Recent studies indicate that therapeutic efficacy of anti-cancer therapy could be correlated with early tumor apoptotic responses. Therefore, evaluation of early tumor apoptosis could be instrumental in prediction of therapy outcome. In vivo imaging of the whole tumor may represent a sensitive and powerful approach, as this method does not involve invasive techniques and provides complete information about apoptosis in the entire tumor. The long-term goal of this proposal is to develop a novel method for sensitive and specific apoptosis imaging for prediction of early tumor apoptotic response to chemotherapy. The main objectives of this proposal are (i) to use a fluorescent dye, TO-PRO-3, for optical imaging of tumor apoptosis in vivo; and (ii) to apply this technique for prediction of drug efficacy. We selected to use TO-PRO-3 because it is permeable only to dead and dying cells and becomes strongly fluorescent only upon binding the DNA of these cells, thus minimizing the background from non-specific absorption to tissues. In addition, its spectral characteristics make it highly suitable for optical imaging. The following Specific Aims are proposed: 1. To develop and optimize optical imaging of tumor apoptosis with TO-PRO-3 in mouse xenografi model of human melanoma. Nude mouse xenograft model of MCF-7 breast carcinoma will be utilized. We will evaluate possible toxicity of TO-PRO-3 and determine dose and time schedules of TO-PRO-3 for the most sensitive detection of tumor apoptosis. Furthermore, we will perform immunohistochemical analysis of drug-treated tumors in order to correlate the in vivo and ex vivo imaging results. Finally, we will confirm the advantage of TO-PRO-3 over 99mTc-labeled annexin V methods for in vivo imaging of tumor drug responses. 2. To correlate the level of drug-induced apoptosis with therapeutic drug responses in melanoma and breast cancer models. In this Specific Aim, we will evaluate drug-induced tumor apoptosis by optical imaging after multiple drug treatments and its correlation with tumor growth inhibition. This will allow determination of its predictive value for disease outcome. Nude mouse xenografts of MCF-7 tumor cell lines will be utilized and the effects of doxorubicin will be evaluated. The proposed study would result in the development of the novel highly sensitive and specific technique for early prediction of tumor drug response. This will allow rapid individual assessment and optimization of treatment of cancer patients while minimizing the unnecessary drug toxicity.
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| Lokshin, Anna; Raskovalova, Tatiana; Huang, Xiaojun et al. (2006) Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells. Cancer Res 66:7758-65 |
