Promising new developments in cancer chemotherapy

The positive impact on survival of traditional chemotherapeutic agents has renewed interest in developing newer cytotoxic agents and orally active com pounds with improved therapeutic indices. In addition, new insights into th e pathways of human tumorigenesis have led to novel approaches aimed at spe cific mechanism-based targets. The taxane class, of which paclitaxel was th e first member, has the unique ability to promote and stabilize microtubule function directly, thereby inhibiting mitotic progression and inducing apo ptotic cell death. Paclitaxel provides treatment benefit in a broad range o f solid tumors including breast, ovarian, and lung cancer. The success with paclitaxel stimulated interest in the microtubule as a new therapeutic tar get. Taxane analogues with improved preclinical efficacy have been identifi ed and are entering clinical trials. The enthusiasm for oral anticancer age nts and the therapeutic importance of platinum compounds has led to the dev elopment of JM216 (satraplatin), a novel platinum IV coordination complex w ith oral activity in cisplatin-resistant cell lines, which is now in phase III trials in prostate cancer. Another compound in late development is DPPE , a chemopotentiator that enhances the in vivo antitumor effects of cytotox ic agents such as doxorubicin, cyclophosphamide, and cisplatin. Agents that inhibit topoisomerase I and II have also been of interest. TAS-103 is a du al topoisomerase I and II inhibitor with preclinical efficacy in a broad sp ectrum of tumors and in multidrug-resistant tumor cell lines. Vaccination s trategies represent a rational therapeutic approach in the minimal residual disease or high-risk adjuvant therapy setting. The GMK and MGV vaccines ut ilizing ganglioside antigens overexpressed on human tumors such as melanoma and small cell lung cancer appear to induce antibody production reliably a t tolerable doses and are under further clinical investigation. Inhibition of matrix metalloproteinases (MMPs) is another attractive target for interv ention in several aspects of tumor progression. Local production of MMPs wi th subsequent degradation of the extracellular matrix is implicated in supp orting tumor growth, invasion, and angiogenesis. The development of orally active, nontoxic MMP inhibitors is critical since these compounds will like ly require chronic administration in conjunction with other therapies. Onco genes and tumor suppressor genes are appealing targets for therapy since th ey are thought to be responsible for a significant number of cancers. Mutat ions in the Ras oncogene occur with great frequency in a number of human ca ncers including lung, pancreas, and colon cancer. Clinical development of p otent and selective inhibitors of farnesyltransferase, the Ras-processing e nzyme, is ongoing. These compounds uncouple Ras activity, affect tumor grow th, and have demonstrated significant antitumor activity against experiment al models of human cancer. The exciting compounds and novel therapeutic app roaches currently under investigation by Bristol-Myers Squibb Pharmaceutica l Research Institute offer great potential as effective cancer chemotherapy agents for the near future.