Chloroethylnitrosoureas (CENUs) alkylate
DNA at specific sites and inhibit DNA replication in
tumor cells. O6-Alkylguanine moieties resulting from alkylation of
guanine bases are thought to be one of most lethal adducts in living cells. Effectiveness of CENUs is known to relate well with an enzymic activity of the
DNA repair enzyme O6-methylguanine-DNA
methyltransferase (MGMT), which recognizes and removes O6-alkylguanine. To improve therapeutic results of CENUs, we have measured MGMT activity of human
brain tumors and studied the relationship between MGMT activity and clinical responsiveness to I-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (
ACNU). Thirty-seven patients with
brain tumors were entered into the study. The
neoplasms included
gliomas, non-glial
tumors, and
brain metastases. The MGMT activity of
gliomas was significantly lower than that of non-glial
tumors and
brain metastases. No significant difference in the
enzyme activity was noted between low- and high-grade
gliomas. Out of the 22
gliomas 5
tumors indicated a value below 60 fmol/mg, suggestive of a methyl excision repair minus (Mer-)
tumor. Two out of 3 evaluable patients with a Mer-
tumor responded well to post-operative
ACNU adjuvant chemotherapy. Our results suggest that
brain tumors include a certain percentage of Mer- phenotype
tumors, and that CENUs such as
ACNU should be applied selectively on
tumors with a low MGMT activity in order to increase the therapeutic effectiveness.