Failure of 2-Deoxy-o-glucose and 5-Thio-o-glucose to Kill Hypoxie Cells of Two Murine Tumors1

We have administered the glycolysis inhibitors 2-deoxy-oglucose and 5-thio-D-glucose to C3H/HeJ mice bearing KHT or 16/C transplantable tumors to seek evidence for hypoxic cell toxicity in vivo. The drugs were given (a) with or without insulin, (o) as large single doses or as multiple hourly injections, and (c) alone or immediately after the tumors had received radiation to kill most of the aerobic cell population. Tumor response was assessed by growth delay or by lung colony assay. Limiting toxicity of 2-deoxy-o-glucose and 5-thio-D-glucose was neurological, leading to seizures and/or death, and this toxicity was increased by insulin. The drugs had at most minimal effects on the growth of either untreated or irradiated tumors at maximal tolerated doses. Despite the known selective toxicity of these glucose analogues for hypoxic cells in tissue culture, we have found them to be ineffective in killing hypoxic cells of two murine tumors. been found to exert minor effects on the growth of some experimental tumors when used alone (1,9, 17, 18) and at concentrations above 5 mM led to selective toxicity for hypoxic cells in multicellular tumor spheroids (20, 21 ). When used with radiation and hyperthermia, 5-TG was reported to prolong survival of mice bearing a transplanted tumor (19). Drugs which have specific toxicity for hypoxic cells would be expected to have only minor effects when used alone to treat solid tumors but might demonstrate considerable activity when used after a dose of radiation sufficient to kill most of the aerobic cells. Hypoxic cell toxicity in vivo by 2-DG and 5-TG may be expected to depend on duration of drug availability and on their uptake into cells; insulin might be expected to influence drug toxicity by stimulating uptake into cells or by lowering glucose concentration (15). We therefore report a study of 2DG and 5-TG used to treat 2 murine tumors; we have admin istered the drugs as single or multiple doses with and without insulin and have given the drugs either alone or in addition to tumor irradiation.