Chemotherapy resistance abrogation in metastatic melanoma.
Melanoma is rapidly increasing in incidence throughout the world. Based on American Cancer Society estimates, there will have been approximately 68,720 new cases of invasive melanoma diagnosed in 2009 in the United States. The increase in melanoma incidence has not been paralleled by the development of new therapeutic agents with a significant impact on survival. The promise of targeted therapy has not yet been brought to bear, making chemotherapy with alkylating agents the mainstay of therapy of metastatic melanoma despite the dismally low response rates. The resistance of tumors to these agents is in part due to DNA repair mechanisms that allow cells to survive alkylation damage. Several novel agents targeting the abrogation of DNA repair pathways alone and in combination with cytotoxic agents have been developed with varying measures of success. This review summarizes the current knowledge of the dysregulation of DNA repair pathways as mechanisms of resistance to chemotherapy in melanoma and their potential as targets for novel developmental therapeutics.
Tawbi
Hussein A
HA
University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA. tawbhx@upmc.edu
Buch
Shama C
SC
D017209:Apoptosis / Q000187:drug effects; D053843:DNA Mismatch Repair; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000502:physiology; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000502:physiology
D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes