Antitumour activity of novel taxanes that act at the same time as cytotoxic agents and P-glycoprotein inhibitors

Taxanes antitumour agents such as paclitaxel and docetaxel represent a succ essful family of chemotherapeutic drugs. Unfortunately, acquired and innate resistance represents a clinical problem for these drugs. We investigated. on a panel of 7 human cancer cell lines, the growth inhibition effect of 3 newly developed taxanes (SB-T-1213, SB-T-1250 and SB-T-101187) with modifi cation at the C10 and C3' positions of the taxane framework. These position s have been previously characterized as critical to make taxanes highly act ive against cells overexpressing the efflux pump P-glycoprotein (P-gp). Pac litaxel and docetaxel were used as reference compounds. Results unambiguous ly indicate the exceptional activity of the novel taxanes toward P-gp posit ive cells (up to >400 fold higher potency than that of paclitaxel). SB-T- 1 213 and SB-T-1250 are also substantially more active than the reference com pounds against P-gp negative cells. To better understand the mechanisms und erlying the enhanced activity of the newly developed taxanes. we performed cell cycle and apoptosis analysis. This study demonstrates that the strikin g growth inhibition effect exhibited by the novel taxanes is ascribed to th eir increased ability in inducing apoptosis and G(2)/M cell cycle block. SB -T-1213 and SB-T-1250 are also more active than reference compounds in indu cing intracellular accumulation of the beta-tubulin subunits. Finally, it i s revealed that these novel taxanes have ability to inhibit the function of the P-gp efflux pump on the basis of the Rhodamine 123 assay. These findin gs strongly suggest that SB-T-1213, SB-T-1250 and SB-T-101187 represent a n ew tool to overcome innate or acquired P-gp mediated taxane-resistance. (C) 2000 Cancer Research Campaign.