6-mercaptopurine Research Articles

Ultrastructural changes in skeletal muscles of rats treated neonatally with 6-mercaptopurine.

The purpose of this study was to characterize the ultrastructural changes in the muscles of 2- and 6-month-old rats that were injected with 6-mercaptopurine monohydrate (6-MP) at 2 mg base/kg sc daily from 2 to 22 days of age. The earliest, usually subsarcolemmal alterations, were disorganization of fibrils at the Z-bands with excessive Z-band-like material and loss of myofibrils. In the most extensive lesions, the entire fiber was involved, with vacuoles within the disorganized fibrils. The peripheral nerves and vessels were unremarkable. Thus 6-MP-induced changes appear to be primarily myogenic in origin.

In vivo inhibition of concanavalin A-induced suppressor T cells by 5-fluorouracil.

Spleen cells of mice inoculated intravenously (iv) with concanavalin A (Con A) suppressed the in vitro normal spleen cell blastogenesis. The suppressor cells, as determined by measuring the inhibition of in vitro T cell blastogenesis by Con A, were resistant to X-irradiation. They lacked surface Ig and were abrogated by treatment with alpha Thy 1.2 antibody and complement, but not with complement alone, indicating that these suppressor cells are not B cells but T cells. Inoculation of 5-fluorouracil (5-FU) inhibited the induction and/or activity of these suppressor cells, whereas that of cyclophosphamide (CY), adriamycin, vincristine, or 3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1-(2-chloroethyl)-1-nitro sou rea (ACNU) did not at any interval tested. Since two other antimetabolic agents, 6-mercaptopurine and 2'-deoxyguanosine, were also effective in inhibiting these suppressor T cells, it was supposed that Con A-induced suppressor T cells are metabolically more active than the other T subpopulations. The findings that CY and ACNU decreased the number of T cells as much as or more than 5-FU did, but that they did not inhibit these suppressor T cells, suggests that 5-FU more or less selectively inhibited this suppressor T-cell subpopulation.

Potentiation of mitomycin C, 6-mercaptopurine, bleomycin, cis-diamminedichloroplatinum and 5-fluorouracil by mycotrienins and mycotrienols.

Mycotrienins I and II and mycotrienols I and II are ansamycin antibiotics containing a triene structure, isolated from Streptomyces rishiriensis. An amphotericin B-resistant clone (AMBR-1) derived from cultured Chinese hamster V79 cells was cross-resistant to mycotrienins I and II, but not to mycotrienol I or II. These four ansamycin antibiotics were found to potentiate significantly the action of some anti-cancer agents including 5-fluorouracil, cis-diamminedichloroplatinum, bleomycin, mitomycin C and 6-mercaptopurine against cultured V79 cells. The action of adriamycin was not potentiated. These four ansamycin antibiotics showed a synergism spectrum similar to that of smaller polyene antibiotics.

Muscular Dystrophy-Like Syndrome in Young Adult Sprague-Dawley Rats Following Neonatal Treatment with 6-Mercaptopurine

Ninety-six male and female rats were injected subcutaneously with 2 mg./kg. of 6-mercaptopurine monohydrate (as the free base) daily from 2 to 22 days of age. An equal number of controls received saline. Clinically, 15 of 77 surviving treated rats exhibited paresis of the hindlegs while 44 (including the 15 with paresis) had flattened croups (gluteal area). Grossly, the gluteal, thigh and lumbar vertebral muscles were markedly atrophied and partially replaced by adipose tissue. Microscopically, the muscles of 50 of 66 treated rats consisted of varying sizes and shaped myofibers which were extensively infiltrated by fat cells. Chains of centrally positioned nuclei, foci of necrosis and inflammation were occasionally observed in the affected muscles. Other regions of the musculature and other organ systems of the treated rats were normal. None of the 77 surviving control rats presented clinical signs, gross or microscopic lesions comparable to the treated rats. The observations presented at this meeting were demonstrated and discussed with respect to their correlations with other clinical, gross anatomical, biochemical and histochemical findings.

Muscular degeneration in rats after postnatal treatment with 6-mercaptopurine.

6-Mercaptopurine monohydrate was injected sc at 2 mg base/kg/day from 2 to 22 days of age to four litters of rat pups (four females, four males per litter). Control neonates were injected sc with basic saline (pH 8). Daily observations for signs of toxicity were made during the treatment period and once weekly thereafter until the rats were 6 months of age. The pups were weighed at 2, 12, 23, 34, 100, and 480 days of age. Fertility was tested at 3 to 6 months of age. From 6 months of age on, the rats were examined for tumors at 3-month intervals until the experiment was terminated at 16 months of age. A reduction in body weight of treated rats began between 34 and 100 days of age and became more pronounced by 16 months of age. Fertility was similar in treated and control groups and there were no detectable tumors in either group. The major finding in treated rats was a delayed onset of hind leg paresis that was first detected at 12 months of age. Light microscopic examination of tissues taken from the hind quarters of these rats at 16 months of age revealed a severe atrophic degeneration with fatty infiltration of sublumbar and thigh muscles.

Sensitization of resistant myeloid leukemia clone cells by anti-cancer drugs to factor-stimulating differentiation.

Studies were made on the effect of cancer chemotherapeutic drugs on in vitro differentiation of a clone (R4) of mouse myeloid leukemic cells (MI) that is resistant to inducers. Treatment of the cells with 50% ascitic fluid (an inducer) plus 0.25 microgram/ml of adriamycin or 0.3 microgram/ml of daunomycin induced phagocytic activity and suppressed cell growth, but had little effect on cell viability; treatment with ascitic fluid or the drugs alone had no effect. In combination with ascitic fluid, mitomycin-C, hydroxyurea, 5-fluorouracil, or bleomycin also induced phagocytic activity, but 6-mercaptopurine, amethopterin, or aminopterin did not. These drugs also induced other differentiation-associated properties, lysozyme activity, and locomotive activity. The present results indicate that some cancer chemotherapeutic drugs sensitive resistant leukemic cells to an inducer of cell differentiation.

Analysis of treatment in childhood leukaemia. V. Advantage of reduced chemotherapy during and immediately after cranial irradiation

This paper compares anti-leukaemic efficiency with toxicity to the patient of chemotherapy during and immediately after central nervous system irradiation. The drug regimen consisted of daily mercaptopurine (MP) and weekly methotrexate (MTX) at the maximum tolerated dose. Of 140 patients with acute lymphoblastic leukaemia allocated to receive this drug regimen during and after cranial irradiation, 8 died in complete remission within 6 months of the end of irradiation. Details of the nature of these deaths are given. This result led the Working Party to modify the chemotherapy scheduled for this stage in treatment. The modified chemotherapy consisted of MP at reduced dosage before and during cranial irradiation and omission of MP and MTX for 3 weeks after irradiation, during which time daily prednisolone with 2 doses of vincristine were substituted. Following that, the treatment reverted to the original schedule of daily MP and weekly MTX at maximum tolerated dose. Of 109 patients allocated to this modified regimen only one died in remission within 24 weeks after cranial irradiation. Analysis of the anti-leukaemic effect of the modified regimen showed that up to 600 days it was at least as effective as the original more intensive regimen. We conclude that there is a definite advantage in keeping chemotherapy to a minimum during and immediately following cranial prophylactic irradiation.

A virological study of interstitial pneumoniae in patients with acute lymphoid leukemia treated with a combination of methotrexate and 6-mercapto purine

A clinical study of 45 patients and a virological survey of 34 patients with acute lymphoblastic leukemia have been undertaken to detail the characteristics of occurrence of interstitial pneumoniae (IP) under maintenance chemotherapy. Our study confirms the link between IP and treatment with MTX but does not support the hypothesis of an allergic reaction to the drug. The virological study has failed to detect one type of viral agent associated with IP but have shown important modifications of humoral immunity against viruses.

Interaction of antitumor agents including doxorubicin or daunorubicin in sarcoma-180 system.

Combination effect of antitumor agents, including doxorubicin and daunorubicin, was evaluated on the concept of pharmacological synergism in ascites sarcoma-180 system. In alternate adminsitration, combinations of doxorubicin plus cyclophosphamide, thio-TEPA, carboquone, actinomycin-D, vinblastine, vincristine, methotrexate, cytarabine, 6-mercaptopurine, or L-asparaginase showed synergism, but in simultaneous one, only three agents, cyclophosphamide, carboquone, and cytarabine, were synergistic. On the other hand, combination of daunorubicin plus one of 8 agents (thio-TEPA, mitomycin-C, bleomycin, actinomycin-D, vinblastine, ancytabine, 6-mercaptopurine, and L-asparaginase) and 6 agents (cyclophosphamide, thio-TEPA, mitomycin-C, bleomycin, actinomycin-D, and vinblastine) provided synergism in alternate and simultaneous administration. Combination effect of agents was affected by the schedule of drug administration for doxorubicin, but weak for daunorubicin. Toxicity of doxorubicin or daunorubicin in combination with other drugs was also affected by the schedule of administration. Combination of a larger number of agents in simultaneous administration provided antagonism compared with an alternate administration.

Interaction of antitumor agents including carboquone in sarcoma-180 system.

Combination effect of antitumor agents including carboquone was evaluated on the concept of pharmacological synergism and not therapeutic synergism in ascites sarcoma-180 system. Combinations of carboquone plus cyclophosphamide, doxorubicin, and Methotrexate in simultaneous administration and carboquone plus doxorubicin in alternate one provided synergism. Combination effect of agents was affected by the schedule of drug administration. Toxicity of carboquone in combination with many antitumor agents, generally, decreased in simultaneous administration. Approved agents in combination with carboquone in simultaneous administration were Mitomycin-C, daunorubicin, Actinomycin-d, vinblastine, vincristine, Ancytabine, and 6-mercaptopurine. Those in alternate administration were Actinomycin-D and vinblastine.

Synthese de C-nucleosides—IX : Purines substituees en position 8 par le desoxy-2 ribose

Benzyl 2-deoxy-3,5-di-O-p-toluyl- d- erythro-pentofuranosyl thioformimidate 3, prepared from nitrile 1, reacts with α-aminocyanoacetic acid derivatives to yield C-imidazole nucleosides which are further cyclized into purines. The 6-mercapto purine 2 is obtained in two different ways.

Immunosuppressive treatment of autologous immune complex nephritis in rats.

Abstract Autologous immune complex nephritis was induced by intraperitoneal injections of homologous kidney extract and Freund's adjuvant in rats. The renal lesion was characterized by widening of the glomerular basement membrane and epimembranous complex deposition, and most animals manifested severe proteinuria and slowly declining glomerular filtration rates. Nine weeks after the initial injection, at a time when florid disease was present, the animals were treated with either cyclophosphamide, 6-mercaptopurine, or methylprednisolone. A fourth group of rats was not treated and served as the control. The rats receiving cyclophosphamide or 6-mercaptopurine continued to have proteinuria and their renal function deteriorated in a manner similar to the untreated animals. Additionally, they manifested a higher mortality rate than the control animals. The steroid-treated group showed equivocal results. No histologic improvement was noted in any of the treated groups. Structural and functional correlation in these studies revealed that (1) immune complex deposition frequently, but not invariably, causes proteinuria and a less striking effect on glomerular filtration rates; (2) the presence of complex deposition was associated with an increment in protein transport droplets in the proximal tubular cells suggesting enhanced reabsorption of the filtered protein. This phenomenon may have accounted for the absence of proteinuria in some of the animals with complex deposition.

Enhanced viral infection in the mouse treated with 6-mercaptopurine.

Abstract Parenteral inoculation of weanling mice with group B Coxsackie viruses and vaccinia virus resulted in essentially nonlethal infection. Simultaneous treatment of weanling mice with 6-mercaptopurine transformed these infections into lethal episodes. High titers of virus were found in the livers of treated mice, whereas no virus was detected in the livers of infected untreated mice. Similar treatment of mice infected with herpes simplex virus did not significantly increase mortality rate, ordinarily 60 to 80 per cent, but treatment with the purine analogue intensified visceral and systemic viral multiplication. Heightened replication of herpes simplex virus in the liver and brain of treated mice was associated with detectable levels of interferon in these tissues. Interferon was not found in the tissues of infected mice which were unexposed to 6-mercaptopurine. Lymphopenia and absolute neutropenia occurred after 6 days of treatment. Neutralizing antibody was variably present in these experimental infections and occasionally absent from the serum of both untreated as well as treated mice at the latter's death. Neither antibody nor interferon may be as crucial in host resistance to viral infections as delayed hypersensitivity. Furthermore, lymphocellular immunity may be more important in resistance to enteroviral infections than suspected in the past.

The crystal and molecular structure of 6-mercaptopurine monohydrate. A second, independent x-ray diffraction determination.

The crystal and molecular structure of 6-mercaptopurine monohydrate. A second, independent x-ray diffraction determination.

Some N-triaryltin and -lead derivatives of certain purines

The preparation of N-triphenylstannyl and N-triphenylplumbyl derivatives of purine, 6-chloropurine, and 6-methylmercaptopurine (triphenylplumbyl derivative only) is described. A novel complex was obtained from the reaction of 6-methylmercaptopurine with bis(triphenyltin) oxide. Novel complexes were also obtained from the reaction of 6-mercaptopurine monohydrate with bis(triphenyltin) oxide, triphenyllead hydroxide, tris(p-fluorophenyl)tin hydroxide, bis[tris(p-chlorophenyl)tin] oxide, and bis(tri-p-tolyltin) oxide.

EFFECT OF DRUGS ON GOLDFISH SCALE HOMOGRAFT SURVIVAL.

SummaryA new screening method for compounds which delay homograft rejection is described using the goldfish scale transplantation technique. It was shown that 6-Mercapto Purine and hydrocortisone acetate substantially delay homograft rejection in these fish. Moreover, sensitive dose-dependent responses were found with these drugs.

Prevention of secondary immune response with 6-mercaptopurine.

Abstract Six-mercaptopurine (6-MP) was known to inhibit the primary immune response in rabbits when given in a dose of 6 mg. per kilogram per day and to have negligible effects on the secondary immune response. In the present study, a 25 day course of 6-MP, in this dosage, before secondary stimulation produced significant depression of antibody production to bovine serum albumin, but did not prevent the response. When the drug was given in higher doses, 12 and 15 mg. per kilogram, beginning at the time of secondary antigenic stimulation, the secondary response was regularly inhibited, with no evidence of undue toxicity from 6-MP. The findings suggest that prior failure to prevent the secondary immune response with 6-MP resulted from inadequate doses or use of inactive preparations of the drug. In a pilot study with a small number of animals it was suggested that 6-MP also interferes with the tertiary immune response. These animals had received 6-MP at the time of secondary stimulation with bovine serum albumin and had shown no antibody. The tertiary response was also deficient, although no additional 6-MP was given. Thus, 6-MP differs from such agents as total body irradiation and cortisone in suppressing at least the primary and secondary responses and perhaps interfering with immunologic memory as well.

Treatment of choriocarcinoma with a combination of cytotoxic drugs.

It is known that both normal embryonic development in the rat and growth of the female genital tract are dependent upon the availability of folie acid (Nelson and Evans, 1949; Hertz and Tullner, 1949). It was therefore postulated by Hertz and his colleagues (Li et al, 1956; Hertz et al, 1958) that trophoblastic tumours originating in the foetal chorion might prove sensitive to folic-acid antagonists. These workers intro duced the administration of anti-folic-acid therapy to patients with malignant trophoblastic tumours and reported five complete remissions and 17 partial remissions in a series of 27 cases. Resistance to folic acid antagonists appeared to develop during therapy in some of their patients. By crude analogy with the antibiotics, it seemed likely that resistance to cytotoxic substances, especially those with an antimetabolite action, would develop less readily when used in combination. There is also some experimental evidence which suggests that combinations of cytotoxic drugs may be more effective than the same drugs used alone (Skipper et al., 1954). Augmented toxic effects on normal tissues would also be expected. The use of a combination of drugs administered concurrently in the treatment of two cases of pulmonary hypertension due to trophoblastic tumours was described briefly by Bagshawe and Brooks (1959). The present paper describes the results of combined cytotoxic therapy in six patients who had chorionic growths. Clearly the use of such combinations of drugs is largely empirical, and much work will be required to find the best combinations. The drugs chosen in the first stage of this study were the folic-acid antagonist methotrexate (4-amino-N10-methylpteroylglutamic acid), which Blocks the conversion of folie to folinic acid, and 6-mercapto purine. The latter drug has also been shown to exert a severe toxic effect on foetal tissues and acts as an antagonist of hypoxanthine and adenine. It was also decided that, should resistance to this combination of drugs develop, then a drug of the nitrogen-mustard group, such as chlorambucil, would be employed in place of the 6-mercaptopurine.

The fate of 6-mercaptopurine in man.

The fate of 6-mercaptopurine in man.