In vivo sensitization of human lung carcinoma to bleomycin by the cysteine proteinase inhibitor E-64.
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| Abstract |
We recently demonstrated that the cysteine proteinase inhibitor, E-64, sensitizes human Burkitt's lymphoma (Daudi) to the antitumor action of bleomycin (BLM) by blocking its metabolism. We now report that E-64 sensitizes the BLM resistant human lung carcinoma A-549 by a mechanism unrelated to the inhibition of BLM metabolism. Treatment of A-549 tumor-bearing nude mice with either BLM (10 mg/kg) or E-64 (40 mg/kg) every other day for 10 days did not inhibit tumor growth. However, a 30 min pretreatment with E-64 prior to BLM caused complete and sustained inhibition of tumor growth. In contrast to our results with Burkitt's lymphoma, E-64 did not inhibit BLM metabolism but rather enhanced the tumor accumulation of BLM; within 10 min of BLM administration, tumors from E-64 pretreated mice showed a 6-fold higher accumulation of BLM A2 compared to non-pretreated xenografts. Furthermore, the level of tumor-associated BLM A2 remained 2-fold higher in E-64 pretreated mice 20 and 30 min after BLM administration. In E-64 pretreated mice, the plasma level of BLM was increased by 2-fold. These results demonstrate that the cysteine proteinase inhibitor, E-64, sensitized human lung carcinoma A-549 to BLM and, contrary to the expected mechanism, this effect of E-64 was not related to the inhibition of BLM metabolism.
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| Authors | J P Jani, J S Mistry, G Morris, J S Lazo, S M Sebti |
| Journal | Oncology research (Oncol Res) Vol. 4 Issue 2 Pg. 59-63 ( 1992) ISSN: 0965-0407 [Print] United States |
| PMID | 1375852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.) |
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