Abstract 4416: Pursuing semi-synthetic taxanes as antitumor agents effective against drug-resistant tumors

Abstract

Abstract Despite the renowned success of Paclitaxel (Taxol) in cancer chemotherapy, it suffers from some disadvantages, especially ineffectiveness against drug-resistant tumors. About ten paclitaxel analogues have been evaluated in clinical trials worldwides, however, none of these drug candidates have shown promising results against drug-resistant tumors in clinical trials. Drug resistance, or multidrug resistance (MDR), is a complex phenomenon, in which various physiological or pathological factors are involved. It has been reasoned that targeting a single factor related to MDR may be disappointing. For patients resistant to taxane chemotherapy, overexpression of ABC transporters, especially P-glycoprotein (P-gp), as well as mutations in β-tubulin and/or overexpression of β-III subtype tubulin may account for the drug resistance. So we decided to pursue highly active paclitaxel analogues and simultaneously effective against drug-resistant tumors through targeting multiple factors related to drug resistance. We designed and synthesized some C-2, 7, 10, 13 modified paclitaxel analogues, based on the rationale at the very beginning to improve interactions with its receptor β-tubulin, as well as decrease interactions with P-gp. Those analogues were subjected to evaluations for the ligand-protein interactions with β-tubulin and P-gp, as well as antitumor activities in drug-sensitive and MDR tumor cells and tumor-bearing animal models. On the basis of a comprehensive analysis of the interactions of paclitaxel analogues with tubulin, it was found that ΔG (free energy change) for drug-tubulin binding at different positions is additive to that of the whole molecule, and the optimal modification for one molecule can be predicted from the free energy contributions of different positions. The more interesting observation for the SARs of these paclitaxel analogues is that we discovered the high affinity taxanes, although exhibiting similar dissociation constants to P-gp as paclitaxel, are still active in P-gp overexpressed MDR cells, in contrast to paclitaxel. On the basis of this observation, we reasoned that enhancement of the binding affinity of taxanes to microtubules may counteract the exportation of those molecules by P-gp from MDR tumor cells, thus make those molecules more effective against MDR. In addition, these high affinity taxanes are also effective against drug resistant tumor cells bearing β-tubulin mutations, as well as β-III overexpression tumor cells. One of the high affinity taxanes also showed effectiveness in nude mice exhibiting drug resistance phenotypes. All above results support that seeking for high affinity taxanes may be an promising approach to pursuing novel antitumor agents effective against drug resistance. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4416.