Metabolic inactivation: a mechanism of human tumor resistance to bleomycin.
The mechanism of human tumor resistance to the antineoplastic drug bleomycin (BLM) is not known. We now provide evidence implicating metabolic inactivation in the resistance of human Burkitt's (Daudi) lymphoma to BLM. Daudi lymphoma and human head and neck squamous cell carcinoma (A-253) cells grown (s.c.) in nude mice were found to be resistant and sensitive to BLM treatment, respectively. Within 1 h of s.c. injection of [3H]BLM A2, Daudi xenografts accumulated less BLM and metabolized this drug to a much greater extent than did A-253 xenografts. The BLM-resistant Daudi xenografts metabolized BLM A2 to at least 6 metabolites and only a small proportion of the drug remained as unmetabolized BLM A2. In the BLM-sensitive A-253 xenografts, however, BLM A2 remained the major component. Incubation of BLM A2 with Daudi cytosolic fractions resulted in a complex mixture of metabolites similar to that formed by Daudi xenografts in nude mice. This BLM metabolite mixture was biologically inactive in plasmid DNA degradation assays. Treatment of mice bearing Daudi xenografts with an inhibitor of BLM hydrolase, L-trans-epoxysuccinyl-leucylamido-(4-guanidino)butane (E-64), prior to [3H]BLM A2 treatment did not affect the amount of BLM accumulated but inhibited BLM A2 metabolism in the xenografts. Furthermore, although E-64 alone did not inhibit the growth of Daudi xenografts, it potentiated the antitumor activity of BLM. These results indicate that Daudi tumors resist BLM by metabolically inactivating it and that inhibition of BLM metabolism in vivo enhances the antitumor activity of BLM and hence overcomes resistance.
Sebti
S M
SM
Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Jani
J P
JP
Mistry
J S
JS
Gorelik
E
E
Lazo
J S
JS
D000818:Animals; D001761:Bleomycin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000188:drug therapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D004351:Drug Resistance; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D008658:Inactivation, Metabolic; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015853:Cysteine Proteinase Inhibitors; D001761:Bleomycin; D006026:Glycoside Hydrolases; D003546:Cysteine Endopeptidases; C031262:bleomycin hydrolase; D007930:Leucine; C024974:E 64