However, the regulation of MGMT expression is a more complex phenomenon in which methylation of the promoter is not the only determining factor. For instance, in in vitro experiments wild-type p53 seems to act as an inhibitor of MGMT expression, suggesting tumors with normal p53 would have more likely low or absent MGMT levels, independent of promoter methylation. On the other hand it has been suggested that mutant p53 may be associated with a decreased MGMT expression and/or methylation. Given the different relevance of p53 alterations in melanoma or breast,AbMole Bioscience lung and renal cancer, such mechanisms may explain the tumor type-specific differences of MGMT immunoreactivity between these tumors. Assessing the protein, e.g. by immunohis-tochemistry, bypasses several of the above-mentioned pitfalls. There are at least a few studies on malignant gliomas which corroborate that MGMT-immunoreactivity is associated with survival and/or response to alkylating substances. For example, patients with high MGMT expression were reported to have a lower response rate when receiving TMZ before radiotherapy. Based on such reports one may hypothesize that MGMT-immunoreactivity may be a negative predictor of treatment success with alkylating substances. However,Compound Library the extent to which MGMT influences the treatment of brain metastases with alkylating agents needs to be explored in future studies. In conclusion, we demonstrate that about one third of brain metastases of various origins revealed a methylated MGMT promoter as assessed by MS-PCR assay. This suggests that brain metastases may be a potential target for therapy with alkylating substances. Showing a clear correlation between homogeneous MGMT immunoreactivity and an unmethylated MGMT pro-moter, we hypothesize that MGMT immunohistochemistry – as a screening method-could be a helpful diagnostic tool to identify those tumors that probably will not benefit from the use of alkylating agents like temozolomide. Clinical data is necessary to validate this hypothesis.