Cimetidine enhancement of cyclophosphamide antitumour activity

Abstract

Summary.-Male DBA2 mice were given 106 P-388 leukaemic cells i.p. and cimetidine (CMT) at 100 mg/kg 1 day for 10 days, or as a single 100mg/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 <0-05), 10 days (P <0.05) and 13 days (P < 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.

Cimetidine and Coumarin Therapy of Renal Cell Carcinoma

“…A series of reports describe regressions induced by immunologic methods in clinical trials (BCG, im mune RNA, autologous tumour cells, polymerized antigen with adjuvant, interferons and others) [13]. Cimetidine, widely used as an anti-ulcer agent, is known to affect H2 receptors on the surface of various target cells [6,19], It has been shown to enhance mitogen responsiveness of human lymphocytes [10], enhance skin test reactivity to a number of antigens [1], to stimulate antibody synthesis [2,7,8], and to extend life of tumour-bearing animals [11], Dorr and Alberts [5] found that cimetidine could enhance cyclo phosphamide antitumour activity. In 1981, successful immunotherapy of tumours in mice with cimetidine, associated with a decrease in suppressor cell levels was reported [17].…”

Histamine receptor antagonism and anti-tumour activity

“…However, unlike Dorr & Alberts (1982), we were unable to demonstrate any enhancement of cyclophosphamide antitumour activity by cimetidine, and this discrepancy may be attributed to the use of a different tumour system, or the fact that Dorr & Alberts administered the drug i.p. directly to the site of the tumour.…”

“…Although the mechanism of H2-receptor involvement in anti-tumour drug activity remains obscure, Gifford et al (1981) and Osband et al (1981) have suggested inhibition of suppressor-cell function by cimetidine, while Dorr & Alberts (1982) explain their results through an interference with the microsomal metabolism of compounds utilizing the P450 system as previously suggested by Pelkonen & Puurunen (1979, 1980, or via a change in liver blood flow as demonstrated for cimetidine by Feely et al (1981).…”

“…Firstly there was the chance observation by Armitage & Sidner (1979) Early studies with H2-receptor antagonists revealed no significant interactions with other compounds (Lesley & Walker, 1977), but a number of reports have now appeared suggesting that the H2-receptor antagonist, cimetidine, significantly interferes with the action of other drugs. These include the anticoagulants (Serlin et al, 1979), the methylxanthines (Desmond et al, 1980b), minor tranquillizers (Desmond et al, 1980a;Klotz et al, 1979) and the barbiturates (Pelkonen & Puurunen, 1980;Dorr & Alberts, 1982).…”

The influence of cimetidine on the pharmacokinetics of 5‐fluorouracil.

“…In addition animal studies have shown that cimetidine can enhance the antitumour activity of cyclophosphamide approximately two-fold (Dorr & Alberts, 1982), an effect presumed to be due to greater concentrations of active metabolites. Increased plasma concentrations of drugs given with cimetidine have been attributed to both inhibition of hepatic microsomal metabolism (Henry et al, 1981; Time (min) Figure 6 Mean plasma concentrations of 5FU following oral administration before (o *) and after (0oo) cimetidine for 4 weeks.…”