The methylation status of a gene present in tumour
cells may be useful for predicting whether cancer patients will respond to treatment
with alkylating agents, according to the results of a recent study. Dr Manel
Esteller (division of cancer biology, Johns Hopkins oncology centre, Baltimore,
United States) and colleagues found that patients who tested positive for methylation
of the MGMT (O6-methylguanine-DNA methyltransferase) promoter gene were 16 times
more likely to respond to treatment with carmustine than those whose test was
negative. The researchers analysed 47 newly diagnosed brain tumours (grade III
or IV gliomas) for methylation of the MGMT gene. Twelve of 19 patients with
methylated promoter genes in their tumours had a partial or complete response
to treatment, whereas only one of 28 patients with unmethylated promoters had
a response. Overall survival and time to progression were also longer in patients
who tested positive for methylation (New England Journal of Medicine
2000;343:1350). In an accompanying leading article (ibid p1408), Dr John Weinstein
(National Cancer Institute, Bethesda) comments on the implications of the study
and says that if the results can be replicated, carmustine therapy might be
reserved for patients whose gliomas had methylated MGMT promoters. He adds:
“Patients with unmethylated MGMT promoter regions in their tumours could be
spared the considerable toxicity of carmustine and could instead be given an
agent more likely to be effective against the tumour.” In a press release issued
on November 8 on behalf of the Virco Group (the biotechnology company that is
developing diagnostic tests based on methylation), Dr Brendan Larder (chief
scientific officer, Virco Group, Cambridge) said that the company was working
to provide cancer physicians and patients worldwide with a routine testing service
early in 2001.
Repair mechanism
The cross-linking of DNA by alkylating agents results in cell death. This process
is inhibited by the DNA-repair enzyme MGMT. If the MGMT promoter gene has no
methyl group attached, it can switch on this inhibition thereby reversing the
formation of lethal cross links at the O6 position of guanine.