In vivo reversal of doxorubicin resistance by a new tiapamil analog Ro11-2933.
The effectiveness of a calcium antagonist analog Ro11-2933 to modulate doxorubicin (DOX) response in DOX-sensitive (WT) and -resistant (DOXr, 200-fold) cell lines was investigated and compared to verapamil (VP) in vitro and in vivo in rats bearing mammary carcinoma using equivalent nontoxic doses. In vitro exposure to a nontoxic concentration of Ro11-2933 (2 microM) normalizes the DOX accumulation defect observed in DOXr cells, increases DOX-induced DNA single-strand breaks and effectively sensitizes DOXr cells to DOX. Ten microM VP was required to obtain an effect equivalent to that seen with 2 microM Ro11-2933. Intravenous administration of DOX at 5 mg/kg to the rat bearing the DOXr tumors has no significant therapeutic effect on tumor growth (P > .5), whereas it was found effective in inhibiting the growth of WT tumors (P < .05). Ro11-2933 or VP administered alone has no significant effect on tumor growth as compared to a saline-treated group (P > .1). Combination of Ro11-2933 with DOX effectively inhibits DOXr tumor growth as compared to DOX alone. Combination of DOX with VP was found less effective than Ro11-2933 and the results were not statistically significant from DOX treatment alone (P > .5). Our data demonstrate that Ro11-2933 is well tolerated after i.v. administration and an effective modulator of DOX resistance in a solid tumor model.
Alaoui-Jamali
M A
MA
Department of Medicine, Montreal General Hospital Research Institute, Canada.
Schecter
R L
RL
Rustum
Y M
YM
Centurioni
M G
MG
Lehnert
S
S
Batist
G
G
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D011437:Propylamines; D004317:Doxorubicin; C054970:Ro 11-2933; D014700:Verapamil