Preclinical Pharmacologic Evaluation of MST-997, an Orally Active Taxane with Superior In vitro and In vivo Efficacy in Paclitaxel- and Docetaxel-Resistant Tumor Models

Abstract

Purpose: Because resistance to paclitaxel and docetaxel is frequently observed in the clinic, new anti-microtubule agents have been sought. The aim of this study was to evaluate the efficacy and oral activity of a novel taxane (MST-997) in paclitaxel-and docetaxel-resistant tumor models in vitro and in vivo. Experimental Design: Tubulin polymerization assays, immunohistochemistry, and cell cycle analysis was used to evaluate mechanism of action of MST-997. The effect of MST-997 on growth inhibition in a panel of paclitaxel-and docetaxel-resistant cell lines that overexpressed P-glycoprotein (MDR1) or harbored h-tubulin mutations were assayed in vitro and in murine xenografts. Results: MST-997 induced microtubule polymerization (EC 50 = 0.9 Amol/L) and bundling, resulting in G 2 -M arrest and apoptosis. In addition, MST-997 was a potent inhibitor of paclitaxeland docetaxel-sensitive tumor cell lines that did not have detectable P-glycoprotein (IC 50 = 1.8 F 1.5 nmol/L). Minimal resistance (1-to 8-fold) to MST-997 was found in cell lines that either overexpressed MDR1 or harbored point mutations in h-tubulin. Most notable, MST-997 displayed superior in vivo efficacy as a single i.v. or p.o. dose either partially or completely inhibited tumor growth in paclitaxel-and docetaxel-resistant xenografts. Conclusions: MST-997 represents a potent and orally active microtubule-stabilizing agent that has greater pharmacologic efficacy in vitro and in vivo than the currently approved taxanes. Our findings suggest that MST-997, which has entered phase I clinical trials, may have broad therapeutic value.

Human Multidrug Resistance Protein 7 (ABCC10) Is a Resistance Factor for Nucleoside Analogues and Epothilone B

“…These agents included the macrolides epothilones A and B (26), the macrocyclic heptapeptide phomopsin (27), the docetaxel analogs MAC-321 and MST-997 (28, 29), and HTI-286, an analog of the tripeptide hemiasterlin (30). Notably, the MRP7-transfected cells exhibited resistance towards epothilone B (5.3 – 6.8-fold; Figure 1D).…”

Antiproliferative and proapoptotic activity of GUT-70 mediated through potent inhibition of Hsp90 in mantle cell lymphoma

“…mt-p53 is known to confer the additional ‘gain of function' as the transcription regulator. Transcriptional activation by mt-p53 has been reported for MDR1 (Sampath et al , 2006), c- MYC (Frazier et al , 1998), or GRO1 (Yan and Chen, 2009), resulting in cell proliferation, antiapoptosis, and tumourigenicity (Blandino et al , 1999). GUT-70-induced degradation of mt-p53 may successfully repress these oncogenic transcriptional activations.…”

Promotion of tubulin assembly by poorly soluble taxol analogs

“…Many investigators use a tubulin assembly assay for antimicrotubule agents in which the protein concentration is constant and the ligand concentration is varied. The concentration of ligand that induces tubulin to assemble to 50% of a maximum level (EC 50 ) is established and used to determine relative activities (6,7,33,34,38). These assays do not provide direct assessment of the affinity of the ligand for the protein, because the activity is a function of both the affinity of the ligand for tubulin and the efficacy of the ligand on protein polymerization (4,39), but since they are simple to perform they remain in wide use.…”

“…Microtubules are an important target for antineoplastic chemotherapy [1][2][3]. Antimicrotubule drug candidates to be tested are frequently introduced into the assembly assay in DMSO [4][5][6][7]. This is particularly true for derivatives and analogs of taxol, which is highly insoluble in aqueous solution.…”