MODULATION OF THIOTEPA ANTITUMOR-ACTIVITY IN-VIVO BY ALTERATION OF LIVER CYTOCHROME P450-CATALYZED DRUG-METABOLISM

The anticancer drug and alkylating agent thiotepa is metabolized by ox idative desulfuration to yield the alkylating metabolite N,N',N ''-tri ethylenephosphoramide (TEPA) in a reaction that is catalyzed by specif ic liver cytochrome P450 (CYP) enzymes, including CYP2B1, the major ph enobarbital-inducible P450 of rat liver, and CYP2C11, a constitutively expressed, male-specific form. The present study investigates the pot ential for modulating the cytotoxicity and antitumor activity of thiot epa by prior treatment of tumor-bearing rats with the CYP2B1 inducer p henobarbital or the CYP2C11 inhibitor 2-diethylaminoethyl-2,2-diphenyl valerate hydrochloride (SKF-525A) and examines the role of TEPA in the cytotoxicity of thiotepa in vivo. Administration of thiotepa to adult male rats bearing 9L gliosarcoma, grown s.c., resulted in dose-depend ent cytotoxicity (ED(90) similar to 12 mg/kg i.v., single dose), as de termined by a tumor excision/in vitro colony formation assay carried o ut 24 hr after drug treatment. Tumor growth delay experiments revealed that thiotepa (5 mg/kg) inhibited 9L tumor growth over a 5- to 7-day period after alkylating agent treatment and this effect was accompanie d by moderate body weight loss. Pretreatment with phenobarbital, under conditions in which liver CYP2B1 levels and liver microsomal thiotepa desulfuration to yield TEPA are both markedly increased, did not alte r thiotepa's short-term (24-hr) cytotoxicity, as judged by a tumor exc ision assay, nor did it affect the extent of bone marrow toxicity asso ciated with drug treatment. However, phenobarbital did block the tumor growth delay effect of thiotepa and it also attenuated the body weigh t loss that occurred during the first 5 days after drug treatment. In contrast, pretreatment with the liver P450 inhibitor 2-diethylaminoeth yl-2,2-diphenylvalerate hydrochloride (40 mg/kg i.p. given 1 hr before thiotepa) inhibited thiotepa elimination in vivo and enhanced the ant itumor activity of thiotepa but this was accompanied by increased body weight loss and some lethality. These findings demonstrate that alter ations in the in vivo antitumor activity and host toxicity of thiotepa can be achieved by modulation of hepatic CYP-dependent thiotepa metab olism and suggest that thiotepa may be more toxic toward this tumor in vivo than TEPA or other metabolites formed by the oxidative desulfura tion pathway.