Effect of the tiapamil analog RO11-2933 on cellular sensitivity to antitumor drugs in sensitive and multidrug resistant human ovarian cancer cells.
The ability of the Tiapamil analog N-(3,4 Dimethoxyphenyl)-N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrocloride (RO11-2933) to influence the cytotoxic activity of Doxorubicin (DX) and seven other antitumor agents was evaluated in sensitive and treatment-induced multidrug resistant human ovarian cancer cells. In vitro treatment of A2780 sensitive cells with 1 microM RO11-2933 for 72hr potentiated by less than 3-fold the cytotoxic effects of each antitumor drug tested, with the exception of Cisplatin and Fluorouracil, which were potentiated by 7.2- and 5.0-fold, respectively. In A2780-DX3 resistant cells, RO11-2933 increased by a mean of 50-fold the cytotoxic effects of the anthracyclines and the Vinka alkaloids analyzed. A potentiation of Cisplatin activity was also observed (6.5-fold), whereas the Tiapamil analog did not significantly modify the antiproliferative activity of Bleomycin, Fluorouracil or Ara-C. Analysis of DX uptake and retention showed that in resistant cells RO11-2933 restored the intracellular DX content to levels comparable to those of sensitive A2780 cells, suggesting that the cytoplasmic membrane might represent a possible site of action of this compound. The results obtained indicate that RO11-2933 might represent an effective agent in combination with several anticancer drugs for the treatment of drug resistant ovarian carcinomas.
Mazzoni
A
A
Department of Pharmacology, National Institute for Cancer Research, Genoa, Italy.
Trave
F
F
Canti
G
G
Franco
P
P
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001692:Biological Transport; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011437:Propylamines / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D011437:Propylamines; C054970:Ro 11-2933