H2-antagonists and carmustine

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....

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Bibliographic Details
Published in:Journal of cancer research and clinical oncology 1989-02, Vol.115 (1), p.41-46
Main Authors: DORR, R. T, SOBLE, M. J
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Bone Marrow - drug effects
Carmustine - administration & dosage
Carmustine - therapeutic use
Carmustine - toxicity
Cimetidine - administration & dosage
Drug Synergism
General aspects
Histamine H2 Antagonists - administration & dosage
Leukemia P388 - drug therapy
Leukemia, Experimental - drug therapy
Male
Medical sciences
Mice
Mice, Inbred DBA
Pharmacology. Drug treatments
Ranitidine - administration & dosage
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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.
ISSN:0171-5216
1432-1335
DOI:10.1007/BF00391598