Background To assist the development of new anti-cancer drugs, it is important to identify biomarkers of treatment efficacy in the preclinical phases of drug development. In order to improve the predictivity of preclinical experiments, more realistic animal models are needed, for example, tumors xenografted directly on the prostate gland of rodents. Purpose To characterize the in-vivo metabolism of healthy rat prostate and of an orthotopic human prostate cancer model using proton magnetic resonance spectroscopy (MRS). Material and Methods The highly metastatic and hormone-independent PC3-MM2 human prostate cancer model was implanted into the ventral prostate lobe of three Nude rats. Healthy Nude (n = 6) and Sprague-Dawley (n = 6) rats were also studied for interspecies comparison of normal prostate metabolism. Magnetic resonance imaging and short echo-time (TE 11.2 ms) single voxel PRESS spectroscopy were performed on dorsal (DP) and ventral (VP) prostate as well as tumor at 4.7 T. The metabolic content and volume of dorsal and ventral lobes were characterized as a function of species and age. Results Slightly lower total creatine (tCr)/water (11.3±2.6 vs. 15.3±3.0, NS), but significantly higher Inositol (Ins)/water (18.9±1.9 vs. 6.6±3.3, P < 0.003) and total choline (tCho)/water (15.0±2.1 vs. 5.6±1.1, P< 0.00007) were observed within healthy DP lobes with respect to VP lobes. No significant variation in metabolic content was seen in healthy DP and VP lobes of Nude rats as a function of age, and no species dependence was observed in their metabolic content. For the orthotopic PC3-MM2 tumor, implanted in VP, the tCr/water ratio was significantly lower (3.1±0.9) than neighboring DP (12.8±1.8, P < 0.00003) and healthy VP (15.3±3.0, P < 0.00006). For Ins, the metabolite ratio in PC3-MM2 was close to that of healthy VP (4.3±2.8 vs. 6.6±3.3, p = NS), but much lower than in neighboring DP (19.1±1.3, P < 0.00005). A similar trend was also observed for tCho, where metabolite ratios in PC3-MM2, healthy VP and neighboring DP were 3.5±0.9, 5.6±1.1, and 15.9±0.8, respectively. Conclusion The in-vivo MRS study of healthy prostate and orthotopic prostate cancer is feasible in rats. Such baseline data could be important when following the modifications in metabolism, including during anti-cancer drug development protocols or following radiotherapy.
Pre-conditioning cryosurgery: Cellular and molecular mechanisms and dynamics of TNF-α enhanced cryotherapy in an in vivo prostate cancer model system