Induction of Apoptosis in Mice with B16 Melanoma by Treatment with the Antimicrotubule Agent TZT-1027.

Abstract

TZT-1027, an inhibitor of tubulin polymerization, is a derivative of dolastatin 10 isolated from the Indian Ocean sea hare Dolabella auricularia. TZT-1027 has good anticancer activity. We investigated the effect on B16 melanoma of TZT-1027 in mice histopathologically and by agarose gel electrophoresis. At 1 mg/kg of TZT-1027, there was a good correlation between the number of mitosis-like cells and apoptotic bodies. In mitosis-like cells, the nuclear membrane had disappeared, and the chromosomes had morphological features typical of mitosis. However, not all cells in mitosis had proliferated. In contrast, at 2 mg/kg of TZT-1027, many apoptotic bodies were detected soon after treatment, but these were not involved in the dynamic changes to mitosis-like cells. Furthermore, TUNEL-positive cells were clearly visible at 1 hr after treatment and the nuclei of these cells showed chromatin margination, cap-shape chromatin clamping, and nuclear condensation on electron microscopy. Therefore, we speculated that the effect on B16 melanoma cells of TZT-1027 differed with the treatment dose, and a dose of 2 mg/kg induces apoptosis in tumor cells by a direct mechanism.