Po-topic IV-01: CU-ATSM an agent for hypoxia imaging and radiotherapy

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Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is in a class of copper bis(thiosemicarbazones) that we have evaluated in vitro and display uptake that is either nonhypoxia selective (eg, Cu-PTSM) to hypoxia selective. In vivo, Cu-ATSM is rapidly retained in hypoxic tumors and myocardium but diffuses out of normoxic tissue. In experimental tumor models the selective uptake of Cu-ATSM was seen to be pO2 dependent and a direct correlation between tissue uptake of Cu-ATSM and decreased tumor oxygenation was observed. In studies using the Langendorff isolated perfused rat heart model, in which oxygen concentration can be controlled, and in canine models of ischemic myocardium, we have shown that specific retention of Cu-ATSM is due to oxygen depletion. In a study of cervical cancer in humans we have shown that Cu-60-ATSM-PET is an excellent method for assessing tumor hypoxia in patients with cervical cancer. We have shown that the results of Cu-60-ATSM-PET correlate well with patient outcome. In radiotherapy studies, the systemic administration of Cu-64-ATSM has been shown to significantly increase the survival time of hamsters bearing human GW39 colon cancer tumors. Radiotherapy experiments were performed in animals bearing either 7-day (0.5–1.0 g) or 15-day (1.5–2.0 g) old tumors. Studies compared animals treated with escalating doses of Cu-64-ATSM that significantly increased the survival time of tumor-bearing animals. The highest dose, 10 mCi Cu-64-ATSM, increased survival to 135 days in 50% of animals bearing 7-day-old tumors, 6-fold longer than control animals’ survival (20 days), with only transient leucopenia and thrombocytopenia but no overt toxicity. High-resolution MRI and PET using a therapeutic administration of 10 mCi were used to monitor tumor volume and morphology and to accurately assess tumor dosimetry, giving a tumor dose of 81 ± 7.5 rad/mCi. We also investigated whether the intratumoral (i.t.) delivery of Cu-64-ATSM into the GW39 tumor resulted in an increased efficacy compared with an i.v. administration. We further investigated whether ATSM labeled with the shorter-lived Cu-61 would result in tumor regression. Studies were performed by administering i.t. a single dose of either 10 mCi of Cu-64-ATSM (n = 9) or 15.7 mCi of Cu-61-ATSM (n = 10). These levels of radioactivity were determined by dosimetry calculations to deliver identical absorbed doses to the GW39 tumor. MicroPET imaging (n = 2) following Cu-64-ATSM injection determined that the i.t. mode of delivery resulted in a significant difference in biodistribution compared with systemic delivery.