Abstract
O6-methylguanine-DNA methyltransferase (MGMT), one of the DNA repair enzymes, 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 O6-(4-, 3- and 2-fluorobenzyl)guanines (4F, 3F and 2F, respectively), three newly synthesized MGMT inhibitors, on 1-(4-amino-2-methyl-5-pyrimidinyl)methy-3-(2-chloroethyl)-3-nitrosoureahydrochloride (ACNU) therapy in C6 tumor xenografts. Treatment with 4F+ACNU and 3F+ACNU significantly decreased tumor volume and extended the delay of growth in comparison to untreated mice (control 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 that O6-(4- and 3-fluorobenzyl)guanines as well as O6-benzylguanines enhance the effect of ACNU on the growth of C6 tumor xenografts in vivo.
Published Version
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