New strategies for cancer management: how can temozolomide carrier modifications improve its delivery?

Abstract

Glioblastoma multiform (GBM) is the most devastating, highly aggressive astrocytic cell neoplasm having a median survival of 12–15 months and a 5-year survival rate of <3% [1]. Surgery along with radiation therapy and/or chemotherapy is the standard treatment strategy for primary brain tumors wherein, the survival advantages are only palliative. Despite clinical and technological advances, a cure for GBM remains elusive due to its diffuse infiltrative pattern of growth (hindering complete surgical resection), cytogenetic heterogeneity (limiting the use of pathway-specific targeted agents) and location (need to cross the blood–brain barrier [BBB]). Temozolomide (TMZ) is the first-line chemotherapy for GBM used in conjunction with radiotherapy or as a single agent for maintenance therapy [1]. It is an imidazotetrazine class DNA alkylating agent that methylates guanine and adenine bases of DNA leading to DNA double-strand breaks, cell cycle arrest and eventual cell death [1]. An autophagy induction leading to cell death has also been reported as a putative mechanism of action of TMZ in cancer cells and GBM patients [2]. Looking at the current therapy for GBM, there is still an unmet medical need resulting due to its inefficient delivery of TMZ to the cancer tissue. Only a modest activity is seen for TMZ, particularly in high-grade gliomas, which is further limited by the development of resistance leaving no viable therapeutic option for recurrent glioblastoma [3]. Further, TMZ is an unstable molecule that undergoes rapid hydrolysis and has significant dose-limiting hematological toxicity that prevents dosage increase [1]. Currently, TMZ is given orally or intravenously (TEMODAR®) at a dose of 75 mg/m2 concomitant with radiotherapy for 49 days followed by 150 mg/m2 (cycle 1) and 200 mg/m2 (cycle 2–6) as a maintenance dose.