ISSN:
1432-0843
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary S 12363, 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 12363 bound to tubulin in crude extracts from brain or L1210 cells with an affinity similar to that of VLB and VCR (apparentK d value: 1.1–1.6, 1.2–1.7, and 0.6–0.8 μM, respectively). After 1 h exposure, the accumulation of 20 nM [3H]-S 12363 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 12363 was retained by the cells vs 36%–47% of the [3H]-VCR and 〈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 12363 (54- to 167-fold) were significantly higher than those observed for [3H]-VCR (5- to 14-fold) or [3H]-VLB (19- to 41-fold). 〉90% of the radioactivity extracted from L1210 cells that had been treated with [3H]-S 12363 was recovered as unmodified drug, demonstrating that [3H]-S 12363 was not metabolized by these cells. S 12362, which differs from S 12363 only in the absolute configuration of the asymmetric carbon atom of its α-aminophosphonic side chain, was 300 times less cytotoxie, bound to tubulin with a lower affinity (apparentK d value, 4.9–9.6 μm), and was neither accumulated nor retained by the cells. Taken together, these results demonstrate that the potency of S 12363 is due at least in part to its cellular accumulation and retention.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00686005
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