Enhancing targeted radiotherapy by copper(II)diacetyl- bis(N4-methylthiosemicarbazone) using 2-deoxy-D-glucose.
Most cancer deaths are a consequence of resistance to conventional chemotherapy and radiation therapy. This may be attributable to unique phenotypic characteristics of solid tumors. We have exploited two well-described characteristics of solid tumors commonly associated with treatment failure, high glucose use and hypoxia, to design a unique therapy based on the selective accumulation of two cytotoxic compounds, 2-deoxyglucose (2-DG) and copper(II)diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM). (64)Cu-ATSM localizes to hypoxic regions of tumors and has been used for administering a high local dose of radiation therapy after uptake by cells. 2-DG, a glucose analog, selectively accumulates in cancer cells and interferes with energy metabolism, resulting in cancer cell death. 2-DG has been shown to potentiate the cytotoxic effect of ionizing radiation and certain chemotherapeutic agents. We have tested the effect of 2-DG on tumor response when combined with (64)Cu-ATSM in a mouse breast tumor model using the highly aggressive mouse mammary carcinoma cell line EMT-6. 2-DG administered up to 2 mg/g of body weight daily resulted in no weight loss or systemic symptoms. EMT-6 mammary tumors had similar uptake of [(18)F]fluoro-2-deoxyglucose before and after 2 weeks of 2-DG treatment as determined by microPET imaging, indicating that resistance to 2-DG uptake does not develop. Pretreatment of tumor-bearing mice with 2-DG resulted in increased uptake of (64)Cu-ATSM by tumors compared with nontreated mice. This effect was not observed with the nonhypoxia-specific agent copper(II)pyruvaldehyde-bis(N(4)-methylthiosemicarbazone. When 2-DG was combined with a single dose of (64)Cu-ATSM (2 mCi), tumor growth was inhibited approximately 60% compared with untreated mice, and animals survived approximately 50% longer than untreated mice or animals treated with each agent alone (32 versus 20 days). The maximum effect on tumor growth and survival was observed when 2-DG was administered daily for the lifetime of the mouse. Our results indicate that 2-DG potentiates the effect of (64)Cu-ATSM on tumoricidal activity and animal survival. We hypothesize that 2-DG alters the metabolic state of the cell, leading to increased uptake of (64)Cu-ATSM by the tumor. This would result in a higher local dose of radiotherapy. The continued presence of 2-DG would then prevent the repair of damaged cells, leading to inhibition of tumor growth. Our data indicate that the strategy of combining tumor-specific cytotoxic agents that function by differing mechanisms can result in an effective, selective, tumor-specific cell death with minimal effect on the host.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D056831:Coordination Complexes; D003301:Copper Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use; D003847:Deoxyglucose / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D013882:Thiosemicarbazones / Q000493:pharmacokinetics* / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D019788:Fluorodeoxyglucose F18; D003847:Deoxyglucose