Use of Mitochondria-Specific Dye MKT-077 as a Radiosensitizer to Preoperatively Treat Locally Advanced Breast Cancer
Abstract
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. During the third year of the project, we completed the proposed in vitro experiments and much of the proposed in vivo work. We have shown that R3230Ac breast cancer cells rapidly take up MKT-077 in a dose-dependent manner, although cells raised on air take up more drug than cells grown under hypoxic conditions. Interestingly, low oxygen levels during drug exposure slow the uptake of MKT-077, regardless of the oxygen level at which the cells were raised. We have also shown that MKT-077 can inhibit cellular oxygen metabolism by up to 70% in R3230Ac cells grown on air (21% O2), 2.5% O2, or 1% O2 in a dose-dependent fashion. The magnitude of consumption inhibition was correlated with cellular drug uptake. Finally, and most importantly, we have demonstrated that IV infusion of 10 mg/kg MKT-077 over 60-80 minutes results in a significant increase in tumor oxygen tension (PO2) and a decrease in hypoxic fraction in R3230Ac mammary tumors growing in Fischer 344 rats. Since lower doses and the same dose infused over a much shorter time did not alter tumor PO2, dose scheduling is extremely important for MKT-077 efficacy. We have requested a no-cost extension to further explore the dosing in Task 3 and possibly perform the proposed radiation study (Task 4).
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2008
- Accession Number
- ADA485466
Entities
People
- Rodney D. Braun
Organizations
- Wayne State University