Heterogeneity of O6-alkylguanine DNA-alkyltransferase expression in human breast tumours

An important determinant of cellular resistance to chemotherapeutic O 6 -alkylating agents, which comprise methylating and chloroethylating agents, is the ability of cells to repair alkylation damage at the O 6 -position of guanine in DNA. This is achieved by a specific DNA repair enzyme O 6 -alkylguanine DNA-alkyltransferase. In this study O 6 -alkylguanine DNA-alkyltransferase expression was measured in human breast tumours using both biochemical and immunohistochemical techniques. O 6 -alkylguanine DNA-alkyltransferase activity was then compared with known clinical prognostic indices to assess the potential role of O 6 -alkylguanine DNA-alkyltransferase in predicting the behaviour of this common malignancy. The application of both biochemical and immunohistochemical techniques was feasible and practical. Most breast tumours expressed high levels of O 6 -alkylguanine DNA-alkyltransferase. Immunohistochemical analysis showed marked variation in expression not only between individuals but also within individual tumours, and in the same patient, between metastases and between primary tumour and metastatic site. O 6 -alkylguanine DNA-alkyltransferase activity in tissue extracts significantly correlated not only with immunohistochemical staining intensity determined by subjective quantitation, but also with measures of protein levels using a computerised image analysis system including mean grey ( P