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O6-alkylguanine-DNA alkyltransferase activity in human malignant melanoma
S Moriwaki1, C Nishigori, H Takebe
1Department of Dermatology, Faculty of Medicine, Kyoto University, Japan.
Abstract:
O6-alkylguanine has been known to be the major lesion in DNA for the cytotoxicity of alkylating agents and it is repaired by O6-Alkylguanine-DNA alkyltransferase (O6-AGT). To examine the relation of O6-AGT to the clinical characteristics in malignant melanoma (MM), O6-AGT activity in 13 human MM tissues was measured. The activity in tumor tissues varied widely from 0 to 0.11 pmol/mg protein. The activity in normal skin tissues was lower and less variable than in the tumors. The activity was not related to the tumor size or clinical stage of melanomas, but it was higher in tumors after chemotherapy with alkylating agents than in those without chemotherapy. In metastatic tissues, in primary tumors of the patients with metastases and in tumors of the patients with bad prognosis, the activity was also high. Two of the tumors, having the highest O6-AGT activity, were both transplantable to nude mice. These results suggest two possibilities; melanomas exposed to the alkylating agents may change to have high O6-AGT activity, followed by the resistance to such agents, or O6-AGT in melanomas may be originally diverse. O6-AGT activity in the tumour tissue may represent the effect of alkylating agents and can be used in selecting the methods of therapy.
Insights
O6-Alkylguanine-DNA alkyltransferase (O6-AGT) activity is elevated in malignant melanoma, particularly after chemotherapy. This suggests O6-AGT levels may indicate treatment response and guide future melanoma therapies.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- O6-alkylguanine is a key DNA lesion from alkylating agents.
- O6-Alkylguanine-DNA alkyltransferase (O6-AGT) repairs this lesion.
- Understanding O6-AGT in malignant melanoma (MM) is crucial for treatment.
Purpose of the Study:
- To investigate the relationship between O6-AGT activity and clinical characteristics in MM.
- To assess O6-AGT activity in human MM tissues.
Main Methods:
- Measurement of O6-AGT activity in 13 human MM tissues.
- Comparison of O6-AGT activity between tumor and normal skin tissues.
- Correlation analysis with clinical parameters like tumor size, stage, and chemotherapy history.
Main Results:
- O6-AGT activity varied significantly in MM tissues (0-0.11 pmol/mg protein).
- Tumor O6-AGT activity was higher than in normal skin.
- Elevated O6-AGT was observed in tumors post-chemotherapy, in metastatic tissues, and in patients with poor prognosis.
- High O6-AGT activity correlated with transplantability to nude mice.
Conclusions:
- MM may develop increased O6-AGT activity in response to alkylating agents, potentially conferring resistance.
- Alternatively, inherent diversity in O6-AGT levels within melanomas may exist.
- O6-AGT activity could serve as a biomarker for alkylating agent efficacy and aid in therapy selection for MM.