Sildenafil and Phosphofiesterase-5 Inhibitors to Reduce Cardiotoxicity and Enhance the Response of Breast Tumors to Doxrubicin
Abstract
In our studies of the interaction between sildenafil and adriamycin in breast tumor cells and cardiomyocytes, we have made the following observations. In breast tumor cells: 1. Sildenafil fails to protect various breast tumor cell lines against the toxicity of adriamycin. 2. Sildenafil moderately enhances the response to adriamycin in breast tumor cells .3. Sildenafil does not alter the extent of DNA damage induced by adriamycin in breast tumor cells. 4. Adriamycin promotes autophagy in breast tumor cells. 5. Sildenafil appears to increase sensitivity to irradiation in breast tumor cells. In cardiomyocytes: 1. Questions are raised relating to the role of reactive oxygen in the cardiotoxicity of adriamycin. 2. The combination of Herceptin with taxol or adriamycin is relatively toxic in cardiomyocytes. Based on these observations, we propose to further explore the basis for adriamycin cardiotoxicity as well as examining the capacity of sildenafil to protect the heart cells from the combination of Herceptin with Adriamycin and with taxol. We will evaluate the influence of sildenafil on autophagy and senescence in both breast tumor cells and cardiomyocytes. We will pursue the unexpected finding that sildenafil appears to increase sensitivity to radiation in the breast tumor cells by attempting to understand the mechanistic basis for this observation. We will also assess the impact of sildenafil on radiation sensitivity in the cardiomyocyte. These proposed studies are of significance because the heart is known to incur damage during irradiation of the breast during therapy for breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2008
- Accession Number
- ADA486150
Entities
People
- David A. Gewirtz
Organizations
- Virginia Commonwealth University