HYPOGLYCEMIA WITH GLYCEROL SALVAGE - A ROLE IN ANTINEOPLASTIC THERAPY

Most tumors are obligate glucose consumers and severe glucose depletio n has anti-neoplastic effects. However; an alternate energy source is necessary to support the host. Since glycerol is utilized by all hypog lycemic sensitive normal tissues but nor tumors, glycerol may be an id eal alternate energy source. The effects of glycerol on tumor growth, animal survival during systemic hypoglycemia induced by 3-mercaptopico linic acid (3-MP, a gluconeogenesis inhibitor) and effects of 3-MP on gluconeogenesis from glycerol were studied Expeliment 1-glycerol effec t on tumor cell growth; and glycerokinase activity assay. Methylcholan threne-induced (MCA) sarcoma cells were plated in either glucose free glucose ol glycerol containing medium Cell counts and viabilities were recorded daily. Cells in glucose group had normal growth pattern and cell viability, while cell counts and viabilities in control and glyce rol groups decreased markedly F344 rats were injected with MCA-sarcoma cells in the flank Glycerokinase activities in tumor and host liver w ere assayed on day 20. Activities were 12.3 +/- 2.8, 148.2 +/- 17.5 as sayed on day 20. Activities were 12.3 +/- 2.8, 148.2 +/- 17.5 mu mol/g protein/min in tumor and liver; respectively. Experiment 2-glycerol e ffect on animal survival during hypoglycemia induced by 3-MP. Followin g a 48 hour fast, 12 Fischer 344 rats were injected (ip) with 3-MP (20 0 mg/kg) and randomized to saline ol glycerol perfusion (100 mg/kg/hr) groups. Four of 6 rats in the saline group died of hypoglycemia. All rats in the glycerol group survived, but blood glucose levels were inc reased as compared to the saline group. Experiment 3-3-MP effect on gl uconeogenesis from glycerol as compared to lactate 5 x 10(6) hepatocyt es were incubated in glucose-free HBSS containing glycerol (20 mM) or lactate (20 mM) in the presence (0.5 mM) or absence of 3-MP. Glucose p roduction was assayed every 30 minutes for 2 hcs. Glucose production f r-om glycerol was not significantly inhibited in the presence of 3-MP as compared to lactate. Conclusion: Glycerol does nor support MCA-sarc oma growth and promotes animal survival during severe systemic hypogly cemia induced by 3-MP. However, glycerol also led to increased glucone ogenesis in this model. The use of hypoglycemic agents with glycerol p rotection of host tissues warrants further study.