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Inhibition of established rat fibrosarcoma growth by the glucose antagonist 2-deoxy-D-glucose
Abstract:
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.
Insights
2-deoxy-D-glucose (2-DG) effectively inhibits sarcoma growth by targeting glucose metabolism. This glucose antimetabolite significantly reduced tumor weight in rats, demonstrating its potential as an anti-cancer agent.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Sarcoma cells exhibit elevated glycolysis compared to normal tissues.
- Tumor growth may be critically dependent on glucose utilization.
- 2-deoxy-D-glucose (2-DG) is a glucose antimetabolite with potential anti-cancer properties.
Purpose of the Study:
- To evaluate the efficacy of 2-deoxy-D-glucose (2-DG) in inhibiting the growth of established methylcholanthrene-induced rat fibrosarcoma.
- To assess the impact of varying 2-DG doses on tumor weight and toxicity.
- To investigate the tissue distribution and retention of radiolabeled 2-DG and the activity of glucose-6-phosphatase (G-6-Pase) in tumor and normal tissues.
Main Methods:
- Methylcholanthrene-induced rat fibrosarcoma models were established with varying tumor cell inoculations or fragments.
- Rats were randomized to receive 2-DG or saline solution at different doses (0.75, 1.5, 1.75 gm/kg) for 10 days.
- Tumor weight was measured, and tissue uptake of [14C]-2-DG and G-6-Pase activity were determined.
Main Results:
- All 2-DG treatment groups showed a significant 50% to 70% reduction in tumor weight compared to controls.
- Substantial toxicity was observed at the highest 2-DG dose (1.75 gm/kg), with minimal toxicity at lower doses.
- Tumors exhibited the highest uptake and prolonged retention of [14C]-2-DG due to low G-6-Pase activity.
Conclusions:
- 2-deoxy-D-glucose (2-DG) effectively inhibits established sarcoma growth by exploiting tumor cell glucose metabolism.
- The mechanism involves rapid tumor cell uptake, impaired metabolism post-phosphorylation, and slow dephosphorylation and release.
- Rat sarcoma growth is reliant on glucose utilization, making it susceptible to inhibition by glucose antagonism.