Temozolomide-Mediated Radiation Enhancement in Glioblastoma:

Abstract Purpose: In this study, we investigated the mechanisms by which temozolomide enhances radi-ation response in glioblastoma cells. Experimental Design:Using a panel of four primary human glioblastoma cell lines with hetero-geneousO6-methylguanine-DNAmethyltransferase (MGMT) protein expression, normal human astrocytes, and U87 xenografts, we investigated (a) the relationship of MGMTstatus with effica-cy of temozolomide-based chemoradiationusing a panel of in vitro and in vivo assays; (b) under-lyingmechanisms bywhich temozolomide enhances radiation effect in glioblastoma cells; and (c) strategies to overcome resistance to radiation + temozolomide. Results: Temozolomide enhances radiation response most effectively in glioblastomas without detectable MGMT expression. On concurrent radiation + temozolomide administration in MGMT-negative glioblastomas, there seems to be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNAdamage compared either with radiation alone or with sequentially administered temozolomide. Our data suggest thatO6-benzylguanine can enhance the antitumor effects of concurrent radiation + temozolomide in MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage. O6-Benzylguanine was most effective when administere