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In Vivo Circumvention of Human Colon Carcinoma Resistance to Bleomycin¹

Department of Pharmacology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261

Metabolic inactivation of bleomycin (BLM) by cysteine proteinaselike enzymes is thought to be a major mechanism of BLM tumor resistance. We now report that the human colon carcinoma COLO-205 is highly resistant to BLM and that E-64, a cysteine proteinase inhibitor, sensitizes COLO-205 to BLM. Treatment of COLO-205-bearing nude mice with either E-64 (40 mg/kg) or BLM (10 mg/kg) alone did not inhibit COLO-205 growth. However, pretreatment with E-64 prior to BLM prevented these xenografts from growing. Analysis by high performance liquid chromatography of in vivo BLM metabolism following [³H]BLM A₂ treatment of COLO-205-bearing nude mice showed a different metabolic profile among the various organs and the tumor. Whereas [³H]BLM A₂ was the only major radioactive peak detected in sera and tumors, several metabolites, including deamido-BLM A₂, were found in kidney, liver, and lung as early as 15 min. Pretreatment of mice with E-64 inhibited tumor, kidney, and lung BLM A₂ metabolism. Furthermore, pretreatment with E-64 increased BLM A₂ accumulation in tumors (6.1-fold), kidney (4.0-fold), lung (2.8-fold), liver (1.8-fold), and serum (1.7-fold). E-64 pretreatment did not enhance the major toxicity of BLM, pulmonary fibrosis, as determined by both lung hydroxyproline levels and histopathology. Thus, the cysteine proteinase inhibitor E-64 affects the metabolic fate and the levels of accumulation of BLM in vivo. These results demonstrate that resistance of human COLO-205 tumors to BLM can be circumvented by E-64 without enhancement of the major side effect of BLM, suggesting a possible clinical use of this combination therapy.

¹ This investigation was supported by American Cancer Society Grants JFRA-248 (S. M. S.) and CH-316 (J. S. L.), NIH Grants CA-48905 (S. M. S.) and CA-43917 (J. S. L.), and NIH Fellowships 1F32-CA-08880 (G. M.) and 1F32-CA-08967 (J. P. J.).

² To whom requests for reprints should be addressed, at Department of Pharmacology, W1354 Biomedical Science Tower, University of Pittsburgh, Pittsburgh, PA 15261.

Received 9/30/91. Accepted 3/11/92.

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