Antitumor activity of docetaxel

Abstract

The mechanism of action, cellular uptake, cytotoxicity, use in drug combinations, resistance profile, and toxicology of docetaxel are reviewed. Docetaxel acts by stabilizing microtubules-enhancing the rate and extent of tubulin polymerization, and inhibiting depolymerization. Docetaxel accumulates in tumor cells to a greater extent than paclitaxel and remains in the cells longer. This may explain why docetaxel is more cytotoxic and less schedule dependent than paclitaxel. Higher concentrations of paclitaxel than docetaxel are required to produce the same cytotoxic effect in many murine and human tumor cell lines. Docetaxel has shown cytotoxicity in 4196 of tumor specimens, compared with 33% for paclitaxel. In vivo, docetaxel has substantial activity against a multitude of murine and human tumor models; in some cases, there was complete remission of advanced disease. Synergism occurs between docetaxel and cyclophosphamide, fluorouracil, vinorelbine, methotrexate, and etoposide. Cross-resistance to docetaxel does not necessarily occur in cell lines that are resistant to other antineoplastic agents. In animal toxicology studies, docetaxel principally affected tissues with a high cell turnover, such as hematopoietic tissue. An intermittent- dose regimen is preferable to allow for resolution of hematopoietic effects. Preclinical study results suggest that docetaxel may be effective against various tumors, whether it is given alone or in combination with other antineoplastic drugs.