Temozolomide (TMZ) is an alkylating agent indicated for use in adult patients with newly diagnosed glioblastoma multiforme and refractory anaplastic astrocytoma. In the current studies, we evaluated the effects of temozolomide treatment schedule and dose on antitumor efficacy and MGMT activity in models of human brain cancer (Daoy) and melanoma (LOX, A375). The objective of these studies was to compare a compressed dose intense schedule of TMZ to a continuous low dose schedule in which the same total dose of TMZ is administered over a longer period of time. For in vitro studies, the same total dose of TMZ was administered as constant daily dosing, single pulse, or intermittent pulse. For in vivo studies the same total cumulative dose of TMZ was administered either on a continuous schedule (e.g., day 1 through day 15 in a 15 day cycle), on a compressed schedule (day 1 through day 5), or intermittently on day 1, 4, 7, 10, 13.

MGMT (O6-methyl guanine methyl transferase) is the enzyme responsible for repair of the O6-methyl guanine lesion induced by TMZ. MGMT protein level, activity, and promoter methylation were measured in tumor cells or xenograft tumors following TMZ treatment. Different tumor models tested in the study have different levels of MGMT, which in turn correlates with sensitivity to TMZ. Treatment with TMZ depleted MGMT in a dose dependent fashion and reduction of MGMT levels correlated with TMZ activity both in-vitro and in-vivo.

MGMT activity and tumor growth inhibition were reduced in a dose-dependent fashion regardless of treatment schedule in both in vitro and in vivo systems. However, the compressed scheduled appeared to have greater efficacy in terms of growth inhibition and decreased MGMT activity at a given cumulative dose. This difference was most pronounced in models with higher MGMT levels and higher resistance to TMZ. These data suggest that compressed high intensity dose schedules with higher doses may be superior to continuous low doses when treating higher MGMT cancers with TMZ.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA