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. 1973 Jun;14(2):257–270.

The effect of microsomal enzyme inhibition on the immunosuppressive and toxic effects of cyclophosphamide

M C Berenbaum, W A Cope, J A Double
PMCID: PMC1553799  PMID: 4717916

Abstract

Cyclophosphamide is activated in vivo to toxic alkylating materials by hepatic microsomal enzymes. In mice and rats, inhibition of these enzymes by chloramphenicol or SKF 525A reduces the toxicity of cyclophosphamide but has less effect in rats and no effect in mice on its immunosuppressive activity, so increasing its therapeutic effectiveness.

In contrast, vitamin A alcohol increases cyclophosphamide toxicity, again without affecting its immunosuppressive activity.

Hepatic activation of cyclophosphamide results in the sequential appearance of several metabolites of varying toxicity. Retardation of activation by microsomal enzyme inhibitors may alter the proportions of the various metabolites present and so lead to the differential effects observed here.

Alternatively, exposure of cells to lower concentrations of active products for longer times would favour survival of cells with substantial ability to repair alkylation damage to DNA but not that of cells with little repair ability. The shape of the dose-response curve for cyclophosphamide acting on immunocytes suggests that their repair abilities are limited. The cells essential for survival, which are differentially protected against cyclophosphamide by administering microsomal enzyme inhibitors, are probably not haemopoietic stem cells but may be intestinal epithelial cells.

The clinical relevance of these experiments is discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ARNOLD H., BOURSEAUX F., BROCK N. Chemotherapeutic action of a cyclic nitrogen mustard phosphamide ester (B 518-ASTA) in experimental tumours of the rat. Nature. 1958 Mar 29;181(4613):931–931. doi: 10.1038/181931a0. [DOI] [PubMed] [Google Scholar]
  2. AXELROD J., REICHENTHAL J., BRODIE B. B. Mechanism of the potentiating action of beta-diethylaminoethyl diphenylpropylacetate. J Pharmacol Exp Ther. 1954 Sep;112(1):49–54. [PubMed] [Google Scholar]
  3. Abbott W. M., Monaco A. P., Russell P. S. The effect of supralethal amethopterin and folinic acid rescue on mouse skin allograft survival. Proc Soc Exp Biol Med. 1971 Feb;136(2):510–513. doi: 10.3181/00379727-136-35300. [DOI] [PubMed] [Google Scholar]
  4. BERENBAUM M. C., BROWN I. N. DOSE-RESPONSE RELATIONSHIPS FOR AGENTS INHIBITING THE IMMUNE RESPONSE. Immunology. 1964 Jan;7:65–71. [PMC free article] [PubMed] [Google Scholar]
  5. BERENBAUM M. C., BROWN I. N. PROLONGATION OF HOMOGRAFT SURVIVAL IN MICE WITH SINGLE DOSES OF CYCLOPHOSPHAMIDE. Nature. 1963 Oct 5;200:84–84. doi: 10.1038/200084a0. [DOI] [PubMed] [Google Scholar]
  6. BERENBAUM M. C., BROWN I. N. THE EFFECT OF DELAYED ADMINISTRATION OF FOLINIC ACID ON IMMUNOLOGICAL INHIBITION BY METHOTREXATE. Immunology. 1965 Mar;8:251–259. [PMC free article] [PubMed] [Google Scholar]
  7. BERENBAUM M. C. PROLONGATION OF HOMOGRAFT SURVIVAL BY METHOTREXATE WITH PROTECTION AGAINST TOXICITY BY FOLINIC ACID. Lancet. 1964 Dec 26;2(7374):1363–1365. doi: 10.1016/s0140-6736(64)91157-2. [DOI] [PubMed] [Google Scholar]
  8. Barratt T. M., Soothill J. F. Controlled trial of cyclophosphamide in steroid-sensitive relapsing nephrotic syndrome of childhood. Lancet. 1970 Sep 5;2(7671):479–482. doi: 10.1016/s0140-6736(70)90108-x. [DOI] [PubMed] [Google Scholar]
  9. Berenbaum M. C. Immunosuppressive agents: generation and consequences of differing dose-response curves. Proc R Soc Med. 1972 Mar;65(3):255–257. doi: 10.1177/003591577206500314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brandes D., Anton E., Schofield B., Barnard S. Role of lysosomal labilizers in treatment of mammary gland carcinomas with cyclophosphamide (NSC-26271)--preliminary report. Cancer Chemother Rep. 1966 Jan-Feb;50(1):47–53. [PubMed] [Google Scholar]
  11. Brock N., Gross R., Hohorst H. J., Klein H. O., Schneider B. Activation of cyclophosphamide in man and animals. Cancer. 1971 Jun;27(6):1512–1529. doi: 10.1002/1097-0142(197106)27:6<1512::aid-cncr2820270636>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  12. Bruce W. R., Meeker B. E., Valeriote F. A. Comparison of the sensitivity of normal hematopoietic and transplanted lymphoma colony-forming cells to chemotherapeutic agents administered in vivo. J Natl Cancer Inst. 1966 Aug;37(2):233–245. [PubMed] [Google Scholar]
  13. Christensen L. K., Skovsted L. Inhibition of drug metabolism by chloramphenicol. Lancet. 1969 Dec 27;2(7635):1397–1399. doi: 10.1016/s0140-6736(69)90937-4. [DOI] [PubMed] [Google Scholar]
  14. DIXON R. L., FOUTS J. R. Inhibition of microsomal drug metabolic pathways by chloramphenicol. Biochem Pharmacol. 1962 Aug;11:715–720. doi: 10.1016/0006-2952(62)90038-2. [DOI] [PubMed] [Google Scholar]
  15. Dixon R. L. Effect of chloramphenicol on the metabolism and lethality of cyclophosphamide in rats. Proc Soc Exp Biol Med. 1968 Apr;127(4):1151–1155. doi: 10.3181/00379727-127-32895. [DOI] [PubMed] [Google Scholar]
  16. Hart L. G., Adamson R. H. Effect of microsomal enzyme modifiers on toxicity and therapeutic activity of cyclophosphamide in mice. Arch Int Pharmacodyn Ther. 1969 Aug;180(2):391–401. [PubMed] [Google Scholar]
  17. Hart P. D., Rees R. J., Niven J. S. The effect of high dosage of methotrexate, associated with folinic acid, on the suppression of tuberculin sensitivity in guinea-pigs. Clin Exp Immunol. 1968 Jan;3(1):91–98. [PMC free article] [PubMed] [Google Scholar]
  18. Hill D. L., Laster W. R., Jr, Struck R. F. Enzymatic metabolism of cyclophosphamide and nicotine and production of a toxic cyclophosphamide metabolite. Cancer Res. 1972 Apr;32(4):658–665. [PubMed] [Google Scholar]
  19. Nathanson L., Maddock C. L., Hall T. C. Exploratory studies of vitamin A and cyclophosphamide in tumor-bearing mice. J Clin Pharmacol J New Drugs. 1969 Nov-Dec;9(6):359–373. [PubMed] [Google Scholar]
  20. Paterson P. Y., Hanson M. A., Gerner E. W. Cyclophosphamide inhibition of experimental allergic encephalomyelitis in Wistar rats. Proc Soc Exp Biol Med. 1967 Mar;124(3):928–932. doi: 10.3181/00379727-124-31888. [DOI] [PubMed] [Google Scholar]
  21. SANTOS G. W., OWENS A. H., Jr A COMPARISON OF THE EFFECTS OF SELECTED CYTOTOXIC AGENTS ON ALLOGENEIC SKIN GRAFT SURVIVAL IN RATS. Bull Johns Hopkins Hosp. 1965 May;116:327–340. [PubMed] [Google Scholar]
  22. STENDER H. S., STRAUCH D., WINTER H., TEXTOR W. DIE WIRKUNG DES CYCLOPHOSPHAMIDS BEI FRAKTIONIERTER ODER MASSIERTER DOSIERUNG AUF DIE ANTIKOERPERBILDUNG. Arzneimittelforschung. 1963 Dec;13:1031–1034. [PubMed] [Google Scholar]
  23. Starzl T. E., Putnam C. W., Halgrimson C. G., Schroter G. T., Martineau G., Launois B., Corman J. L., Penn I., Booth A. S., Jr, Groth C. G. Cyclophosphamide and whole organ transplantation in human beings. Surg Gynecol Obstet. 1971 Dec;133(6):981–991. [PMC free article] [PubMed] [Google Scholar]
  24. Steinberg A. D., Kaltreider H. B., Staples P. J., Goetzl E. J., Talal N., Decker J. L. Cyclophosphamide in lupus nephritis: a controlled trial. Ann Intern Med. 1971 Aug;75(2):165–171. doi: 10.7326/0003-4819-75-2-165. [DOI] [PubMed] [Google Scholar]
  25. Struck R. F., Kirk M. C., Mellett L. B., el Dareer S., Hill D. L. Urinary metabolites of the antitumor agent cyclophosphamide. Mol Pharmacol. 1971 Sep;7(5):519–529. [PubMed] [Google Scholar]
  26. Valeriote F. A., Tolen S. J. Survival of hematopoietic and lymphoma colony-forming cells in vivo following the administration of a variety of alkylating agents. Cancer Res. 1972 Mar;32(3):470–476. [PubMed] [Google Scholar]
  27. Withers H. R., Elkind M. M. Microcolony survival assay for cells of mouse intestinal mucosa exposed to radiation. Int J Radiat Biol Relat Stud Phys Chem Med. 1970;17(3):261–267. doi: 10.1080/09553007014550291. [DOI] [PubMed] [Google Scholar]
  28. van Putten L. M., Lelieveld P. Factors determining cell killing by chemotherapeutic agents in vivo. I. Cyclophosphamide. Eur J Cancer. 1970 Aug;6(4):313–321. doi: 10.1016/0014-2964(70)90096-4. [DOI] [PubMed] [Google Scholar]

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