Anna Maria Casazza

Paclitaxel (Taxol): mechanisms of Resistance.

Paclitaxel (Taxol #®) is one of the most promising new anticancer agents developed in recent years [1]. Taxol® has been approved for the treatment of refractory ovarian [2,3] and breast cancer [4] in several countries, and has shown activity against after human malignancies, such as lung cancer head and neck cancer, esophageal cancer, hematological malignancies, and melanomas. However, even in patients with responding tumors, response rates have not been superior to 50%, and relapses have always been the case, indicating that (1) even among the sensitive tumor types, there are examples of cancers that are naturally resistant to Taxol therapy (and these tumors are defined as having intrinsic resistance or insensitivity to Taxol, and (2) treatment with Taxol inexorably leads to development of resistance to paclitaxel (and these tumors are defined as having acquired resistance to Taxol). An understanding of the mechanisms of intrinsic or acquired resistance of cancer cells to paclitaxel can result in (1) design of better therapeutic modalities (drug combinations, sequences, schedule of treatment) for the treatment of cancer patients; (2) development of appropriate experimental models that represent as closely as possible the clinical cause of paclitaxel insensitivity or resistance; and (3) identification of novel anticancer drugs, and in particular paclitaxel analogs, active against paclitaxel-resistant cancer cells. An agent active against such tumor cells in vitro and in vivo would, in fact, be an important candidate for clinical development.

Screening Methodologies for the Discovery of Novel Cytotoxic Antitumor Agents

Publisher Summary This chapter describes the screening methodologies for the discovery of novel cytotoxic antitumor agents. Several antitumor agents exert their cytotoxic effect because of interaction with cellular DNA, and in vitro techniques that measure this interaction can be used for antitumor drug screening. The identification of DNA binding compounds can be accomplished by observing altered migration of supercoiled, covalently closed, circular DNA in agarose gels. This approach provides several advantages for identifying DNA-binding agents. Several antitumor compounds that have proven successful in the clinic such as etoposide, teniposide, and possibly the anthracyclines are considered to exert their cytotoxic effects through interaction with topoisomerase II. The camptothecins, the only known inhibitors of topoisomerase I, are now being developed in the clinic because of their promising antitumor activity in experimental tumor models. It is found that when addressing the issue of whether inhibition of catalytic activity or intermediate stabilization should be the desired activity of a topoisomerase-targeted anticancer agent, consideration should be given to the fact that essentially all topoisomerase-active anticancer agents known today appear to produce their effect by intermediate stabilization rather than by inhibition of catalytic activity.