Radionuclide Therapy of Breast Cancer in Mice with Tritiated 2-Deoxy-D-Glucose

Objectives: To evaluate the therapeutic potential of tritium labeled 2-deoxy-D-glucose in treating breast cancer using a mouse model.

Introduction: Previous research shows a tumoricidal effect on cancer cells from beta positive radiation (positrons) in tumor-bearing mice treated with high doses of F-18 2-deoxy-D-glucose (FDG). The glucose analog 2-deoxy-D-glucose is taken up by cells via the glucose transporter. The lack of a hydroxyl group at the second carbon position prevents this molecule from completing the glycolysis pathway. This results in a high rate of intracellular trapping of 2-deoxy-D-glucose in metabolically active cancer cells. The therapeutic potential of beta minus radiation in treating cancer is well established. Tritium is a unique beta minus emitter with a low energy, short range, and high linear-energy-transfer (LET) decay particle. The therapeutic effectiveness of beta minus radiation delivered via tritium labeled 2-deoxy-D-glucose has not been tested. Hypothesis: Due to preferential uptake and intracellular trapping of 2-deoxy-D-glucose in metabolically active cancer cells, beta minus radiation delivered to tumor-bearing mice via tritiated 2-deoxy-D-glucose will have a therapeutic effect.

Methods: Luciferase-positive 4T1 mouse mammary tumor cells were implanted in mammary fat pads of thirty-six BALB/c mice. After two weeks of tumor growth, three groups of nine mice were stratified based on dose, and each group received a single injection of tritiated 2-deoxy-D-glucose. A fourth group of nine mice received a saline injection and served as a control arm. The high-dose, medium-dose, and low-dose arms received approximately 650 µCi, 50 µCi, and 5 µCi of tritiated 2-deoxy-D-glucose respectively. Mice were imaged weekly with an in vivo infrared optical imaging system to monitor tumor luminescence. Tumors were also measured weekly with calipers. The experiment continued for seven weeks following tumor implantation.

Results: A single mouse in the high-dose arm demonstrated tumor growth, followed by regression, and finally resolution of detectable tumor. Tumor implantation in a mouse in the low-dose arm failed to establish and was never detectable. Tumors in the remaining mice in all treatment arms demonstrated growth rates and metastatic rates comparable to those in the control arm. No mice showed evidence of toxicity from the treatment. One mouse in the low-dose arm expired on the last day of the experiment due to tumor burden prior to euthanasia. Discussion: While only one mouse in the high-dose arm responded to the therapy, this result may demonstrate therapeutic potential of tritiated 2-deoxy-D-glucose. The fact that no mice showed signs of toxicity suggests that the activities used were likely well under the maximum tolerated dose. There are multiple modifications to the dosing regimen that could potentially increase tumor uptake relative to normal tissue uptake, thereby increasing radiation dose to the tumor.

Conclusions: This experiment demonstrates that tritium labeled 2-deoxy-D-glucose is well tolerated in mice at the administered doses. While most of the mice had progression of disease, one mouse in the high-dose arm had evidence of a significant in vivo tumoricidal effect. Further experimentation is needed to determine if the observed tumoricidal effect may be duplicated and optimized with higher doses of the radiopharmaceutical. Acknowledgements: Research reported in this abstract was supported in part by the Cancer Animal Models shared resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.