Introduction: 3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are effective inhibitors of cancer-cell metabolism in vivo and in vitro. Studies in glioma are limited by the inability of 3-BrPA to cross the blood-brain-barrier and a dose-limiting toxicity of DCA. We hypothesized that intracranial delivery of 3-BrPA and DCA would be safe and significantly increase survival in a rat glioma model.
Methods: Cytotoxicity of 3-BrPA was analyzed in two rodent (9L and F98) and two human (U87 and U251) glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable polymers and the maximally tolerated dose (MTD) was determined in F344 rats. Forty rats were then implanted intracranially with 9L gliosarcoma. Rats were randomized to 5 treatment groups: 1) Control, 2) oral DCA (80mg/kg daily), 3) 50%DCA polymer, 4) 5%3-BrPA polymer, 5) 5%3BrPA polymer+oral DCA.
Results: 3-BrPA was found to be cytotoxic in all four glioma cell lines at doses >1mg/100?L. The MTD of 3-BrPA polymer was 5%, while the MTD was not achieved for DCA polymer, even when loading was as high as 50%. In the 9L model, controls had a median survival of 13 days and 5%3-BrPA had a median survival of 18 days (p=0.0027). The median survival of 50%DCA polymer was 17 days compared to 11 days for oral DCA (p=0.0050) and the 13 days for control (p=0.02). 5%3-BrPA polymer combined with oral DCA did not have significant survival beyond 5%3-BrPA polymer alone (p=0.7123). Oral DCA did not significantly increase survival beyond control (p=0.22)(Please see attached figure).
Conclusions: The intracranial delivery of 3-BrPA and DCA polymer was safe and showed significantly increased survival, a possible novel approach to glioma therapy.
Patient Care: The intracranial delivery of 3-BrPA and DCA polymer was safe and showed significantly increased survival, introducing a possible novel approach to glioma therapy.
Learning Objectives: To determine that 3-bromopyruvate and dichloroacetate are effective inhibitors of cancer-cell metabolism in vivo and in vitro.
To determine that intracranial delivery of these agents may be helpful in glioma therapy.