INTRODUCTION: Finding new ways to improve the efficacy and/or overcome resistance to conventional chemotherapy for brain tumor patients is an ongoing research paradigm. Interlaced TherapyTM is a synergistic cancer therapy involving sequential administration of a T-type calcium channel blocker and a cytotoxic agent. For the purpose of this study, mibefradil dihyrdochloride (MBFD), a T-type calcium channel blocker was interlaced with the standard of care treatment - temozolomide (TMZ) for GBM. Different dosing strategies were tested to maximize efficacy of combination. METHODS: Intracranial (ic) adult brain tumor xenografts (D-270 MG) were grown in athymic BALB/c mice. Three days after ic implantation groups of 10 mice were randomly treated with either drug vehicle/control, MBFD alone PO, TMZ alone IP, or the interlaced therapy of agents. Tumor responses for ic xenografts were assessed by difference in median survival. Two sets of studies were conducted to determine most efficacious delivery of combination: 1) Extended treatment regimen with TMZ, and 2) Time optimization of interlaced approach. RESULTS: The interlaced therapy of MBFD and TMZ demonstrated statistically significant (p<0.001) increases in median survival of 142%, 168%, 174%, and 163% vs. control animals when TMZ is delivered on a regimen of 3, 5, 10, and 15 days respectively. More importantly, interlaced therapy produced significant (p<0.026) increases in survival of 48%, 65%, 68% and 61% at 3, 5, 10, and 15 day dosing regimens vs. TMZ alone. When the TMZ dosing regimen was held constant (5 days) and delivered 0.5, 12, 24, 36 and 48 hours after MBFD, the combination produced statistically significant (p<0.001) increases in median survival of 168%, 158%, 105%, 84% and 74% respectively vs. control animals. More importantly, interlaced therapy produced significant (p<0.042) increases in survival of 65%, 58% and 26% respectively at 0.5, 12 and 24 hour time points vs. TMZ alone. CONCLUSION: Our results establish the therapeutic efficacy of the delivery of MBFD and TMZ via Interlaced TherapyTM against D-270 MG xenografts grown intracranially. Furthermore, this study clearly demonstrates that the synchronization of MBFD with TMZ can be optimized. As such, the blockade of T type calcium channels may well be a target that produces clinically effective, safe synchronization that can be used in conjunction with conventional chemotherapy to render it more effective. The results from this study will be used to help guide clinicians as they move forward with clinical trial design to produce the most efficacious combination of MBFD + TMZ using Interlaced TherapyTM.

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 LB-76. doi:1538-7445.AM2012-LB-76