Use of Mitochondria-Specific Dye MKT-077 as a Radiosensitizer to Preoperatively Treat Locally Advanced Breast Cancer

摘要

The major goal of this project is to determine if the rhodacyanine analog dye, MKT-077, can be used to inhibit breast cancer cell oxygen metabolism and raise tumor oxygen levels, thereby radiosensitizing the tumor. In the second year, we had to switch breast cancer cell lines from the human MDA-MB 231 line to the rat R3230Ac mammary adenocarcinoma line, because we were unable to grow xenografts from the human cells. We have now used the R3230Ac cells in the in vitro experiments to determine drug uptake and subsequent MKT- 077-induced metabolic inhibition, as outlined in Tasks 1 and 2. As noted in the Year 1 report, we are determining MKT-077 drug uptake and metabolic inhibition using cell suspensions. This approach has been successful, and we have been able to show that the cells rapidly take up the drug in a dose-dependent manner, whether the cells have been raised on air or under hypoxic conditions. We have also shown that MKT-077 can inhibit cellular oxygen metabolism by up to 70% at a dose of 6 g/ml in R3230Ac cells grown on 2.5% O2. Our modeling has shown that the magnitude and time course of the inhibition are both concentration- dependent. In addition, we have begun the in vivo work in Fischer 344 rats. Infusion of 7.5 mg/kg MKT-077 resulted in a small rise in PO2 of about 2 mm Hg 10 minutes after the end of the infusion. We are currently completing the in vitro experiments and plan to expand the in vivo work by determining the effects of other drug doses and measuring PO2 histograms.