O6-(fluorobenzyl)guanine and chloroethylnitrosourea in xenografted rat brain tumor in vivo.
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)methyl-3-(2-chloroethyl)-3-nit rosoureahydrochloride (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.
Takahashi
M
M
Neurosurgical Service, Akita University Hospital, Japan. masataka@rnac.ne.jp
Mineura
K
K
Watanabe
K
K
Kohda
K
K
D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000139:chemically induced / Q000503:physiopathology*; D002455:Cell Division; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000235:genetics; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D015376:Nimustine / Q000494:pharmacology*; D009603:Nitroso Compounds; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D051381:Rats; D014183:Transplantation, Heterologous
D001593:Benzyl Compounds; D004273:DNA, Neoplasm; D009603:Nitroso Compounds; C406582:O(6)-(fluorobenzyl)guanine; D015376:Nimustine; D006147:Guanine; C041148:N-(2-chloroethyl)-N-nitrosoacetamide; D019853:O(6)-Methylguanine-DNA Methyltransferase