title: Evaluation of the time-schedule dependency for the cytotoxic activity of the new vinca alkaloid derivative, S 12363 (vinfosiltine).
abstract: S 12363 is a new vinca alkaloid derivative obtained by appending an optically active alpha-aminophosphonate at the C23 position of 04-deacetyl vinblastine. The present study concerns four different human tumour cell lines, which represent the spectrum of vinca alkaloid clinical activity. The influence of time exposure on S 12363 growth inhibition was studied in vitro. Cells were exposed to the drug during the following exposure times: 5, 15, 30 min and 1, 3, 6, 12, 24, 48, 72, 144 h. The concentrations of S 12363 applied were between 1 x 10(-2) and 1 x 10(3) nmol/l. The cytotoxic effects were assessed by using the methyltetrazolium (MTT) semi-automated test. Considering the IC50 values in terms of concentration (C) x time (T), I (C x T)50, it was shown that for an equal growth inhibitory effect (50% of cell death) the increased exposure times required higher cumulative drug exposures. More precisely, only very long exposure (greater than 24 h) resulted in very high I (C x T)50. The drug exposure ratios which correspond to I (C x T)50 values for 144 h divided by the I (C x T)50 values for 0.25 h ranged between 2.8 and 18.3. If T and C had symmetrical effects on the final growth inhibition, the I (C x T)50 ratios should have been equal to one. For all cell lines investigated there were similar dose-response curves following two types of S12363 exposure: a single day exposure or three successive daily exposures, the total C x T values being the same in both experimental situations. The basic pharmacological information provided by the present study may encourage further clinical trials of this potentially interesting new vinca alkaloid.
authors.affiliation: Centre A. Lacassagne, Nice, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Fischel
authors.forename: M
authors.initials: M
authors.lastname: Berlion
authors.forename: P
authors.initials: P
authors.lastname: Formento
authors.forename: J P
authors.initials: JP
authors.lastname: Bizzari
authors.forename: G
authors.initials: G
authors.lastname: Milano
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D014748:Vinca Alkaloids / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014748:Vinca Alkaloids; C064005:S 12363