Temozolomide is a prodrug that spontaneously degrades to the active metabolite, MTIC, under physiologic conditions. MTIC is an alkylating agent that preferentially methylates the O6-position on guanine. The DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT) removes the methyl group from the O6-position of guanine, repairing the lesion produced by MTIC. AGT is expressed in many tumors and has been associated with tumor resistance and poor clinical response to methylating agents, such as the nitrosoureas and temozolomide. O6-Benzylguanine (O6BG) is an AGT substrate that permanently inactivates AGT. O6BG depletes tumor AGT, blocks repair of the lesion produced by temozolomide and thereby enhances its cytotoxicity. A pediatric phase I trial using the combination of temozolomide and O6BG on a daily x 5 days schedule every 4 weeks will be conducted in children with refractory solid tumors and brain tumors to determine the maximum tolerated dose (MTD) of temozolomide when given in combination with a biologically active dose of O6BG. Pharmacokinetic studies of O6BG and temozolomide will also be performed
NIH ExPorter
NIH ExPorter