Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

H2-Antagonists and carmustine

  • 31 Accesses

  • 3 Citations

Summary

The highly metabolized nitrosourea carmustine (BCNU) is an anticancer agent which alkylates DNA and is metabolized to both active and inactive species by cytochrome P-450 enzymes. Other highly metabolized anticancer drugs have altered toxicities when some histamine H2 antagonists are coadministered. To test this hypothesis with BCNU, DBA/2J male mice were given a single injection of cimetidine (CMT 100 mg/kg) or ranitidine (RNT 25 mg) at various times up to 30 min before, or up to 60 min after a BCNU injection. Spleen colony assays for normal bone marrow stem cell viability showed enhanced toxicity for BCNU when CMT was administered concomitantly. In P-388 leukemia-bearing DBA/2J mice, both CMT and RNT significantly enhanced the antitumor effects of BCNU doses of 30 mg/kg. Pharmacokinetic analyses of BCNU elimination in Cd-1 mice showed marked prolongation of BCNU elimination and increased (BCNU concentration) x time products when CMT was concomitantly administered. These results demonstrate that enhanced BCNU bone marrow toxicity and antitumor activity is produced by CMT. The effect appears to be related to impaired drug clearance when the two agents are administered concurrently. RNT slightly enhanced BCNU antileukemic effects, but it did not significantly alter BCNU myelotoxicity nor drug elimination patterns.

This is a preview of subscription content, log in to check access.

References

  1. Bruce WR, Meeker BE, Valeriote FA (1966) Comparison of the sensitivity of normal hematopoietic and transplanted lymphoma colony-forming cells to chemotherapeutic agents administered in vivo. J Natl Cancer Inst 37:233–245

  2. DeVita VT, Carbone PP, Owens AB, Gold GL, Krant MJ, Edmonson J (1965) Clinical trials with 1,3-bis(2-chloroethyl)-1-nitrosourea, NSC-409962. Cancer Res 25:1876–1881

  3. Dixon WJ, Massey FJ (1969) Introduction to statistical analysis. McGraw-Hill, New York

  4. Dorr RT, Soble MJ, Alberts DS (1986) Interaction of cimetidine but not ranitidine with cyclophosphamide in mice. Cancer Res 46:1795–1799

  5. Feely J, Wilkinson GR, Wood AJ (1981) Reduction of liver blood flow and propronolol metabolism by cimetidine. N Engl J Med 304:692–695

  6. Henner WD, Peters WP, Eder JP, Antman K, Schnipper L, Frei E III (1986) Pharmacokinetics and immediate effects of high-dose carmustine in man. Cancer Treat Rep 70:877–880

  7. Hess WA, Kornblith PL (1985) Combination of lomustine and cimetidine in the treatment of a patient with malignant glioblastoma: a case report. Cancer Treat Rep 69:733

  8. Hill DL, Kirk MC, Struck RF (1975) Microsomal metabolism of nitrosoureas. Cancer Res 35:296–301

  9. Jackson JE, Powell JR, Wandell M, Bentley J, Dorr R (1981) Cimetidine decrease theophylline clearance. Am Rev Respir Dis 123:615–617

  10. Kann HE Jr (1981) Carbamoylating activity of nitrosoureas. In: Prestayko AW et al. (eds) Nitrosoureas: current status and new development. Academic Press, New York, pp 95–105

  11. Kann HE Jr, Kohn KW, Lyles JM (1974) Inhibition of DNA repair by the 1,3-bis(2-chloroethyl)-1-nitrosourea breakdown product, 2-chloroethyl isocyanate. Cancer Res 34:398–402

  12. Klotz U, Reimann I (1980) Delayed clearance of diazepam due to cimetidine. N Engl J Med 302:1012–1014

  13. Klubes P, Miller HG, Cerna I, Trevithick J (1979) Alterations in the toxicity and antitumor activity of methyl-CCNU in mice following pretreatment with either phenobarbital or SKF 525A. Cancer Treat Rep 63:1901–1907

  14. Kohn KW (1977) Interstrand cross-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitrosoureas. Cancer Res 37:1450–1454

  15. Levin VA (1981) Chemotherapy of recurrent brain tumors. In: Prestayko AW, Crooke ST, Baker LH, Carter SK, Schein PS (eds) Nitrosoureas: current status and new development. Academic Press, New York, pp 259–268

  16. Levin VA, Hoffman W, Weinkam RJ (1978) Pharmacokinetics of BCNU in man: a preliminary study of 20 patients. Cancer Treat Rep 62:1305–1312

  17. Levin VA, Stearns J, Byrd A, Finn A, Weinkam RJ (1979) The effect of phenobarbital pretreatment on the antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperdyl-1-nitrosourea (PCNU), and on the plasma pharmacokinetics and biotransformation of BCNU. J Pharmacol Exper Ther 208:1–6

  18. Loo TL, Dion RL (1965) Colorimetric method for the determination of 1,3-bis(2-chloroethyl)-1-nitrosourea. J Pharm Sci 55:492–497

  19. Loo TL, Dion RL, Dixon RL, Rall DP (1966) The antitumor agent, 1,3-bis(2-chloroethyl)-1-nitrosourea. J Pharm Sci 55:492–497

  20. Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170

  21. Marsh JC, DeConti RC, Hubbard SP (1971) Treatment of Hodgkin's disease and other cancers with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU-NSC-409962). Cancer Chemother Rep 55:599–606

  22. Metzler CM, Elfring GL, McEwen AJ (1974) A package of computer programs for pharmacokinetic modeling. Biometrics 30:512–513

  23. Osband ME, Shen Y-J, Shlesinger M, Brown A, Hamilton D, Cohen E, Lavin P, McCaffrey R (1981) Successful immunotherapy with cimetidine in mice. Lancet I:636–638

  24. Reed DJ, May HE (1978) Cytochrome P-450 interactions with the 2-chloroethyl-nitrosoureas and procarbazine. Biochimie (Paris) 60:989–999

  25. Salmon SE (1976) Nitrosoureas in multiple myeloma. Cancer Treat Rep 60:789–794

  26. Selker RG, Moore P, LoDolce D (1978) Bone marrow depression with cimetidine plus carmustine. N Engl J Med 299:834 (letter)

  27. Till JE, McCullock EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–223

  28. Volkin RL, Shadduck RK, Winkelstein A, Zeigler ZR, Selker RG (1982) Potentiation of carmustine-cranial irradiation-induced myelosuppression by cimetidine. Arch Intern Med 142:243–245

  29. Weiss RB, Issell BF (1982) The nitrosoureas: carmustine (BCNU) and lomustine (CCNU). Cancer Treat Rev 9:313–330

  30. Winzor DJ, Ioannoni B, Reilly PE (1986) The nature of microsomal monooxygenase inhibition by cimetidine. Biochem Pharmacol 35:2157–2161

  31. Young RC, DeVita VT Jr, Serpick AA, Canellos GP (1971) Treatment of advanced Hodgkin's disease with 1,3-bis(2-chloroethyl)-1-nitrosourea BCNU. N Engl J Med 285:475–479

Download references

Author information

Correspondence to R. T. Dorr.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dorr, R.T., Soble, M.J. H2-Antagonists and carmustine. J Cancer Res Clin Oncol 115, 41–46 (1989). https://doi.org/10.1007/BF00391598

Download citation

Key words

  • Carmustine
  • BCNU
  • H2 Antagonists
  • Cimetidine
  • Rantidine