The
taxanes,
paclitaxel (PTX) and
docetaxel (DTX), belong to a novel class of anticancer drugs that stabilize microtubules and lead to
tumor cell death. While both agents are widely used for the treatment of lung, breast, and
ovarian cancer, many
tumor types are refractory or develop resistance to these drugs. We describe here a novel analogue of DTX, designated
MAC-321 [Microtubule/Apoptosis/Cytotoxic: 5beta, 20-epoxy-1, 2alpha-, 4-, 7beta-, 10beta-, 13alpha-hexahydroxytax-11-en-9-one 4
acetate 2
benzoate 7-propionate 13-ester with (2R,3S)-N-tertbutoxycarbonyl-3-(2-furyl)
isoserine], that overcomes
P-glycoprotein-mediated resistance to PTX and DTX in preclinical model systems. Similar to PTX or DTX,
MAC-321 enhanced the rate of
tubulin polymerization in vitro and caused the bundling of microtubules in cells.
MAC-321 inhibited proliferation of a panel of 14 tumor cell lines with minimal variation in potency (IC(50) = 2.2 +/- 1.4 nM; range = 0.6-5.3 nM). Unlike PTX or DTX, the IC(50) of
MAC-321 did not vary in cells that expressed low to moderate levels of
P-glycoprotein. Even under extraordinary conditions in KB-V1 cells, which highly overexpress
P-glycoprotein, resistance to
MAC-321 was 80-fold compared with that of PTX (1400-fold) and DTX (670-fold). In addition, equivalent or less resistance to
MAC-321 compared with PTX or DTX was observed in four cell lines that contain distinct point mutations within the
taxane-binding site of
beta-tubulin. Most importantly,
MAC-321 displayed superior in vivo efficacy because: (a)
MAC-321 either partially or completely inhibited
tumor growth in three
tumor models that overexpressed
P-glycoprotein and were resistant to PTX; and (b) unlike PTX or DTX,
MAC-321 was highly effective when given orally.
MAC-321 was also highly effective when given as single i.v. dose. Our findings suggest that
MAC-321, which is currently under clinical evaluation, may have broad therapeutic value.