O-6-(fluorobenzyl)guanine and chloroethylnitrosourea in xenografted rat brain tumor in vivo

O-6-methylguanine-DNA methyltransferase (MGMT), one of the DNA repair enzym es; potently repairs DNA damage induced by chloroethylnitrosoureas (CENUs). Depletion of MGMT activity after treatment with MGMT inhibitors increases the sensitivity of tumor cells to CENUs. We tested the effect of O-6-(4-, 3 - and 2-fluorobenzyl)guanines (4F, 3F and 2F, respectively), three newly sy nthesized MGMT inhibitors, on 1-(4-amino-2-methyl-5-pyrimidinyl)methy-3-(2- chloroethyl)-3-nitrosoureahydrochloride (ACNU) therapy in C6 tumor xenograf ts. Treatment with 4F + ACNU and 3F + ACNU significantly decreased tumor vo lume and extended the delay of growth in comparison to untreated mice (cont rol group, p < 0.05). Both groups showed significantly lower proliferating indices than the control group (p < 0.05) 12 h after treatment. In contrast , 2F did not enhance the ACNU anti-tumor effect. These results indicate tha t O-6-(4- and 3-fluorobenzyl)guanines as well as O-6-benzylguanines enhance the effect of ACNU on the growth of C6 tumor xenografts in vivo.