Effects of P-MAPA immunotherapy associated with antiangiogenic therapy in the treatment of chemically induced prostatic lesions in rats

Abstract

The low level of effectiveness of current therapies against proliferative prostate lesions may be related to modulation of steroid hormone receptors in the mechanisms of tissue repair, angiogenesis and reactive oxygen species (ROS). In many cancers, the interaction of steroid hormone receptors with the ROS increases primary lesions triggering the rapid progression and increasing the malignancy of lesions. Further, the multifaceted nature of the process of angiogenesis in malignant tumors suggests that antiangiogenic drugs in combination with agents that modulate pro and antioxidants species may be more effective than therapies involving only a single agent. The development of immunotherapies against cancer became a valuable treatment option. In this context, P-MAPA shows a new perspective on the combat of some types of cancers, including the prostatic, because of its versatility and minimal cytotoxicity. Thus, considering the importance of alternative treatments that reduce rates of recurrence, progression and their impact on clinical outcomes of patients with proliferative prostate lesions, the aims of this study are to characterize and to compare the morphological, the molecular and the biochemical effects of antiangiogenic therapy associated with P-MAPA in the treatment of chemically induced prostatic lesions, as well as, to establish possible mechanisms of action of these therapies involving repairer and inducer factors and the repair of cell injury, sex steroid hormone receptors, angiogenesis and antioxidant enzymes. A total of 40 male rats of the Fischer 344 strain are going to be used. For induction of prostatic lesions, 20 animals are going to receive daily subcutaneous dose of 100 mg/Kg of testosterone cypionate. Thereafter, the animals are going to be anesthetized for inoculation of 15 mg/Kg of N-methyl-N-nitrosourea (MNU) in the ventral lobe of the prostate capsule every 15 days, totalizing two doses. One week after the last dose of MNU, 20 animals are going to receive subcutaneous injections of 5mg/kg of testosterone cypionate every other day for 120 days. The other 20 animals will be considered as Control Groups. After 120 days of induction, all animals shall undergo ultrasound exams to check for prostate lesions and subsequently subdivided into eight groups (5 animals per group): control group (Group 1): is going to receive subcutaneous injections of 5 ml / kg of 0.9% saline solution three times per week for 30 days; Control Group P-MAPA (Group 2) is going to receive subcutaneous injections of 5 mg/kg of P-MAPA, three times per week for 30 days; Control Group + TNP-470 (Group 3): is going to receive subcutaneous injections of 15 mg/kg of TNP-470, three times a week for 30 days; Control Group + P-MAPA + TNP- 470 (Group 4) is going to receive simultaneous treatment with P-MAPA and TNP-470 according to the same protocols as set forth in Groups 2 and 3; Group MNU (Prostatic Lesions - Group 5): is going to receive the same treatment as Group 1 and Group MNU + P-MAPA (Group 6): is going to receive the same treatment as Group 2 and Group MNU + TNP-470 (Group 7): receive the same treatment as Group 3 and Group MNU + P-MAPA + TNP- 470 (Group 8) is going to receive simultaneous treatment with P-MAPA and TNP-470 according to the same protocols as set forth in Groups 2, 3, 4, 6 and 7. After 150 days of treatment, samples of the ventral prostate lobe of all animals are going to be collected and tested for histopathological, immunohistochemical, western blotting, biochemical and toxicological analysis. (AU)