Most
neoplasms are dependent on
glucose as their primary fuel, and their ambient
glucose levels tend to be rather low owing to wasteful aerobic glycolysis and poor perfusion. Previous attempts to starve
tumors by inducing
hypoglycemia have foundered on the fact that the CNS and other tissues have high
glucose requirements. Burt has proposed that, inasmuch as
hypoglycemia-sensitive normal tissues can make efficient use of
glycerol, whereas many or most
cancers cannot,
hypoglycemic cancer therapy may be feasible if
glycerol is concurrently infused. Unfortunately, when Burt used
3-mercaptopicolinate to inhibit gluconeogenesis and thereby induce
hypoglycemia in fasted
tumor-bearing subjects, infused
glycerol served as gluconeogenic substrate, raising the serum
glucose level. Agents which inhibit gluconeogenesis more distally - namely at the level of
glucose-6-phosphatase or of
fructosediphosphatase - may prevent the gluconeogenic response to
glycerol, making
glycerol-rescued
hypoglycemic therapy of
cancer feasible. In fact, certain new drugs being developed for diabetes
therapy -
chlorogenic acid derivatives and 'compound A' - are potent inhibitors of
glucose-6-phosphatase, and both
AICA riboside and 2,5-anhydro-D-mannitol have potential as clinical inhibitors of
fructosediphosphatase.
Insulin also can inhibit gluconeogenesis, both proximally and distally, and can potentiate
hypoglycemia by promoting muscle
glucose uptake; thus, coinfusion of high-dose
insulin and of
glycerol may represent an alternative viable strategy. Further research along these lines may enable
glycerol-rescued
hypoglycemia to become a feasible
cancer therapy that has particular value as a
complement to antiangiogenic measures.