Towards an understanding of the biological basis of response to cisplatin-based chemotherapy in germ-cell tumors

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Abstract
Chemotherapy is far more successful in young male patients with germ-cell tumors than in adults suffering from almost any other solid tumor. Various attempts have been made to understand the sensitivity of these tumors towards cisplatin-based chemotherapy; however, to date no explanation has been generally accepted. Recent data underline the need to seek further explanations, other than the previously postulated high intrinsic level of wild-type P53 protein, for the exquisite curability of germ-cell tumors. In this regard, the DNA repair pathways, in particular the DNA mismatch repair and nucleotide excision repair pathways, have received attention. This review summarizes the data currently available on the cellular basis for chemotherapy response in these tumors by systematically following cisplatin—presumably the most active drug in the treatment of this disease—on its course from entering the cell to the execution of apoptosis. The emerging picture points towards a multifactorial explanation for the unique chemosensitivity of germ-cell tumors, including a lack of export pumps, an inability to detoxify cisplatin and repair the respective DNA damage, and an intact apoptotic cascade not disturbed by anti-apoptotic stimuli. Even though no uniform pattern of relevant resistance factors has been identified in patients suffering from refractory disease, a significant number of these cases may be caused by defects in the DNA mismatch repair pathway.