Relationship between the cellular accumulation and the cytotoxicity of S12363, a new Vinca alkaloid derivative
| Autor: | Jean A. Boutin, Valérie Pérez, Gilbert Lavielle, Alain Pierré, Patrick Hautefaye, Ghanem Atassi, D. Saint-Dizier, Stéphane Léonce |
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| Rok vydání: | 1992 |
| Předmět: |
Cancer Research
Vinca medicine.drug_class Stereochemistry Biology Toxicology Tritium Vinblastine Binding Competitive Vinca alkaloid Cell Line Tubulin medicine Tumor Cells Cultured Cytotoxic T cell Animals Humans Pharmacology (medical) Leukemia L1210 Vinca Alkaloids Chromatography High Pressure Liquid Pharmacology Alkaloid Brain biology.organism_classification Antineoplastic Agents Phytogenic Oncology Cell culture Vincristine biology.protein L1210 cells medicine.drug Protein Binding |
| Zdroj: | Cancer chemotherapy and pharmacology. 29(5) |
| ISSN: | 0344-5704 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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