Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1982 Jan;45(1):35–43. doi: 10.1038/bjc.1982.5

Cimetidine enhancement of cyclophosphamide antitumour activity.

R T Dorr, D S Alberts
PMCID: PMC2010952  PMID: 7059463

Abstract

Male DBA2 mice were given 10(6) P-388 leukaemic cells i.p. and cimetidine (CMT) at 100 mg/kg 1 day for 10 days, or as a single 100 mg/kg injection 30 min before cyclophosphamide (CTX). CMT significantly prolonged the survival of groups of mice receiving 50, 100 and 200 mg/kg of CTX 3 days after tumour inoculation. Median survival increased by 5.5 days (P less than 0.05), 10 days (P less than 0.05) and 13 days (P less than 0.05) respectively. The addition of CMT had the effect of roughly doubling the CTX dose, without increasing the lethality. CMT produced the only long-term survival seen in the study (1-2/10) CMT alone had no apparent antitumour activity. CMT significantly prolonged mean pentobarbital sleep to 28.6-60 min vs only 10 min for phenobarbital treated mice. Both CMT regimens increased the plasma concentration time products for CTX-induced metabolites (NBP) by about 1.3 fold (in contrast to a 33% reduction with phenobarbital). On average the single-dose CMT regimen produced the greatest effect on survival, on pentobarbital sleep duration and on total NBP reactive species. Probable mechanisms for the CMT-CTX interaction include competitive microsomal enzyme inhibition and/or acutely depressed hepatic blood flow. Caution should be used in combining CMT with full doses of CTX and any other highly metabolized antineoplastic agents in man.

Full text

PDF
36

Selected References

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

  1. Alberts D. S., Peng Y. M., Chen H. S., Struck R. F. Effect of phenobarbital on plasma levels of cyclophosphamide and its metabolites in the mouse. Br J Cancer. 1978 Aug;38(2):316–324. doi: 10.1038/bjc.1978.204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alberts D. S., van Daalen Wetters T. The effect of phenobarbital on cyclophosphamide antitumor activity. Cancer Res. 1976 Aug;36(8):2785–2789. [PubMed] [Google Scholar]
  3. 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]
  4. Bus J. S., Short R. D., Gibson J. E. Effect of phenobarbital and SKF 525A on the toxicity, elimination and metabolism of cyclophosphamide in newborn mice. J Pharmacol Exp Ther. 1973 Mar;184(3):749–756. [PubMed] [Google Scholar]
  5. Campbell M. A., Plachetka J. R., Jackson J. E., Moon J. F., Finley P. R. Cimetidine decreases theophylline clearance. Ann Intern Med. 1981 Jul;95(1):68–69. doi: 10.7326/0003-4819-95-1-68. [DOI] [PubMed] [Google Scholar]
  6. Chang H. K., Morrison S. L. Bone-marrow suppression associated with cimetidine. Ann Intern Med. 1979 Oct;91(4):580–580. doi: 10.7326/0003-4819-91-4-580. [DOI] [PubMed] [Google Scholar]
  7. Cohen J. L., Jao J. Y. Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat. J Pharmacol Exp Ther. 1970 Aug;174(2):206–210. [PubMed] [Google Scholar]
  8. De Galocsy C., Van Ypersele de Strihou C. Pancytopenia with cimetidine. Ann Intern Med. 1979 Feb;90(2):274–274. doi: 10.7326/0003-4819-90-2-274_1. [DOI] [PubMed] [Google Scholar]
  9. Desmond P. V., Patwardhan R. V., Schenker S., Speeg K. V., Jr Cimetidine impairs elimination of chlordiazepoxide (Librium) in man. Ann Intern Med. 1980 Aug;93(2):266–268. doi: 10.7326/0003-4819-93-2-266. [DOI] [PubMed] [Google Scholar]
  10. Desmond P. V., Patwardhan R., Parker R., Schenker S., Speeg K. V., Jr Effect of cimetidine and other antihistaminics on the elimination of aminopyrine, phenacetin and caffeine. Life Sci. 1980 Apr 14;26(15):1261–1268. doi: 10.1016/0024-3205(80)90071-5. [DOI] [PubMed] [Google Scholar]
  11. Feely J., Wilkinson G. R., Wood A. J. Reduction of liver blood flow and propranolol metabolism by cimetidine. N Engl J Med. 1981 Mar 19;304(12):692–695. doi: 10.1056/NEJM198103193041202. [DOI] [PubMed] [Google Scholar]
  12. Field R. B., Gang M., Kline I., Venditti J. M., Waravdekar V. S. The effect of phenobarbital or 2-diethylaminoethyl-2,2-diphenylvalerate on the activation of cyclophosphamide in vivo. J Pharmacol Exp Ther. 1972 Feb;180(2):475–483. [PubMed] [Google Scholar]
  13. GEHAN E. A. A GENERALIZED WILCOXON TEST FOR COMPARING ARBITRARILY SINGLY-CENSORED SAMPLES. Biometrika. 1965 Jun;52:203–223. [PubMed] [Google Scholar]
  14. Gifford R. R., Ferguson R. M., Voss B. V. Cimetidine reduction of tumour formation in mice. Lancet. 1981 Mar 21;1(8221):638–640. doi: 10.1016/s0140-6736(81)91555-5. [DOI] [PubMed] [Google Scholar]
  15. Hakim R., Fujimoto J. M. Inhibition of renal tubular transport of morphine by -diethylaminoethyl diphenylpropylacetate in the chicken. Biochem Pharmacol. 1971 Oct;20(10):2647–2662. doi: 10.1016/0006-2952(71)90174-2. [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. Heagerty A. M., Donovan M. A., Castleden C. M., Pohl J. F., Patel L., Hedges A. Influence of cimetidine on pharmacokinetics of propranolol. Br Med J (Clin Res Ed) 1981 Jun 13;282(6280):1917–1919. doi: 10.1136/bmj.282.6280.1917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Henn R. M., Isenberg J. I., Maxwell V., Sturdevant R. A. Inhibition of gastric acid secretion by cimetidine in patients with duodenal ulcer. N Engl J Med. 1975 Aug 21;293(8):371–375. doi: 10.1056/NEJM197508212930802. [DOI] [PubMed] [Google Scholar]
  19. Jackson J. E., Powell J. R., Wandell M., Bentley J., Dorr R. Cimetidine decreases theophylline clearance. Am Rev Respir Dis. 1981 Jun;123(6):615–617. doi: 10.1164/arrd.1981.123.6.615. [DOI] [PubMed] [Google Scholar]
  20. Jao J. Y., Jusko W. J., Cohen J. L. Phenobarbital effects on cyclophosphamide pharmacokinetics in man. Cancer Res. 1972 Dec;32(12):2761–2764. [PubMed] [Google Scholar]
  21. Klaassen C. D. Biliary flow after microsomal enzyme induction. J Pharmacol Exp Ther. 1969 Aug;168(2):218–223. [PubMed] [Google Scholar]
  22. Klotz U., Anttila V. J., Reimann T. Cimetidine/diazepam interaction. Lancet. 1979 Sep 29;2(8144):699–699. doi: 10.1016/s0140-6736(79)92104-4. [DOI] [PubMed] [Google Scholar]
  23. MCPHERSON C. W. REDUCTION OF PSEUDOMONAS AERUGINOSA AND COLIFORM BACTERIA IN MOUSE DRINKING WATER FOLLOWING TREATMENT WITH HYDROCHLORIC ACID OR CHLORINE. Lab Anim Care. 1963 Oct;13:737–744. [PubMed] [Google Scholar]
  24. Mailman R. B., Kulkarni A. P., Baker R. C., Hodgson E. Cytochrome P-450 difference spectra: effect of chemical structure on type II spectra in mouse hepatic microsomes. Drug Metab Dispos. 1974 May-Jun;2(3):301–308. [PubMed] [Google Scholar]
  25. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966 Mar;50(3):163–170. [PubMed] [Google Scholar]
  26. Marchand C., Brodeur J. Change in colloidal gold clearance in rats treated with SKF 525-A. Rev Can Biol. 1970 Sep;29(3):294–298. [PubMed] [Google Scholar]
  27. McCarthy D. M., Olinger E. J., May R. J., Long B. W., Gardner J. D. H2-Histamine receptor blocking agents in the Zollinger-Ellison syndrome. Experience in seven cases and implications for long-term therapy. Ann Intern Med. 1977 Dec;87(6):668–675. doi: 10.7326/0003-4819-87-6-668. [DOI] [PubMed] [Google Scholar]
  28. Osband M. E., Hamilton D., Shen Y. J., Cohen E., Shlesinger M., Lavin P., Brown A., McCaffrey R. Successful tumour immunotherapy with cimetidine in mice. Lancet. 1981 Mar 21;1(8221):636–638. doi: 10.1016/s0140-6736(81)91554-3. [DOI] [PubMed] [Google Scholar]
  29. Pelkonen O., Puurunen J. The effect of cimetidine on in vitro and in vivo microsomal drug metabolism in the rat. Biochem Pharmacol. 1980 Nov 15;29(22):3075–3080. doi: 10.1016/0006-2952(80)90448-7. [DOI] [PubMed] [Google Scholar]
  30. Plaut M., Lichtenstein L. M., Gillespie E., Henney C. S. Studies on the mechanism of lymphocyte-mediated cytolysis. IV. Specificity of the histamine receptor on effector T cells. J Immunol. 1973 Aug;111(2):389–394. [PubMed] [Google Scholar]
  31. Posnett D. N., Stein R. S., Graber S. E., Krantz S. B. Cimetidine-induced neutropenia: a possible dose-related phenomenon. Arch Intern Med. 1979 May;139(5):584–586. [PubMed] [Google Scholar]
  32. Rosso R., Donelli M. G., Franchi G., Garattini S. Impairement of drug metabolism in tumor-bearing animals. Eur J Cancer. 1971 Dec;7(6):565–577. doi: 10.1016/0014-2964(71)90064-8. [DOI] [PubMed] [Google Scholar]
  33. Selker R. G., Moore P., Lodolce D. Bone-marrow depression with cimetidine plus carmustine. N Engl J Med. 1978 Oct 12;299(15):834–834. [PubMed] [Google Scholar]
  34. Serlin M. J., Sibeon R. G., Mossman S., Breckenridge A. M., Williams J. R., Atwood J. L., Willoughby J. M. Cimetidine: interaction with oral anticoagulants in man. Lancet. 1979 Aug 18;2(8138):317–319. doi: 10.1016/s0140-6736(79)90340-4. [DOI] [PubMed] [Google Scholar]
  35. Shearer G. M., Melmon K. L., Weinstein Y., Sela M. Regulation of antibody response by cells expressing histamine receptors. J Exp Med. 1972 Nov 1;136(5):1302–1307. doi: 10.1084/jem.136.5.1302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sladek N. E. Therapeutic efficacy of cyclophosphamide as a function of its metabolism. Cancer Res. 1972 Mar;32(3):535–542. [PubMed] [Google Scholar]
  37. Struck R. F., Kirk M. C., Witt M. H., Laster W. R., Jr Isolation and mass spectral identification of blood metabolites of cyclophosphamide: evidence for phosphoramide mustard as the biologically active metabolite. Biomed Mass Spectrom. 1975 Feb;2(1):46–52. doi: 10.1002/bms.1200020109. [DOI] [PubMed] [Google Scholar]
  38. Yates M. S., Hiley C. R., Roberts P. J., Back D. J., Crawford F. E. Differential effects of hepatic microsomal enzyme inducing agents on liver blood flow. Biochem Pharmacol. 1978;27(22):2617–2621. doi: 10.1016/0006-2952(78)90336-2. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES