title: Relationship between the cellular accumulation and the cytotoxicity of S12363, a new Vinca alkaloid derivative.
abstract: S12363, a new vinca alkaloid derivative, was considerably more cytotoxic to murine L1210 cells and five human tumor cell lines (HL60, HT-29, COLO 320DM, NCI-H460, and PANC-1) than was vincristine (VCR) or vinblastine (VLB). S 12,363 bound to tubulin in crude extracts from brain or L1210 cells with an affinity similar to that of VLB and VCR (apparent Kd value: 1.1-1.6, 1.2-1.7, and 0.6-0.8 microM, respectively). After 1 h exposure, the accumulation of 20 nM [3H]-S 12,363 by L1210 cells was 4- to 18-fold that of [3H]-VLB and [3H]-VCR, respectively. After the cells had been preloaded for 1 h with the labeled drugs and then incubated for 3 h in drug-free medium, 37%-55% of the [3H]-S 12,363 was retained by the cells vs 36%-47% of the [3H]-VCR and less than 6% of the [3H]-VLB. Similar results were obtained for the five human cell lines tested. The accumulation factors (intracellular vs extracellular concentrations) found for [3H]-S 12,363 (54- to 167-fold) were significantly higher than those observed for [3H]-VCR (5- to 14-fold) or [3H]-VLB (19- to 41-fold). Greater than 90% of the radioactivity extracted from L1210 cells that had been treated with [3H]-S 12,363 was recovered as unmodified drug, demonstrating that [3H]-S 12,363 was not metabolized by these cells. S 12,362, which differs from S 12,363 only in the absolute configuration of the asymmetric carbon atom of its alpha-aminophosphonic side chain, was 300 times less cytotoxic, bound to tubulin with a lower affinity (apparent Kd value, 4.9-9.6 microM), and was neither accumulated nor retained by the cells. Taken together, these results demonstrate that the potency of S 12,363 is due at least in part to its cellular accumulation and retention.
authors.affiliation: Division de Cancérologie Experimentale, Institut de Recherches Servier, Suresnes, France.
authors.forename: A
authors.initials: A
authors.lastname: Pierré
authors.forename: V
authors.initials: V
authors.lastname: Pérez
authors.forename: S
authors.initials: S
authors.lastname: Léonce
authors.forename: J A
authors.initials: JA
authors.lastname: Boutin
authors.forename: D
authors.initials: D
authors.lastname: Saint-Dizier
authors.forename: P
authors.initials: P
authors.lastname: Hautefaye
authors.forename: G
authors.initials: G
authors.lastname: Lavielle
authors.forename: G
authors.initials: G
authors.lastname: Atassi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007939:Leukemia L1210 / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D014316:Tritium; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D014747:Vinblastine / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity; D014748:Vinca Alkaloids / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D014750:Vincristine / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014404:Tubulin; D014748:Vinca Alkaloids; D014316:Tritium; C064005:S 12363; D014750:Vincristine; D014747:Vinblastine