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Anti-proliferative activity of a new class of taxanes (14β-hydroxy-10-deacetylbaccatin III derivatives) on multidrug-resistance-positive human cancer cells
Authors:Mariagrazia Distefano  Giovanni Scambia  Cristiano Ferlini  Cristiana Gaggini  Rosa De Vincenzo  Antonella Riva  Ezio Bombardelli  Iwao Ojima  Andrea Fattorossi  Pierluigi Benedetti Panici  Salvatore Mancuso
Abstract:Paclitaxel, docetaxel and a series of new analogs synthesized from 14β-hydroxy-10-deacetylbaccatin III (14-OH-DAB), a natural diterpene closely related to the core synthon of the 2 above prototypes, were tested in vitro for their growth-inhibitory activity on different human cancer cell lines, including some expressing the classic multidrug-resistant (MDR) phenotype (MCF-7 ADRr and CEM VBLr). The 14-OH-DAB derivatives showed enhanced anti-proliferative activity as compared to the parent compounds on the MDR-positive cancer cell lines. Particularly, IDN 5109 showed a 25- to 30-fold higher activity than paclitaxel. The fold change in activity between paclitaxel and analogs (IC50 paclitaxel/IC50 analogs) on the MDR-positive cell lines was calculated and a significant correlation observed. As far as the MDR-negative MDA-MB 231 cells are concerned, docetaxel and IDN 5109 exhibited a more potent activity than paclitaxel. On the basis of the data obtained on cell growth inhibition, we selected the most active compounds to study their effect on the cell cycle. Cell cycle analysis showed that all of the compounds tested were able to induce cell cycle block at G2/M in a concentration-dependent manner. The amount of cell block, measured as a G1/G2 ratio, was correlated significantly (p < 0.001) with apoptosis, as evaluated in the sub-G1 region (% of DNA fragmentation), thereby suggesting that the G2/M-blocked cells underwent apoptosis. To confirm the occurrence of apoptosis in this system, DNA gel agarose electrophoresis was performed and showed the typical ladder pattern. Int. J. Cancer 72:844–850, 1997. © 1997 Wiley-Liss, Inc.
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