Abstract
Abstract
The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that alters the body's metabolism to burn fats in preference to carbohydrates. The use of fats as a primary energy source leads to a state of ketosis and the accumulation of ketone bodies in the blood. KetoCal (Nutricia North America, Gaithersburg, MD) is a nutritionally complete, commercially available 4:1 (fat: carbohydrate + protein) ketogenic formula that is an effective non-pharmacologic treatment for the management of pediatric epilepsy. Diet-induced changes to brain homeostasis as a result of ketosis have shown potential as an alternative treatment for other neurological diseases including malignant gliomas. We previously showed that Bio-Serv F3666 (Frenchtown, NJ), a rodent KD with a fat to carbohydrate + protein ratio of 6:1, potentiates the activity of both radiation and temozolomide (TMZ) therapy. We studied the efficacy of KetoCal as an adjuvant treatment for malignant glioma in combination with radiation or TMZ.
GL261-luc cells expressing luciferase were stereotactically implanted into the right frontal lobe of albino C57BL/6 mice (NCI, Frederick, MD). Following intracranial implantation, animals were fed standard rodent chow (SD) and were randomized to treatment groups on day 3 (SD vs KetoCal with and without radiation or TMZ) based on bioluminescent signal (IVIS® Spectrum, Caliper Life Sciences, Hopkinton, MA). Blood levels of β-hydroxybutyrate (βHB) and glucose were measured using a Keto-Site reflectance meter (GDS Technologies, Elkhart, IN) and HemoCue Glucose System (HemoCue AB, Ängelholm, Sweden). βHB and glucose levels were checked one and two weeks following the initiation of diet treatment. Mice were maintained on a 12 hour light/dark cycle and KetoCal or SD was available ad libitum.
Animals fed KetoCal had elevated levels of βHB (p=0.0173), decreased levels of glucose (p=0.0224) and increased median survival of approximately 6 days relative to animals on SD. To determine if KetoCal enhanced the effect of radiation; mice received 2 × 4 Gy whole brain radiation in combination with SD or KetoCal. Irradiated animals fed SD had a median survival of 44.5 days, while irradiated animals maintained on KetoCal demonstrated a complete loss of bioluminescence, suggesting the absence of viable tumor cells. These animals have been followed for >170 days with no visible signs of recurrent tumor (p=0.0061). Animals fed KetoCal in combination with TMZ (5×50mg/kg) had a median survival of 37 days compared to 28 days for animals treated with TMZ and maintained on SD (p=0.0043).
In summary, the 4:1 fat: carbohydrate + protein ratio in KetoCal appears to provide a higher anti-tumor effect than a 6:1 formulation when used in addition to radiation or TMZ. The effect is particularly pronounced when used in combination with radiation. This suggests that cellular metabolic alterations brought about through changes in the diet may be useful for the treatment of human malignant gliomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 624. doi:10.1158/1538-7445.AM2011-624