Characterization of the pharmacological antitumor effects of S 12363, a new vinca alkaloid.
S 12363 is a new highly potent vinca alkaloid derivative characterized by the grafting of an a-aminophosphonate, bioisoster of the valine, at the C23 position of O4-deacetyl vinblastine. Using a cell image processor Samba 200 (System for Analytical Microscopic Biomedical Applications), we have studied the effect of S 12363 on cell proliferation of four mammary (MXT, MCF-7, T47-D and MDA-MB231) and two melanoma (HBL and DRD 3) tumor cell lines, and on cell cycle kinetic parameters on human T47-D and HBL tumor cell lines. S 12363 significantly inhibited the growth of these 6 tumor cell lines in a time- and concentration-dependent manner. Three concentrations were tested for 24, 48, 72 and 96 hours incubation times. The human breast T47-D, MCF-7 and melanoma DRD3 and HBL tumor cells were the most sensitive to S 12363. This compound was effective at all doses tested (0.1, 1 and 10 ng/ml) after at least a 24 hour incubation period. The murine MXT and human MDA-MB231 tumor cells were about 10 fold less sensitive than the other cell lines. S 12363 disturbed the cell cycle of T47-D and HBL cell lines and induced a significant accumulation of cells in the G2 + M phases to the detriment of the G0 + G1 phases. The antitumor activity of S 12363 was confirmed in vivo on 2 disseminated murine tumor models, i.e. P388 leukemia implanted subcutaneously and M5076 reticulum-cell sarcoma inoculated intraperitoneally. S 12363 was at least as active as reference compounds vinblastine or vincristine with active doses 5 to 20 times lower.
Atassi
G
G
Université Libre de Bruxelles, Laboratoire de Pharmacologie, Bruxelles, Belgium.
Berlion
M
M
el Oche
Y
Y
Bizzari
J P
JP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004341:Drug Evaluation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy*; D008325:Mammary Neoplasms, Experimental; D008545:Melanoma; D051379:Mice; D008815:Mice, Inbred Strains; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D014748:Vinca Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity
D000970:Antineoplastic Agents; D014748:Vinca Alkaloids; C064005:S 12363