Preclinical Pharmacologic Evaluation of MST-997, an Orally Active Taxane with SuperiorIn vitroandIn vivoEfficacy in Paclitaxel- and Docetaxel-Resistant Tumor Models

Our findings suggest that microtubule-stabilizing taxane-997, which has entered phase I clinical trials, may have broad therapeutic value

Deepak Sampath


Scholarcy highlights

  • Because resistance to paclitaxel and docetaxel is frequently observed in the clinic, new anti-microtubule agents have been sought
  • microtubule-stabilizing taxane-997 is an analogue of docetaxel with two major substitutions at carbon 10 and the 13 side chain of the baccatin core. These modifications highlight the structural diversity of MST-997
  • At the maximum concentration of 24 Amol/L of MST997, the overall rate of tubulin polymerization was similar to docetaxel; the net amount of polymerized tubulin was slightly enhanced in the presence of MST-997
  • In the absence of GTP, paclitaxel was a weak inducer of tubulin polymerization
  • resistance to MST-997 and paclitaxel in the HCT-15 colon tumor cell line, which overexpresses very high levels of MDR1, was 1.9- and 53.4-fold, respectively, compared with HCT-116 colon cells that are sensitive to these agents
  • Maximum tumor growth inhibition at 90% was observed in all animals tested at 70 mg/kg MST-997
  • The level of potency of MST-997 in these MDR1-positive tumor cells lines translated in vivo as single i.v. dose at f70% of the maximum tolerated dose resulted in >95% inhibition of tumor xenografts that were resistant to paclitaxel and docetaxel even when these agents were given in their optimal schedules of q4d  3 or q5d  2, respectively
  • Multiple low doses of microtubule-stabilizing taxane-997 was more effective than MAC-321, given at a similar schedule and dose, at overcoming drug resistance in the HCT-15 cell lines, which overexpresses high levels of MDR1

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