Differential in vitro action of S-12363, a new vinblastine derivative, and of its epimer on microtubule proteins.
The action of two epimers of a new vinblastine derivative that differ in their in vivo antitumor activity and their cytotoxicity was studied in vitro in brain microtubule proteins. These two compounds, called S-12363 and S-12362, could not be distinguished from one another or from other active vinca alkaloids by their ability to prevent microtubule assembly. However, they differed strongly both from one another and from vincristine and vinblastine in their ability to induce the formation of tubulin paracrystals and in the stability of the paracrystals following temperature shifts from 0 degree to 37 degrees C and vice versa. The most potent drug, S-12363, induced considerable tubulin aggregation, which was even more pronounced than that observed in the presence of vincristine. Previous results have shown that S-12363, in contrast to vincristine, induces no neurotoxic effects. This observation is in disagreement with a direct relationship between tubulin aggregation and neurotoxicity.
Wright
M
M
C.N.R.S., Laboratoire de Pharmacologie et de Toxicologie Fondamentales, Toulouse, France.
Garès
M
M
Verdier-Pinard
P
P
Moisand
A
A
Berlion
M
M
Legrand
J J
JJ
Bizzari
J P
JP
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D008854:Microscopy, Electron; D008868:Microtubule Proteins / Q000032:analysis / Q000187:drug effects* / Q000302:isolation & purification / Q000648:ultrastructure; D009391:Nephelometry and Turbidimetry; D012756:Sheep; D013696:Temperature; D014747:Vinblastine / Q000494:pharmacology; D014748:Vinca Alkaloids / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D008868:Microtubule Proteins; D014748:Vinca Alkaloids; C064005:S 12363; D014750:Vincristine; D014747:Vinblastine