The Mode of Action of Vinca Alkaloids

Abstract

P388 leukemia-bearing mice were given a single i.p. injection of [¹⁴C]-vincristine and the levels of radioactivity in the tumors and host tissues were determined as a function of time. The highest levels of radioactivity were found in the gallbladder followed by the tumor, spleen and liver, respectively. 24 h after drug administration the tumor contains 5.8% of the radioactivity detected in the tumor 1 h after drug administration. The tumor thus does not retain the alkaloid for a long period of time. At subcellular level tubulin was found to bind the highest amount of the alkaloid, followed by the fraction containing Golgi and plasma membranes. P388 tumor sensitive to vincristine (VCR) and formyl-leurosine (F-leu) incorporates three times more VCR and four times more F-leu than the resistant line of the same tumor. The different drug uptake as well as the different Vinca alkaloid binding capacity of membrane fractions of the sensitive and resistant P388 leukemias suggests that the composition and/or the structure of the cell membrane has changed in the resistant line. Vinca alkaloid-induced cell cycle changes were evaluated by cytophotometry. The cytotoxic effect of Vinca alkaloids does not correlate with their ability to arrest cells in metaphase. Multinuclear cells showing higher ploidy could be detected in the later phase of the treatment; these cells are the representatives of the surviving population. Selective killing of G₁ cells is supposed to be a possible way of the cytotoxic action of Vinca alkaloids.