Analysis of O(6)-methylguanine-DNA methyltransferase in melanoma tumours in patients treated with dacarbazine-based chemotherapy.
In a retrospective study we analysed the levels of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) in melanoma metastases in patients receiving dacarbazine (DTIC) either as a single drug or as part of combination chemotherapy regimens, and related the expression levels to the clinical response to treatment. Biopsies of subcutaneous and lymph node metastases obtained before chemotherapy in 65 patients with disseminated malignant melanoma were examined for MGMT protein levels by immunohistochemistry using a monoclonal anti-human MGMT antibody. All patients received chemotherapy with DTIC, given either as a single drug or in combination with vindesine and in some cases cisplatin. DTIC as single agent was given to 44 patients, while 21 received combination chemotherapy. Objective responses to chemotherapy were seen in 12 patients, while 53 patients failed to respond to treatment. The expression of MGMT was determined according to the proportion of antibody-stained tumour cells, using a cut-off level of 50%. In 12 of the patients more than one metastasis was analysed, and in seven of these cases the MGMT expression differed between tumours in the same individual. Among the responders a larger proportion (six out of 12, 50%) had tumours containing less than 50% MGMT-positive tumour cells than among the non-responders (12 out of 53, 23%). These data are consistent with the hypothesis that MGMT contributes to resistance to DTIC-based treatment, although the difference between responders and non-responders with respect to the proportion of MGMT-positive tumour cells was not statistically significant (P = 0.077).
Ma
S
S
Department of Oncology/Pathology, Radiumhemmet, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Egyházi
S
S
Martenhed
G
G
Ringborg
U
U
Hansson
J
J
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D003606:Dacarbazine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis* / Q000276:immunology / Q000502:physiology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis* / Q000276:immunology / Q000502:physiology; D015588:Observer Variation; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use*; D014751:Vindesine / Q000008:administration & dosage
D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011355:Prodrugs; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin; D014751:Vindesine