Deoxyglucose treatment of non-small cell lung cancer

Abstract

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Objectives: In recent years the success of PET imaging with the glucose analog fluorodeoxyglucose (FDG) has demonstrated that markedly accelerated glucose use is a common feature of most malignant tumors. Therefore, glucose utilization appears to be an attractive therapeutic target in a variety of cancers. In the present study we performed experiments to determine the sensitivity of non-small cell lung cancer (NSCLC) to treatment with the glucose analog deoxyglucose (DG).

Methods: We used the human NSCLC cell line HCC4006 as a tumor model. Cells were incubated in vitro with deoxyglucose at concentrations ranging from 0.05 to 1.2 mg/mL. The glucose concentration in the culture media was 2 mg/mL. Cell viability was assessed by trypan blue staining after 1/2/3/4 days of incubation. In addition exogenous glucose use of cancer cells was assessed by measuring FDG uptake of cells before and early during deoxyglucose treatment. In Vivo eight to ten weeks old severe combined immunodeficient (SCID) mice were co- injected with approximately 500mg/kg DG spiked with 300µCi [18F]FDG. Then 1h dynamic microPET scans were performed and the biodistribution of DG in various organs was determined.

Results: The IC50 of DG for growth inhibition of HCC4006 cells was approximately 0.1 mg/mL. FDG-uptake of cells co-incubated with 2 mg/ml glucose and 0.1 mg/ml deoxyglucose was not significantly different from cells incubated with 2 mg/ml glucose alone. This indicates that at this concentration deoxyglucose had only minimal effects on tumor cell glucose utilization by competitive inhibition of glucose transport and phosphorylation. Therefore, the growth inhibitory effect of deoxyglucose is likely related to intracellular accumulation of deoxyglucose-6 phosphate. DG tissue concentrations were determined for liver, kidney, heart, brain and skeletal muscle. Between 5% and 9% of the injected dose of DG reached these organs, corresponding to tissue concentrations of 0.6-1.1 mg/ml DG. Treatment with 500 mg/kg DG twice/week was well tolerated by the animals.

Conclusions: Deoxyglucose may inhibit tumor cell growth by other mechanisms than competitive inhibition of glucose transport and phosphorylation. This may facilitate the use of deoxyglucose for cancer treatment in patients, where competitive inhibition of cerebral glucose utilization is a major concern. Treatment of mice with 500 mg/kg DG does not cause significant side effects and achieves tissue concentrations of DG that can markedly inhibit growth of non-small cell lung cancer cells. These findings are promising for the use of DG for the treatment of non-small cell lung cancer.