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Bleomycin Hydrolase Activity and Cytotoxicity in Human Tumors¹

Departments of Pharmacology [J. S.L., C. J. B.] and Obstetrics and Gynecology [P. E. S.], Yale University School of Medicine, New Haven, Connecticut 05510

A sensitive new method to assay bleomycin (BLM) metabolism was developed using an ion-paired, reverse-phase high-pressure liquid chromatography technique in conjunction with fluorescence detection that allowed levels of BLM less than 20 ng/ml to be detected. The metabolism of bleomycin B₂ in homogenates from benign and malignant human tumors was studied, and all 14 tumors were capable of metabolizing bleomycin to desamidobleomycin B₂. Metabolites other than desamidobleomycin B₂ were not detected. BLM hydrolase activities in individual tumors varied more than 7-fold. The importance of BLM hydrolase in limiting the therapeutic effectiveness of BLM was examined by measuring BLM hydrolase activity and the response of human tumors to BLM in culture. Response to BLM in culture was measured by dissociating human tumors to form single-cell suspensions and exposing the cells to 0.05 or 1 µg/ml of BLM for 1 hr. Colony formation after BLM treatment was determined in soft agar and, when compared to that of untreated cells, varied by more than 100-fold. No correlation was observed, however, between BLM hydrolase activity and response to BLM in soft agar. Thus, human tumors can metabolize BLM, and while BLM hydrolase activity may be important in tumor resistance to the drug, these data suggest that either (a) the enzyme activity in the tumor homogenate does not reflect that in the clonogenic cells or (b) other mechanisms of resistance may be operative.

¹ This research was supported by USPHS CA-28852 and CA-08341 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Yale University, P.O. Box 3333, 333 Cedar St., New Haven, Conn. 06510.

Received 12/28/81. Accepted 7/ 1/82.

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