Abstract 3893: Inhalational temozolomide–a new mode of treating malignant gliomas

Abstract

Abstract Temozolomide (TMZ) is the standard of care chemotherapy for treatment of malignant gliomas; it is currently delivered orally or intravenously. Perillyl alcohol is a monoterpene which has been used to treat patients with malignant gliomas via an intranasal delivery system. Recently, we have constructed a new chemical entity (NCE) by conjugating temozolomide to perillyl alcohol via a carbamate bond. This new compound has been named TMZ-POH (NEO212). This new compound has been tested in-vitro in a number of assays. Its mechanism of action does not appear to be MGMT mediated, as addition of O6-benzylguanine has no effect on its cytotoxicity in glioma cells regardless of their MGMT status. On the other hand, TMZ-POH appears to induce endoplasmic reticulum stress (ERS) in malignant glioma cells, as demonstrated by an increase in glucose-regulated protein 78 (GRP78) and the apoptotic protein CHOP expression. MTT assays demonstrate that TMZ-POH is effective in both temozolomide sensitive and resistant U251, U87, LN229 malignant glioma cell lines. IC50 for colony formation assays (CFA) was determined for U251 temozolomide sensitive and resistant cells to be 18 uM and not achieved (0-60 uM). TMZ-POH, on the other hand, had IC50 of 10 uM and 30 uM respectively for TMZ sensitive and resistant U251 glioma cells. MTT assays using glioblastoma cancer stem cells (CSC) demonstrated that TMZ-POH induced IC50 cytotoxicity at 200 uM, compared to no cytotoxicity in the TMZ treated CSC. Moreover, TMZ-POH demonstrated no toxicity on normal astrocytes. Treatment of glioma cells with TMZ alone, POH alone, TMZ dissolved in POH, and TMZ-POH demonstrated that TMZ-POH was two orders of magnitude more cytotoxic than TMZ dissolved in POH. These data lead us to conclude that TMZ-POH is a NCE which may be evaluated for potential intranasal drug delivery to treat patients with malignant gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3893. doi:1538-7445.AM2012-3893