title: Pharmacological properties of a new alpha-aminophosphonic acid derivative of vinblastine.
abstract: S 12363 is a new vinca alkaloid derivative obtained by grafting an optically active alpha-aminophosphonate at the C23 position of O4-deacetyl vinblastine. This compound was as potent as Vincristine (VCR), and less potent than Vinblastine (VLB), in inhibiting in vitro tubulin polymerization. However, S 12363 was found to be 7 to 553 and 12 to 74-fold more cytotoxic than VCR and VLB, respectively, when tested on a panel of 2 murine and 6 human tumor cell lines using the Microculture Tetrazolium Assay. S 12362, which differs only by the configuration of the asymmetric carbon atom of the side chain, was 18 to 59-fold less cytotoxic. At equitoxic doses, all these compounds induced a "G2 + M" phase accumulation of L1210 cells, suggesting a similar mechanism of action. S 12363, administered i.p. or i.v., was at least as active as reference compounds on two murine transplantable tumors (P388 leukemia and B16 melanoma) while the optimal dosage was 20-fold lower: 0.15-0.20 mg/kg versus 2-5 mg/kg, respectively. S 12362 was practically inactive at 1-3 mg/kg. The hematological toxicity of S 12363 (0.1 mg/kg) was similar to that of VLB (4 mg/kg). The exceptionally high potency of S 12363 did not appear to be due to a better interaction with tubulin, its intracellular target, but rather to some properties conferred by the alpha-aminophosphonic acid, such as a facilitated uptake and/or a better cellular retention.
authors.affiliation: Institut de Recherches Servier, Suresnes, France.
authors.forename: A
authors.initials: A
authors.lastname: Pierré
authors.forename: G
authors.initials: G
authors.lastname: Lavielle
authors.forename: P
authors.initials: P
authors.lastname: Hautefaye
authors.forename: G
authors.initials: G
authors.lastname: Seurre
authors.forename: S
authors.initials: S
authors.lastname: Leonce
authors.forename: D
authors.initials: D
authors.lastname: Saint-Dizier
authors.forename: J A
authors.initials: JA
authors.lastname: Boutin
authors.forename: C A
authors.initials: CA
authors.lastname: Cudennec
mesh_terms: D000818:Animals; D004285:Dogs; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013237:Stereoisomerism; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000494:pharmacology*
chemical_list: D014404:Tubulin; D014748:Vinca Alkaloids; C064005:S 12363; D014747:Vinblastine