In vivo sensitization of human lung carcinoma to bleomycin by the cysteine proteinase inhibitor E-64.
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.
Jani
J P
JP
Department of Pharmacology, University of Pittsburgh, School of Medicine, PA.
Mistry
J S
JS
Morris
G
G
Lazo
J S
JS
Sebti
S M
SM
D000818:Animals; D001761:Bleomycin / Q000627:therapeutic use*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D015853:Cysteine Proteinase Inhibitors; D001761:Bleomycin; D007930:Leucine; C024974:E 64