DDDR-31. THE CHEMOTHERAPEUTIC ACTIVITY OF TEMOZOLOMIDE IS ANTAGONIZED BY ITS HYDROLYSIS PRODUCT, AIC

Abstract Temozolomide is the only FDA-approved drug that has demonstrated improved overall survival in patients with Glioblastoma. Despite the clinical impact it has had, overall survival today largely remains less than two years with current standard-of-care. Temozolomide is a prodrug that undergoes hydrolysis releasing 5-amino-4-imidazole carboxamide (AIC) before it can alkylate DNA. The DNA damage response invoked by TMZ depletes NAD+ levels. We present evidence from mass spectrometry LC-MS/MS studies that AIC released from TMZ can be aberrantly incorporated into the purine synthesis pathway, augmenting purine, and NAD+ synthesis and contributing to chemo- and radiation- resistance. The chemotherapeutic efficacy is therefore antagonized by its own hydrolysis product. TMZ analogs that do not generate AIC will likely have greater activity.