Preclinical Experience With Docetaxel in Gastrointestinal Cancers

Docetaxel is a semisynthetic taxane that acts primarily by promoting microtubule assembly and preventing the depolymerization of assembled microtubules, thereby inducing mitotic block and inhibition of cell proliferation. This agent also induces apoptosis and appears to prevent angiogenesis. Although docetaxel has shown efficacy in a wide variety of tumors, it has only recently been evaluated in the treatment of gastrointestinal cancers. Data from preclinical studies have shown that docetaxel has substantial in vitro and in vivo activity against gastric, esophageal, and pancreatic tumors. The cytotoxic activity of docetaxel is generally time- and dose-dependent, and greater than that produced by other chemotherapeutic agents, including paclitaxel and anthracyclines. Studies evaluating combination regimens suggest that docetaxel has additive-to-synergistic antitumor activity against gastrointestinal cancers over that produced by the individual agents, and the increased antitumor activity appears to be schedule-dependent. These data suggest that docetaxel has promising therapeutic activity in the treatment of gastrointestinal cancers and provides a rationale for its inclusion in therapeutic protocols either as a single agent or in combination regimens. In addition to combination regimens with conventional chemotherapeutic agents, early studies with a number of novel molecularly targeted therapies in combination with docetaxel have shown encouraging results. These studies provide a basis for pursuing future clinical trials with docetaxel-based combinations of novel therapies for improving response rates in the treatment of gastrointestinal cancers.