CISPLATIN HAS BEEN A MAINSTAY of chemotherapy of various solid tumors for years. A significant body of investigations into its therapeutic effects has two important components. The first, predominantly explored by oncologists, studies the mode of cytotoxic action on tumor cells and ways of preventing resistance to cisplatin. The second, combating cisplatin nephrotoxicity, is a domain of nephrologists. The two rarely intersect, although it is not unreasonable to think that common mechanisms may be in place. In this vein, both groups of investigators are focusing on regulators of cell cycle and determinants of cell death. Members of the cyclin-dependent kinase (Cdk) family, of which 11 are known so far, form noncovalent complexes with AE cyclins, each responsible for control of a specific point in the cell cycle. The retinoblastoma gene, mutated in a rare tumor that gave the name to the gene, has been found to be aberrant in many other cancers (see a review in Ref. 3). Its protein product (pRb), a member of the pocket protein family, is a key regulator of the E2F family of transcription factors, which consists of seven known members, in turn being critical for cell proliferation and apoptosis. Therefore, a big question is how to enhance the therapeutic effect of cisplatin and at the same time not compromise the kidney. This requires a more detailed view of the individual participants and their function in specific cells.

Lessons learned from E2F knockout mice convincingly demonstrated that these transcription factors [E2F1-3 (activators), E2F4-5 (repressors)] critically participate in cell proliferation and apoptosis. Proapoptotic actions are likely mediated via induction of caspase expression and/or the p53 pathway (reviewed in Ref. 2). E2F1J/J mice are prone to develop sarcomas of the reproductive tract, lymphomas, and lung tumors, presumably due to the defect in p53-dependent apoptosis of damaged cells. Since pRB binds to both activator and repressor E2Fs, it may differentially affect downstream E2F functions.