Metabolic inactivation : a mechanism of human tumor resistance to bleomycin

• Published in: Cancer research (Chicago, Ill.) Vol. 51; no. 1; pp. 227 - 232
• Main Authors: SEBTI, S. M, JANI, J. P, MISTRY, J. S, GORELIK, E, LAZO, J. S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 1991
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Bleomycin - metabolism; Bleomycin - pharmacokinetics; Bleomycin - pharmacology; Burkitt Lymphoma - drug therapy; Carcinoma, Squamous Cell - drug therapy; Chemotherapy; Chromatography, High Pressure Liquid; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors - pharmacology; DNA Damage; Drug Resistance; Glycoside Hydrolases - antagonists & inhibitors; Head and Neck Neoplasms - drug therapy; Humans; Inactivation, Metabolic; Leucine - analogs & derivatives; Leucine - pharmacology; Medical sciences; Mice; Mice, Nude; Neoplasm Transplantation; Pharmacology. Drug treatments; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Therapeutic efficiency; Squamous cell carcinoma; Rodentia; Cytotoxicity; Malignant hemopathy; Malignant tumor; Lymphoma; Activity metabolism relation; Resistance; Vertebrata; Antibiotic; Chemotherapy; Experimental disease; Mammalia; Sensitivity resistance; Treatment; Mouse; Animal; Metabolic inactivation; Head and neck; ENT disease; Subcutaneous administration; Mechanism of action
• ISSN: 0008-5472; 1538-7445

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.