title: O6-benzylguanine increases the sensitivity of human primary bone marrow cells to the cytotoxic effects of temozolomide.
abstract: The sensitivity of human primary bone marrow granulocyte/macrophage precursor cells to the cytotoxic effects of the methylating antitumor agent temozolomide (8-carbamoyl-3- methylimidazo[5,1-d]-1,2,3,5-tetrazin-4-[3H]-1) was investigated using an in vitro colony-forming assay. In the eight samples examined, there was a range of sensitivities with D37 values from 18.2 to > 55 microM. When cells were simultaneously exposed to the O6-alkylguanine-DNA alkyltransferase (ATase) inactivating agent, O6-benzylguanine (O6BeG; 10 microM), the cytotoxicity of temozolomide was substantially increased with D37 values between 5 and 38.5 microM. O6BeG also increased temozolomide sensitivity in the human colon carcinoma cell line, WiDr, and this was shown to correlate with the O6BeG-mediated depletion of ATase activity. Where the extent of sensitization produced by O6BeG could be calculated, there was a correlation between this and the D37 value in the absence of O6BeG (R = 0.996); thus, sensitization was more extensive in the cells that were inherently more resistant to temozolomide. These data have implications for possible increased hematological toxicity in clinical protocols designed to exploit O6BeG or other agents to deplete ATase activity in tumors cells prior to treatment of patients with temozolomide or related agents.
authors: Cancer Research Campaign Department, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
authors: L J
authors: LJ
authors: Fairbairn
authors: A J
authors: AJ
authors: Watson
authors: J A
authors: JA
authors: Rafferty
authors: R H
authors: RH
authors: Elder
authors: G P
authors: GP
authors: Margison
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008780:Methyltransferases / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; C064976:O(6)-benzylguanine; D006147:Guanine; D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide