PT - JOURNAL ARTICLE AU - Dolan, M. Eileen AU - Mitchell, R. Brian AU - Mummert, Christine AU - Moschel, Robert C. AU - Pegg, Anthony E. TI - Effect of <em>O</em><sup>6</sup>-Benzylguanine Analogues on Sensitivity of Human Tumor Cells to the Cytotoxic Effects of Alkylating Agents DP - 1991 Jul 01 TA - Cancer Research PG - 3367--3372 VI - 51 IP - 13 4099 - http://cancerres.aacrjournals.org/content/51/13/3367.short 4100 - http://cancerres.aacrjournals.org/content/51/13/3367.full SO - Cancer Res1991 Jul 01; 51 AB - The effect of O6-benzylguanine, O6-(p-chlorobenzyl)guanine, and O6-(p-methylbenzyl)guanine on the sensitivity of various human tumor cell lines to alkylating agents is evaluated. The sensitivity of human colon tumor cells, HT29, to the chloroethylating agents, 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 2-chloroethyl(methylsulfonyl) methanesulfonate (clomesone), and chlorozotocin was increased by pretreatment for 2 h with 25 µm of each analogue. O6-Benzylguanine was slightly more effective as a sensitizer in HT29 cells than the p-chlorobenzyl and p-methylbenzyl analogues. However, all analogues sensitized SF767 glioma cells to the cytotoxic effects of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and clomesone to the same degree. Both cell lines were sensitized to the methylating agents streptozotocin and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide, the active intermediate of 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide, by pretreatment with 10 µm O6-benzylguanine for 2 h. The number of Raji cells surviving 50 µm clomesone decreased 3-fold upon pretreatment for 2 h with 1 µm O6-benzylguanine. The degree of enhancement was dependent on the amount of alkyltransferase protein present in cell lines. For example, HT29 cells (alkyltransferase activity, 381 fmol/mg protein) exhibited a greater degree of enhancement when treated with O6-benzylguanine than SF767 (77 fmol/mg protein) and M19-MEL melanoma (36 fmol/mg protein) cells. There was no enhancement observed in mer- cell lines, U251 (&lt;2 fmol/mg protein), and BE (3 fmol/mg protein), or with alkylating agents which did not produce a cytotoxic lesion at the O6 position of guanine in DNA such as cisplatin or 4-hydroperoxycyclophosphamide. Our studies suggest that O6-benzylguanine analogues may have utility in mer+ tumors as an adjuvant to a variety of alkylating agents which produce a toxic lesion at the O6 position of guanine. ©1991 American Association for Cancer Research.