Cellular pharmacology of doxorubicinol alone and combined with verapamil in pancreatic cancer cell lines.
The cellular accumulation/retention and cytotoxicity of doxorubicinol (DOXOL) were determined in three pancreatic cancer cell lines, which display primary or intrinsic resistance to doxorubicin (DOX). The studies reported here were performed in the presence and in the absence of verapamil, a calcium antagonist which we have previously shown to potentiate the cytotoxicity of DOX in our panel of pancreatic cancer cell lines. The accumulation/retention of DOXOL, as assayed by HPLC, was not enhanced by 6.6 microM verapamil in these cell lines. No aglycone metabolites were detected in any of the cell lines. The DOXOL cytotoxicity was enhanced 2.0 to 2.9-fold in two of the cell lines. The dose-related accumulation of DOX, as compared to that of DOXOL, was 7.5 to 10-fold greater at 0.1 microM, 3.6 to 6.5-fold greater at 1.0 microM, and 1.9 to 2.4-fold greater at 10 microM. In contrast, for two of our more sensitive cell lines, DOX was 25 to 27 times more cytotoxic than DOXOL. The present study suggests that (a) verapamil's effect on the cytotoxicity of DOX is not mediated by changes in the accumulation/retention nor the cytotoxicity of DOXOL; (b) metabolism of DOXOL does not influence its cytotoxicity nor that of DOX; and (c) DOXOL'S lower antitumor potency as compared to DOX cannot be fully explained by differences in intracellular accumulation.
Chang
B K
BK
Department of Medicine, Medical Center, Augusta, Georgia 30910.
Brenner
D E
DE
Gutman
R
R
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D006224:Cricetinae; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000008:administration & dosage*
D004317:Doxorubicin; D014700:Verapamil; C010013:adriamycinol