In vitro and in vivo effects of clinically important camptothecin analogues on multidrug-resistant cells.
The cytotoxic alkaloid camptothecin (CPT) and several of its analogues, including the clinically relevant topotecan (TPT), irinotecan (CPT-11), and 9-aminocamptothecin, were evaluated for differential cytotoxic effect and DNA damage induction in multidrug-sensitive (AuxB1) and multidrug-resistant (MDR) (CHRC5) Chinese hamster ovary cells. CPT, 10-hydroxycamptothecin, and 10,11-methylenedioxycamptothecin produced equivalent amounts of cell growth inhibition and/or DNA single-strand breakage in the two cell lines. TPT, SN-38 (the active metabolite of CPT-11), and 9-aminocamptothecin were 12-, 9-, and 10-fold, respectively, less toxic to the MDR than to the wild-type cells. These findings are consistent with differences in yields of DNA single-strand breaks produced in AuxB1 and CHRC5 cells by 2-hr incubations with the various compounds. In both assays, the resistance ratios of the topoisomerase I inhibitors were approximately one-tenth those of known MDR drugs such as vinblastine or amsacrine. Thus, cultured cells that overexpress P-glycoprotein have the potential to develop some level of cross-resistance to all three topoisomerase I inhibitors currently in the clinic. The chemical basis for cross-resistance of cultured MDR cell lines to certain CPT analogues is not yet understood, but is likely more complex than positive charge alone. TPT had a reasonable therapeutic effect on B6D2F1 female mice implanted with MDR sublines of P388 leukemia, compared with its effect on mice implanted with wild-type P388 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Mattern
M R
MR
Department of Biomolecular Discovery, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Hofmann
G A
GA
Polsky
R M
RM
Funk
L R
LR
McCabe
F L
FL
Johnson
R K
RK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016466:CHO Cells; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004249:DNA Damage; D004351:Drug Resistance; D005260:Female; D000077146:Irinotecan; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D019772:Topotecan
D000970:Antineoplastic Agents; C080125:9-aminocamptothecin; D000077146:Irinotecan; D019772:Topotecan; D002166:Camptothecin