[Drug resistance of malignant melanoma. Mechanisms and possible modulation].
Response rates of metastatic malignant melanoma to cytostatic treatment are disappointingly low. Although immunomodulators such as interferons are more commonly being used in combination with cytostatics, no major breakthrough has been achieved. The mechanisms underlying the high chemoresistance of melanoma cells are so far ill-defined, and investigations are only just being initiated. Several mechanisms of chemoresistance have, however, been studied with other tumours and might be relevant for human melanoma: (1) "Classical" multidrug resistance, determined by the expression of the p-glycoprotein which resembles a membrane pump that eliminates natural and synthetic agents from the cell interior. Different drugs, including calcium antagonists, interfere with its function and can thus modulate chemoresistance. Preliminary data from investigations of these mechanisms indicate that p-glycoprotein is not, however, involved in the multidrug resistance of malignant melanoma. (2) Detoxification, involving glutathione-S-transferases (GST). GST are a multigene family of enzymes which inactivate alkylating agents by conjugation to glutathione. Their relevance for chemoresistance in melanoma has not yet been clarified. (3) Topoisomerase II, which is involved in DNA recombination and DNA transcription events and represents the target of several inhibitory cytotoxic agents. Low levels of the enzyme render cells resistant to the action of specific drugs. Again nothing is yet known regarding the relevance of this mechanism in human melanoma. Further studies of these potentially important resistance mechanisms are thus urgently needed in order to develop more effective therapies for advanced malignant melanoma.
Schadendorf
D
D
Universitätsklinik Rudolf Virchow, Hautklinik, FU Berlin.
Czarnetzki
B M
BM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects* / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D009362:Neoplasm Metastasis; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D059005:Topoisomerase II Inhibitors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D059005:Topoisomerase II Inhibitors; D005982:Glutathione Transferase; D004250:DNA Topoisomerases, Type II
Chemoresistenz des malignen Melanoms. Mechanismen und Modulationsmöglichkeiten.