has one more valence unit than sulfur, permitting an extra radical, besides the two chlorethyl groups.
Mustard Gas:
Basic structure of nitrogenated mustard:
Cyclophosphamide:
Chlorambucil:
Melphalan:
N, N’, N’’ Triethylenthiophosphoramide:
Busulfan:
In methylchlorethamine, commonly known as nitrogenated mustard, the R is a methyl group. Methylchlorethamine is very reactive and therefore irritating to the skin and mucous membranes. This is why it cannot be administered orally. The average life of mechlorethamine, after administration via perenteral injection, is of only a few minutes and less than 0.01% is excreted in the urine. The majority of it is inactivated upon reaction with water, amino acids, proteins and other compounds in the blood and tissues.
In Chlorambucil, R is the aminophenylbutyric acid. The capacity for borrowing of the aromatic ring lessens the velocity of the formation of carbon ions and permits chlorambucil to have a longer average life in the serum. Therefore, it is less reactive and permits oral administration.
In Cyclophosphamide, R is a cyclic phosphamide ester. The cyclophosphamide is inactive until the cyclic group is split by a phosphatase or a phosphamidase.
Cyclophosphamide is absorbed partially when administered orally; 17 to 31% is found in the feces unchanged. Though part of the medication is excreted in the urine in a metabolized form, as metabolites with local irritating properties which produce cystitis, the majority is eliminated in the feces. In Donatian therapy this is the preferred medication, in small doses, since we have never observed any symptoms of intoxication.
Today, methotrexate is the only folic acid antagonist in clinical use, though many of the biochemical studies in this field have been done with another: aminopterine.
Folic acid is biochemically inactive and therefore must be reduced to tetrahydrofolic acid by the enzyme dihydrofolicoreductase. This reaction is carried out in two stages, forming dihydrofolic acid as an intermediate substance. The enzyme for both reactions is the same. Once tetrahydrofolic acid is produced, it can be transformed into other derivatives, which are important substances that function as coenzymes, carriers of chemical units of a lone atom of carbon to many synthetic reactions that are vital to the organism.
The two most important reactions in which the coenzymes of tetrahydrofolic acid are involved are: 1) the thymidylatecosynthesase reaction in which the deoxyuridilic acid is transformed into thymidilic acid through the addition of a methyl group in the 5th position of the uracil ring with the coenzyme for this reaction, 5,10,methylenotetrahydrofolic acid and 2) the reaction through which N5,10 anhydroformyl of tetrahydrofolic acid is required for the transfer of the formyl groups in the 2nd and 8th positions of the purine ring. Therefore, this reaction is intimately involved in purine synthesis. It seems that the inhibition of the first of these two reactions is what leads to the anti-tumoral effects of the folic acid antagonists.
Methotrexate acts to impede the reduction of folic acid to tetrahydrofolic acid by occupying the dihydrofolicoreductase with an affinity 100,000 times greater than the affinity the enzyme has for folic acid.
Though the tying up of the dihydrofolicoreductase avoids more DNA synthesis and resulting cell division, the production of proteins under the influence of the RNA that has already been formed and the production of RNA from preformed DNA will not be inhibited. If subsequent doses of methotrexate are not administered, the cells will be capable of recuperating when enough dihydrofolicoreductase is produced to initiate DNA synthesis. Therefore, it can be observed that the duration of the contact of methotrexate with the tissues, and not its concentration in the blood, is the critical factor that will determine the effects of the medication. As a consequence, the cells with rapid mitosis like the bone marrow cells, those of the hair follicles of the scalp and those of the mucous membrane of the intestine will be the most susceptible to the folic acid antagonists. We also use this medication, but in very small doses and in very few and special cases.
The mechanism of action of the purine antagonists continues to be a challenge to researchers. As far as we know, there are three purine antagonists in clinical use; 6-mercaptopurine (6-NP), 6—thioguanine (6-TG) and azathioprine, whose action is based on the same mechanism. However, the problem that confronts the investigator is that these compounds inhibit many different enzymes.
For example, 6-mercaptopurine must first be converted into ribonucleotide-6-mercaptopurine before it can act. The enzyme for the formation of 6-MP-ribonucleotide and 6-TG-ribonucleotide (iosine-guaninapyrophosphoryllase or hypoxanthineguaninephosphoribosyltransferase) is the same enzyme that converts hypoxanthine into inosinamonophosphate and guanine into guanilic acid. Tumoral cells that are resistant to 6-NP do not have this enzyme.
This is a small glossary of these compounds:
Uracil. One of the main pyrimidinic bases found in RNA.
Thymine. Another of the two pyrimidine bases found in DNA. It has the same structure as uracil except for the replacement of a hydrogen atom by a methyl group at the 5th position of the ring.
5-fluorouracil. [5FU] This is the antitumoral agent that is commercially available; it has the same structure as uracil except for the presence of an atom of fluorine at the 5th carbon of the ring. When fluoridated pyrimidines are spoken of nowadays, 5-fluorouracil (FU) and 5-fluorodeoxyuridine. (FUdR) are included.
FUdR carries out its antitumoral effect by competing with deoxyuridilic acid for the enzyme thymidyllicosynthesase. Deoxyuridilic acid is the deoxyribotid of uracil and the reaction of the thymidyllicosinthesase involves the methylation of the pyrimidine ring at the 5th position to produce thymidilic acid, the deoxyribotid of thymine.
Vinblastine and Vincristine are the natural alkaloids that are extracted from the vinca plant and only differ in their chemical structure by the replacement of a methyl radical in vinblastine by a formyl group in vincristine. Though it does not seem that there is crossed resistance between the two in human tumors, the mechanism of both appears to be the same.
Both substances cause the detention of mitosis in metaphase by fixing the microtubular proteins necessary for the formation of the mitotic spindles. They also inhibit DNA and RNA synthesis.
Dactinomycin. This is the most active and least toxic of a group of antibiotics isolated from an agar culture of a species of Streptomyces.
It connects to the DNA, but not to the RNA, in the presence of guanine in a double heliocoidal configuration to form a relatively stable complex. The degree of fixation parallels the quantity of guanine in the DNA molecule. It has been demonstrated that dactinomycin inhibits RNA synthesis because it becomes fixed to the stie of the base of the DNA where the RNA polymerase ordinarily functions. Goldberg has proposed a molecular model that shows the peptide chains of dactinomycin which fill in the base of the DNA to a distance of 3 pairs of bases.
Dactinomycin also inhibits DNA synthesis, but only in concentrations that affect the physical properties of the DNA molecule. Dactinomycin has been a useful tool for understanding the biochemical actions of hormones because it prevents RNA synthesis.
Dactinomycin causes superinduction, which is an increase in the quantity of enzyme used, due to which the production of a repressor of the synthesis of said enzyme is prevented.
Cytarabine. This is cytosine arabinoside (1-beta-arabino-furanosil-cytosine). This compound is a synthetic nucleotide that differs from the natural nucleotides cytidine and deoxycytadine in that the residue of the sugar is arabinose instead of ribose or deoxyribose. It acts by blocking the action
of DNA polymerase, and is phase-specific.
Procarabazine. This is a compound synthesized by Roche. Its chemical formula is N-Isopropyl-alpha-(2-methylhydracine)-p-toluamide. It is a derivative of methyihydracine. This agent causes the fragmentation of the DNA molecule and interferes with RNA and DNA synthesis. It is a potent carcinogen and one of the most effective iminunosuppressors that exist.
Hyroxyurea. Synthesized by Squibb and Sons, it is a phase-specific agent and only affects the cells that are synthesizing DNA. The duration of a dose of hydroxyurea, like cytarabine, is relatively short and almost always produces a megaloblastic appearance of the bone marrow.
Pipbroman. Chemically, it is 5-(3.3-dimethyl-1-triacene)-imidazol-4-carboxamide. Little is known about the mechanism of Its action. Its average life in the plasma is 30 to 45 minutes. 40% of the original compound is found in the urine 6 hours after administration.
Hexamethylmelamine. This is a synthetic compound that acts as a pyrimidine antimetabolyte.
Mithramycin. Its mechanism is similar to that of dactinomycin. It is also a product of Streptomyces and appears to attach itself to DNA to prevent RNA synthesis.
Daunorubicin. Also known by the names Daunomycin and Rubidomycin, it is made up of two structural units: an aminosugar, daunosamine, and a pigmented tetracyclic kenone, dunomycinone. It inhibits DNA and RNA synthesis.
BCNU. Chemically It is 1.3-bis-(2-chloroethyl)-1-nitrousurea. It is an alkylating agent, but does not show crossed resistance effects from other alkylating agents. Since it is soluble in lipids it can cross the hematoencephalic [blood-brain] barrier. It causes chromosomic defects in patients with leukemia and Ewing’s sarcoma, which are treated with it.
Mitomycin. This is an antibiotic isolated from the broth of a strain of Streptomyces, and acts as an alkylating agent of both DNA and RNA, causing alkylation of crossed bonds of DNA.
Streptonigrin. This is an antibiotic isolated from the broth filtrates of a strain of Streptomyces, and has a suppressive effect on bacterial DNA synthesis. In very low concentrations, streptonigrin inhibits the mitosis of human leukocytes and causes extensive breakage of chromosomes.
L-aparaginase. This is an enzyme obtained from E. coli that acts hydrolyzing the amino acid L-asparagin. It has been demonstrated that L-asparaginase represents the first chemotherapeutic agent to exploit a qualitative difference between the normal and tumoral cells, since tumoral cells depend on exogenous sources of L-asparagin and die when the circulating amino acid is hydrolyzed, while normal cells can synthesize their own from L-aspartic acid with asparaginsynthesase.
0-p’-DDP (1.1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane). This is an agent used for the treatment of carcinomas of the adrenal cortex and is derived from DDT. The generic name it falls under is MITOTANE.
Doses of Alkylating Medications (according to other authors)
Triethylentiophosphoramide is administered in doses of 6o mg in 30-60 ml of sterile water for a vesical carcinoma, through the urethra, every week for 4 weeks. The volume of liquid is retained for two hours, and for 12 hours before each dosage, the patient should not drink water to avoid diluting the medication.
After several weeks have elapsed, a second phase of treatment is begun with 6o mg every other week for four administrations. Then 60 mg every other week for four administrations. Then 6o mg every 4 to 6 weeks as a prophylactic during at least a year.
The toxic effects triethyientiophosphoramide (TTPA) affect primarily the bone marrow, suppressing the leukocytes and platelets more than the erythrocytes.
In the treatment of ovarian carcinoma, for which it is the preferred medication, the powder is dissolved in 5 ml of sterile water and injected in the vein. The most accepted treatment consists of one saturation dose of 75 mg divided into 5 applications per day.
Chlorambucil is the suggested medication for the treatment of chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, and ovarian carcinoma. The initial dose is 0.1 to 0.15 mg/kg/day orally. The toxic effects of this also affect primarily the bone marrow, and are in general irreversible.
Busulfan is an extremely useful medication for the treatment of chronic mielogenous leukemia; 4-5 mg are administered per day.
There is no unified opinion as to the dosification of cyclophosphamide. The following schema are used today in the major cancer centers of the world:
1. 30 mg/kg/IV, then 10—15 mg/kg/week for 7 weeks.
2. 30-50 mg/kg/IV, then the same dose IV every 4 weeks, for seven applications.
3. 4 mg/kg/day orally for 4 days, then 28 mg/kg/day for 4 days, then maintenance doses of 3 mg/kg/day for 7 days.
4. Daily oral doses of 3 mg/kg/day for 30 days.
The ideal dose of melphalan (Alkeran) is 10 mg/day orally for 7 days, followed by 4 mg/day for 30 days. It is a very useful medication for the treatment of multiple myeloma, of ovarian carcinoma, Wladenstrom’s macrogiobulinemia and true polycytemia. In experienced hands, its toxic effects are minimal.
The main use of methotrexate is in the treatment of acute leukemia in children. When administered as a medication it only produces remissions of 40-68%. Approximately half of the responses are total, with a return to normal of the bone marrow, the peripheral blood cell count, and recovery of health and general well-being.
Methotrexate yields good results with uterine carcinomas. The classic paper about this is by Hertz, Lewis and Lipsett and appeared in 1966. The hydatidiform mole, the destructive chorioadenoma and the choriocarcinoma need not be distinguished as they are stages of the development of malignancy.
Results with Donatian therapy In choriocarcinoma treatment are so good that hysterectomy is reserved for those patients who have complications like uncontrollable hemorrhaging or septicemic infection. In our opinion, Donatian therapy is the preferred mode of treatment for choriocarcinoma, destructive chorioadenoma and hydatidiform mole with metastasis.
The dosification scheme for methotrexate has undergone many variations, and what seems to us to be the best system is that used by Farber, Del Regato, Acermann, Greenwald and Goldstein, as well as by Damasheck, Dacie, Diammond, Wintrobe and Williams.
Delmonte, Jukes and Greenwald have shown that the toxic effects of methotrexate depend on the duration of the contact of the medication with the tissues and not on its concentration in the blood. Its toxic effects are due to the inhibition of nucleic acids in rapidly proliferating cells and this is why it is manifested in the hematopoietic tissue, bucal and intestinal mucous membranes, the skin and the hair follicles. When superficial, painful, whitish or yellowish ulcers with red edges appear, it is critical to suspend methotrexate treatment and administer cytrovorum (?) (15-30 mg/day).
Methotrexate always causes abortion or a deformed fetus when administered in the first trimester of pregnancy. If excessive doses of methotrexate are inadvertently given, cytrovorum (folic acid, Leucovorin, Lederle) should be injected in doses of 3-6 mg, IM, every 4 hours for 7 days.
In sum, methotrexate is a very useful agent for the treatment of acute infantile leukemia and choriocarcinoma. Its administration is considered standard for the manifestations of leukemia in the central nervous system. Its most serious toxic effects appear in the hematopoietic sy8tem and the digestive apparatus, according to other’s experience.
Dosification of the three Purine antagonists (according to other authors)
6-mercaptopurine (Purinethol). This is administered in one application of 2.5 mg/kg/day.
Thioguanine. This is administered in one oral dose of 2 mg/kg/day. Because it is not catabolyzed by xanthinoxidase, it is not necessary to diminish the doses when administered with allopurinol. One recent study (Carey, 1976) points out that the combination of thioguanine and cytarabine is more effective than 6-mercaptopurine and cytarabine for the treatment of acute leukemia in the adult.
Azathiopurine (muran). This has never been used extensively in the treatment of malignant neoplasias, but as an immunosuppressant to avoid the rejection of grafts and transplants. It has also been used in the autoimmunological diseases.
Doses of Pyrimidine Antagonists
5-Fluorouracil. This is available in ampules of 10 ml as an aqueous solution with 50 mg/mi of the compound and a sodium hydroxide buffer. It is administered intravenously without further dilution, using a number 23 or 25 needle.
Cytarabine. IV infusion of 50 mg/m2 for one hour every day for 22 days. Cytarabine produces a remission rate of 25% in adult patients with acute leukemia.
Vinca Alkaloids (Mirto). Vinblastine and Vincristine belong to a group of mitotic inhibitors which includes griseofulvin (?), colkycin (?) and podo— phyllin (?).
Vinblastine is administered in the least toxic manner, 10 mg diluted in 10 ml of sterile water, IV. It is necessary to verify that the needle is needed in the vein because infiltration outside of the vein causes a very intense local reaction. It is enough to administer 0.1 mg/kg/IV every week for 7 weeks.
Vincristine. Young and Finkel point out that small doses of vincristine are better for the treatment of reticular cell sarcomas, because its neurotoxicity blocks the retention of this medication for a prolonged period. They use 0.005 mg/kg, twice a week.
Dactinomycin (sosmegen). This was introduced by Farber for spectacular results In the treatment of Wilms' tumor and uterine choriocarcinomas. It has been concluded that Dactinomycin prevents the metastasis of Wilms’ tumor and when administered systematically at the moment the tumor is excised, followed by local radiation of the site of the tumor immediately after the operation, survival for 2 years (equivalent to cure) rose from 40 to 89% of patients.
For Wilms’ tumor doses of 0.015 mg/kg/day IV are used for 5 to 7 days. For the treatment of uterine choriocarcinoma with metastasis the dose is 0.01 mg/kg/day for 5 days.
Other Agents, Techniques, Combination therapy
Procarbacine chiorhydrate. Nowadays procarbacine chiorhydrate is only used as a palliative for patients with Hodgkin’s disease and it has also been shown to cause remission in patients with disseminating malignant melanoma. Procarbacine chiorhydrate is available in 50 mg capsules that are ivory colored. Its toxic effects depress the bone marrow.
The dosage used is 50 mg, once the first day, 100 mg the second day, then 100 mg after breakfast and 50 mg after dinner, until reaching a dosage of 5 capsules (250 mg) per day, which should be maintained for 2-3 weeks. Afterwards the treatment can be sustained with doses of 50 mg/day every third day.
Hydroxyurea. This is used for the treatment of patients with chronic granulocytic leukemia and malignant melanoma. The dosage is 20-30 mg/kg, orally, divided into two administrations daily.
Pipobroman. This is a medication produced by Abbott Laboratories that should never have been put on the market, because it has never been used for any malignant disease. Rarely does the oncologist need this medication since there are many other available agents for the treatment of chronic granulocytic leukemia and true polycytemia which were the diseases it was suggested for.
Mitramycin. Produced by Pfizer, it is a medication of limited use and serious toxic effects. Its two major suggested applications are in cases of carcinoma of the testicle and hypercalcemia due to metastasis. Nowadays, the recommended dosage is 25 mg/kg/day/IV for 10 days.
Daunomycin. This is a new antibiotic used for the treatment of acute leukemia, especially the lymphoblastic variety. It is particularly useful in combination with prednisone (?) and vincristine for inducing remission in refractory patients with leukemia.
Mathe, using a combination of prednisone, vincristine and daunomycin in the treatment of 27 patients with acute lymphoblastic leukemia, achieved complete remission in 19 out of the 27 patients. The dosage used varies considerably, but in general a dosage of 7 mg/kg/day should be used when administered in isolation, and 4-5 mg/kg/day when used in association with other oncolytic agents.
BCNU. This is 1.3-bis—(2—chloroethyl)—1-nitrousurea; best results have been obtained when using it for the treatment of patients with Hodgkin’s Disease.
BCNU is available as a lyophilized powder in ampules of 100 mg, which should be kept refrigerated until ready for use. The powder Is dissolved in 3 ml of pure ethanol, and then in 27 ml of distilled water. This is then dissolved in approx. 250 ml normal saline solution and administered via IV over 30—60 minutes.
Mytomycin C. Though Japanese oncologists have published impressive results on the use of mytomycin C in the treatment of gastric carcinoma, other authors have not been able to confirm them. Gastric carcinoma is almost incurable, just as is broncogenous carcinoma, with or without surgical treatment, because the patient usually suffers from immunological paralysis caused by the secretions of the cells of this kind of neoplasm.
With Donatian therapy, the rate of cure has reached 45.3%.
Streptonigrin. This is an effective agent for the treatment of lymphomas, but its toxic potential is very great, and this limits its usefulness. Nevertheless, it can constitute part of treatment when used in conjunction with other medications.
Streptonigrin plays no role in the treatment of solid tumors, but can be useful in the treatment of patients with immature lymphomas, Hodgkin’s disease, and reticular cell sarcomas.
L-asparaginase. This is a medication that seems to exploit a ‘qualitative difference’ between certain tumoral cells and all normal cells. However, L—asparaginase is only useful today in cases of acute lymphoblastic leukemia where it shows good results in up to 60% of the cases. There is no depression of the bone marrow and its toxic potential is in hypoalbuminemla and reducing some of the factors involved in coagulation. Therefore, it is better to use it in doses of 100 IU/kg/day.
Streptozotocin. This is an antibiotic isolated from a strain of Streptomyces, and has been successfully used in the treatment of tumors of the cells of the Isles of Langerhans. There is no principled basis, as of yet, for a generally applicable posology.
o,p’-DDD (Mitotane, Lysodren). This is administered in tablets of 500 mg orally. The usual dose is 8-10 g/day, though occasionally as much as 16-19 g/day have been given. It has been used for the treatment of adrenocortical carcinoma.
Bleomycin. This has been tested mainly in Japan and is a mixture of antibiotics isolated from a strain of Streptomyces found in a Japanese coal mine. It is effective against carcinomas of the squamous cells of the skin, especially cancer of the penis, epidermoid carcinoma of the head and neck, and occasionally against uterine, cervical, and esophageal cancers.
Its greatest use is in the treatment of carcinoma of the penis, where success nears 7O-8O%. It is also effective in cases of Hodgkin’s disease and, to a certain extent, in other lymphomas. Its toxic effects on the lungs, which are the most worrisome, are frequently mortal, but fortunately occur in less than 5% of patients.
Adriamycin. This is an antibiotic that appears to be very similar to daunomycin in terms of mechanism of action, efficacy, and toxic effects, except that it has less possible cardiotoxicity. It is administered IV in doses of 0.4-0.8 mg/kg/day.
Combined medication treatments. Numerous authors have described the theoretical basis for therapeutic synergy. Concepts such as sequential, concurrent, and complementary inhibition refer to the combined attack on the enzymatic system in tumoral cells, and normal cells as well. Today there are two proven systems of combined medication therapy: VAMP and MOPP.
VAMP is made up of vincristine, mercaptopurine and prednisone. MOPP is made up of mechiorethamine, mercaptopurine and prednisone.
In our opinion, the addition of oncolytic medications does not definitively and permanently better the rate of cure or survival for patients with malignant neoplasia1 but does, however, expose these patients to greater effects of the toxic reactions that block the immunological system. For this reason, we prefer to avoid combined medication treatments of this type.
We do, however, advocate the combination of medications with Donatian therapy, because such a combination does not in any way increase the intoxicated state the patient already suffers from and it is a form of treatment that has practically no side effects.
Treatment of malignant pleural hemorrhage. We only use Donatian therapy.
