McCarty M F
Pantox Laboratories, San Diego, California 92109, USA.
Med Hypotheses. 2001 Mar;56(3):286-9. doi: 10.1054/mehy.2000.1156.
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.
大多数肿瘤依赖葡萄糖作为主要燃料，由于有氧糖酵解的浪费和灌注不良，其周围的葡萄糖水平往往相当低。以前试图通过诱导低血糖来饿死肿瘤的尝试都失败了，原因是中枢神经系统和其他组织对葡萄糖的需求量很大。伯特提出，鉴于对低血糖敏感的正常组织能够有效利用甘油，而许多或大多数癌症组织则不能，如果同时输注甘油，低血糖癌症治疗可能是可行的。不幸的是，当伯特使用3-巯基吡啶酸盐抑制糖异生从而在禁食的荷瘤受试者中诱导低血糖时，输注的甘油充当了糖异生底物，提高了血糖水平。在更下游抑制糖异生的药物——即在葡萄糖-6-磷酸酶或果糖二磷酸酶水平——可能会阻止对甘油的糖异生反应，使甘油挽救的癌症低血糖治疗变得可行。事实上，正在开发用于糖尿病治疗的某些新药——绿原酸衍生物和“A化合物”——是葡萄糖-6-磷酸酶的有效抑制剂，而AICA核苷和2,5-脱水-D-甘露醇都有作为果糖二磷酸酶临床抑制剂的潜力。胰岛素也可以在近端和远端抑制糖异生，并通过促进肌肉摄取葡萄糖来增强低血糖；因此，高剂量胰岛素和甘油的共同输注可能是一种可行的替代策略。沿着这些思路的进一步研究可能会使甘油挽救的低血糖成为一种可行的癌症治疗方法，作为抗血管生成措施的补充具有特殊价值。
