Chemotherapeutics, chemoresistance and the management of melanoma.

Melanoma is one of the most aggressive forms of cancer with a continuously growing incidence worldwide. Survival mainly depends on primary tumor thickness, ulceration and sentinel node status at the time of diagnosis. Adjuvant therapies with interferons are able to prolong the recurrence-free survival, but the effects on overall survival are limited. Once, melanoma has metastasized to distant sites, the prognosis is fatal with median survival times between 7 and 9 months. Albeit removal of localized distant metastases is currently the most effective approach in metastatic melanoma in particular cases, chemo- and chemoimmunotherapy has to be regarded as standard treatment in the majority of patients. However, all available cytotoxic drugs and combinations applied so far have only a small impact on overall survival, if any. A fundamental cause of the limited efficacy of chemotherapy in advanced melanoma has to be seen in chemoresistance mechanisms. In melanoma, the intrinsic and mainly anti-apoptotic resistance, due to the physiological role of the UV exposed melanocytes, is prevailing. Further resistance mechanisms discussed in melanoma are DNA repair, multidrug transporter and the existence of cancer stem cells. Promising therapeutic options accrue from the growing insights into signaling pathways of melanoma that cause chemo- and apoptosis-resistance. The development of drugs targeting those mechanisms and their administration in combination with chemotherapy is currently one of the fascinating novel treatment approaches in melanoma.