Effects of PMAPA immunotherapy associated with antiangiogenic therapy in the treatment of chemically induced prostatic lesions in rats

The low level of effectiveness of current therapies against proliferative prostatic lesions may be related to the modulation of steroid hormone receptors, tissue repair mechanisms, angiogenesis and reactive oxygen species formation. The multifaceted process of angiogenesis in malignant tumors suggests that the combination of drugs with antiangiogenic agents modulating pro and antioxidants species is more effective than single agent therapies. In this scenario, we highlight PMAPA, an immunomodulator which opens a new perspective to fight some types of cancers, including prostate cancer (PC). In the present study, we characterized and compared the morphological and molecular effects of antiangiogenic therapy combined with PMAPA immunotherapy in the treatment of prostatic lesions and seek to establish possible mechanisms of action of these therapies involving molecular factors of cell injury, sex hormone steroid receptors, angiogenesis and antioxidant enzymes. 25 male rats Fischer 344 were used. For induction of prostatic lesions, 20 animals received daily subcutaneous dose of 100mg/kg of testosterone cypionate and were anesthetized for instillation of 15 mg/kg of MNU in the prostate capsule of the ventral lobe, one every 15 days, totaling 2 doses. After the last dose of MNU, animals received subcutaneous injections of 5 mg/kg of testosterone cypionate every other day for 120 days. Other 5 animals were considered control. After induction, the animals were divided into 5 groups: control group: received subcutaneous injections of 5 ml/kg of 0.9% saline solution three times a week for 30 days; MNU group received subcutaneous injections of 5 ml/kg of 0.9% saline solution three times a week for 30 days; MNU+TNP470 group: received subcutaneous injections of 15 mg/kg of TNP470 three times a week for 30 days; MNU+PMAPA group: received subcutaneous injections of 5 mg/kg of PMAPA three times a week for 30 days and MNU+TNP470+PMAPA group: both treated with TNP470 and PMAPA. After 150 days, samples of prostate ventral lobe of all animals were collected, weighed and normalized by body weight of each animal and submitted to histopathology, immunohistochemistry and Western Blotting. Our results demonstrated that our chemical induction method of prostatic lesions was effective in the promotion of premalignant (PIN and PIA) and malignant (adenocarcinoma) lesions in Fischer 344 strain, making it a suitable model for trials of efficacy and toxicity of new therapeutic perspectives against PC. PMAPA and TNP470¿s effects were different on premalignant and malignant lesions and affected steroid hormone receptors levels and tissue repair, oxidative stress and angiogenesis pathways. PMAPA demonstrated significant antitumor activity against intermediate grade and high-grade adenocarcinomas and was also effective against proliferative inflammatory atrophy (PIA). The association of PMAPA with TNP470 was the best therapeutic approach against PIN and PIA, but was less effective against prostate adenocarcinoma than PMAPA alone (AU)