Abstract
The effectiveness of the radiosensitizer gemcitabine (GEM) was evaluated in a mouse glioma along with the imaging biomarker diffusion-weighted magnetic resonance imaging (DW-MRI) for early detection of treatment effects. A genetically engineered murine GBM model [Ink4a-Arf−/− PtenloxP/loxP/Ntv-a RCAS/PDGF(+)/Cre(+)] was treated with gemcitabine (GEM), temozolomide (TMZ) +/− ionizing radiation (IR). Therapeutic efficacy was quantified by contrast-enhanced MRI and DW-MRI for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ and radiation showed a significant reduction in growth rates as early as three days post-treatment initiation. Both combination treatments (GEM/IR and TMZ/IR) resulted in improved survival over single therapies. Tumor diffusion values increased prior to detectable changes in tumor volume growth rates following administration of therapies. Concomitant GEM/IR and TMZ/IR was active and well tolerated in this GBM model and similarly prolonged median survival of tumor bearing mice. DW-MRI provided early changes to radiosensitization treatment warranting evaluation of this imaging biomarker in clinical trials.
Highlights
50% of all patients diagnosed with brain tumors have the most malignant form, glioblastoma multiforme (GBM)
The addition of temozolomide to radiation alone in the treatment paradigm for GBM patients resulted in a median survival benefit of 2.5 months gaining acceptance as standard of care [2]
Methylation of the MGMT promoter occurs in about 30 to 60% of glioblastoma patients which is associated with favorable patient outcome using alkylating agents [44,45]
Summary
50% of all patients diagnosed with brain tumors have the most malignant form, glioblastoma multiforme (GBM). Despite aggressive treatments that consist primarily of surgical resection followed by chemoradiotherapy the prognosis remains poor with a median survival of 14 months from diagnosis [1]. The standard of care for glioma patients continues to be concurrent temozolomide and radiotherapy which provides a modest improvement in survival over radiation alone [2]. With a better understanding of the genetic make-up of GBM [3], molecular and genetic profiling is being investigated for biomarkers to predict treatment efficacy [4]. One prognostic factor identified as a reliable biomarker for GBM sensitivity to temozolomide is the methylation status of O6-methylguanine-methyl-transferase (MGMT) [5]. Patients with active MGMT, an enzyme responsible for DNA repair, were found to receive little benefit from treatment by alkylating agents (i.e. Temozolomide)
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