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O6-methylguanine-DNA methyltransferase in human normal and tumor tissue from brain, lung, and ovary
Abstract:
The resistance of human tumor strains in culture to cell killing by alkylating nitrosoureas is correlated with their levels of the DNA repair activity O6-methylguanine-DNA methyltransferase. Strains with the Mer- phenotype have no activity and are extremely sensitive. However, the relationship between the sensitivity of human tumors in vivo and transferase levels is not known, and even the existence of Mer- human tumors in vivo has been questioned. In this study 73 human tumor and normal tissue samples from brain, lung, and ovary were assayed for transferase levels and methylpurine glycosylase activity. For each organ, transferase levels varied over 100-fold, and Mer- tumors were detected in each group. There was no correlation between transferase and glycosylase levels, indicating that the absence of transferase in some tumor samples was not an artifact due to necrosis or inactivation of enzymes in the extract.
Insights
Human tumors exhibit varying levels of O6-methylguanine-DNA methyltransferase, a DNA repair enzyme. This study confirms the existence of Mer- (deficient) human tumors in vivo, which are highly sensitive to chemotherapy.
Area of Science:
- Molecular Biology
- Oncology
- DNA Repair Mechanisms
Background:
- Alkylating nitrosoureas are chemotherapy agents.
- Resistance to these agents in human tumor strains in culture correlates with O6-methylguanine-DNA methyltransferase (MGMT) levels.
- Tumor strains with the Mer- phenotype lack MGMT activity and are highly sensitive to chemotherapy.
Purpose of the Study:
- To investigate the relationship between MGMT levels and the sensitivity of human tumors in vivo.
- To determine if Mer- human tumors exist in vivo.
Main Methods:
- Assayed 73 human tumor and normal tissue samples from brain, lung, and ovary for MGMT levels and methylpurine glycosylase activity.
- Analyzed MGMT levels across different organs and tumor types.
Main Results:
- MGMT levels varied over 100-fold within each organ.
- Mer- tumors were detected in brain, lung, and ovary tissues.
- No correlation was found between MGMT and methylpurine glycosylase levels, ruling out necrosis or enzyme inactivation as causes for low MGMT.
Conclusions:
- Mer- human tumors exist in vivo.
- MGMT levels significantly influence tumor sensitivity to alkylating nitrosoureas.
- These findings have implications for predicting chemotherapy response in various human cancers.