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Gene Determines Carmustine Sensitivity

Kate Traynor

Researchers have identified a genetic mechanism that may predict whether brain tumors will succumb to the cytotoxic drug carmustine. This finding raises the possibility that clinicians could reserve carmustine therapy for patients most likely to respond to the drug.

According to the researchers, whose study was published in the Nov. 9 New England Journal of Medicine, the critical factor determining a tumor's susceptibility to carmustine is whether the MGMT gene contains methyl groups.

The MGMT gene encodes an enzyme that reverses the damage inflicted on gliomas' DNA by alkylating agents such as carmustine. The presence of methyl groups on the MGMT promoter—a DNA region that activates transcription of the gene—can block activation of MGMT and subsequent synthesis of the protective enzyme, leaving cells susceptible to alkylation.

In this small study, 19 of 47 glioma patients had tumors with MGMT promoters that contained methyl groups. Carmustine therapy reduced the size of the tumors by at least 50 percent for 12 of the 19 patients. That type of response was found for only one of the 28 patients with tumors lacking a methylated promoter.

The study, conducted between April 1993 and November 1998, enrolled adults who had been referred to a university hospital in Spain. Thirty men and 17 women consecutively diagnosed with anaplastic astrocytomas or glioblastoma multiforme tumors participated. Half of the patients were at least 55 years old when their tumors were diagnosed.

Tumor specimens were isolated from the patients for genetic analysis before the start of therapy.

Patients received intraarterial cisplatin at a dosage of 50 mg per square meter of body-surface area. Each patient underwent whole-brain radiation therapy. Intravenous carmustine was administered at 100 mg per square meter every four weeks. Half of the patients required three courses of carmustine treatment.

Fifteen of the patients also underwent autologous bone marrow transplantation and high-dose chemotherapy with carmustine and cisplatin.

Patients' response to therapy was measured by using computed tomographic and magnetic resonance imaging scans. The response was called "complete" if no tumor was detected after therapy and the corticosteroid dosage was unchanged. None of the patients with unmethylated MGMT promoters had a complete response, but two patients with methylated promoters did.

Patients whose tumors lacked methyl groups on the MGMT promoter were 9.5 times as likely as the other patients to die from the disease. According to the researchers, who also examined the effects of a patient’s age and tumor grade, methylation of the MGMT promoter was the only factor that correlated with patient survival.