The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice

We have evaluated two synthetic epothilone analogues lacking the 12,13-epox ide functionality, 12,13-desoxyepothilone B (dEpoB), and 12,13-desoxyepothi lone F (dEpoF). The concentrations required for 50% growth inhibition (IC50 ) for a variety of anticancer agents were measured in CCRF-CEM/VBL1000 cell s (2,048-fold resistance to vinblastine). By using dEpoB, dEpoF, aza-EpoB, and paclitaxel, the IC50 values were 0.029, 0.092, 2.99, and 5.17 muM, resp ectively. These values represent 4-, 33.5-, 1,423- and 3.133-fold resistanc e, respectively, when compared with the corresponding IC50 in the parent [n onmultiple drug-resistant (MDR)] CCRF-CEM cells. We then produced MDR human lung carcinoma A549 cells by continuous exposure of the tumor cells to sub lethal concentrations of dEpoB (1.8 yr), vinblastine (1.2 yr), and paclitax el (1.8 yr). This continued exposure led to the development of 2.1-, 4,848- , and 2,553-fold resistance to each drug, respectively. The therapeutic eff ect of dEpoB and paclitaxel was also compared in vivo in a mouse model by u sing various tumor xenografts. dEpoB is much more effective in reducing tum or sizes in ail MDR tumors tested. Analysis of dEpoF, an analog possessing greater aqueous solubility than dEpoB, showed curative effects similar to d EpoB against K562, CCRF-CEM, and MX-1 xenografts. These results indicate th at dEpoB and dEpoF are efficacious antitumor agents with both a broad chemo therapeutic spectrum and wide safety margins.