Inhibition of established rat fibrosarcoma growth by the glucose antagonist 2-deoxy-D-glucose.
Inhibition of established rat fibrosarcoma growth by the glucose antagonist 2-deoxy-D-glucose.
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作者：
K. Kern;J. Norton
肉瘤细胞表现出比正常组织更高的糖酵解率，可能依赖于葡萄糖的利用来生长。因此，我们测试了葡萄糖抗代谢物2-脱氧-d -葡萄糖（2- dg）在三组F344大鼠中通过增加肿瘤皮下接种(2 × 10（6)个细胞，1 × 10(7)个细胞和1毫米肿瘤碎片）抑制已建立的甲基胆碱诱导的大鼠纤维肉瘤的能力。从肿瘤植入后第3天开始，连续10天，随机给予2-DG或生理盐水，剂量分别为0.75、1.5、1.75 gm/kg。第14天切除肿瘤并称重。在腹腔注射放射性标记的2-DG后，我们测量了肿瘤、脑、肝脏和肌肉组织[14C]-2-DG的水平。在这些组织中，我们测定了葡萄糖-6-磷酸酶（G-6-Pase）的活性，这种酶可以使细胞内糖酵解抑制剂2-DG-6-磷酸去磷酸化，从而逆转2-DG的抗肿瘤作用。与生理盐水对照组相比，2-DG治疗组的肿瘤重量均显著减少50%至70%。2-DG在最高剂量时毒性显著，但在中、低剂量时毒性最小。肿瘤对[14C]-2-DG的摄取最大，低水平的G-6-Pase导致长时间滞留和最高组织水平的放射性标记2-DG。使用2-DG抑制已建立的肉瘤生长，因为它能迅速转运到肿瘤中，磷酸化后不能代谢，并且被去磷酸化并缓慢地从肿瘤细胞中释放。大鼠肉瘤的生长依赖于葡萄糖的利用，葡萄糖拮抗剂可以有效地抑制肉瘤的生长。
Sarcoma cells exhibit higher rates of glycolysis than normal tissues and may be dependent on glucose utilization for growth. Accordingly, we tested the ability of the glucose antimetabolite 2-deoxy-D-glucose (2-DG) to inhibit the growth of an established methylcholanthrene-induced rat fibrosarcoma in three groups of F344 rats with increasing subcutaneous inoculations of tumor (2 X 10(6) cells, 1 X 10(7) cells, and 1 mm tumor fragments). Rats were randomized to receive 2-DG or saline solution at doses of 0.75 gm/kg, 1.5 gm/kg, or 1.75 gm/kg, beginning 3 days after tumor implantation and continuing for 10 days. Tumors were removed and weighed on day 14. We measured tissue [14C]-2-DG levels in tumor, brain, liver, and muscle after intraperitoneal injection of radiolabeled 2-DG. In these same tissues we determined the activity of glucose-6-phosphatase (G-6-Pase), an enzyme which dephosphorylates the intracellular glycolytic inhibitor 2-DG-6-phosphate, thus reversing the antitumor effect of 2-DG. All groups treated with 2-DG had a significant reduction in tumor weight of 50% to 70% when compared with saline solution-treated controls. Toxicity was substantial at the highest dose of 2-DG, but minimal toxicity was noted at intermediate and low doses. Tumor had the greatest uptake of [14C]-2-DG, with low levels of G-6-Pase leading to prolonged retention and highest tissue levels of radiolabeled 2-DG. Use of 2-DG inhibits established sarcoma growth because it is rapidly transported into tumors, cannot be metabolized after phosphorylation, and is dephosphorylated and released slowly from tumor cells. Rat sarcoma growth is dependent on glucose utilization and can be effectively inhibited by glucose antagonism.