Effect of p-mapa associated with block receptor type 1 angiotensin (AT1) in the Cancer of bladder non-muscle invasive treatment

Abstract

The high rates of non-muscle invasive bladder cancer (NMIBC) recurrence may be related to the low effects of these therapies on the mechanisms of tissue repair, angiogenesis, and Reactive Oxygen Species (ROS). Nowadays, the most effective therapy for NMIBC is the Bacillus Calmette-Guerin (BCG) immunotherapy associated with transurethral resection. However, BCG causes side effects of different intensities from irritative symptoms to serious systemic reaction, which contributes to treatment interruption besides increasing cancer index recurrence after treatment, up to 30%. Also, the multifaceted nature of the angiogenesis process in malignant tumors suggests that the combination of drugs with antiangiogenic agents that modulate antioxidant species may be more effective than therapies involving only a single agent. In this context, stands out the immunomodulator P-MAPA for its versatility and minimal cytotoxicity revealed by preliminary studies in vivo and in vitro opening a new perspective for combating some types of cancers, including bladder cancer (NMIBC). Furthermore, the association of antiangiogenic drugs (Losartan) and P-MAPA may be an alternative more effective than conventional therapies with regard to the recurrence of tumors in non-muscle invasive bladder tumors and their malignancy. The aim of this study is to characterize and compare the histopathological and molecular effects of the immunomodulator P-MAPA concomitant to use of losartan (receptor blocker type 1 angiotensin II - AT1) in the NMIBC treatment of induced rats, as well as establish possible mechanisms of action of these immunotherapies involving cellular repair pathways and angiogenesis. For NMIBC, 20 animals are going to be chemically induced with a dose of 1.5 mg/kg of N-methyl-N-nitrosourea (MNU) dissolved in 0.3 ml sodium citrate (1M pH 6.0) every 15 days (week 0, 2, 4, 6), a total of four doses. The other five animals that did not receive MNU will be considered as the control group (Group 1). Two weeks after the last dose of MNU, the animals will be examined by cystography to evaluate the occurrence of tumor and subsequently divided into 4 groups (5 animals per group): Group MNU (Cancer - Group 2): is going to receive an intravesical dose of 0.3 mL 0.9% saline solution for 6 consecutive weeks; Group MNU + LOSARTAN (Group 3): is going to receive an oral dose of 75 mg/kg Losartan dissolved in 0.2 mL of 0.9% saline once a day for 6 consecutive weeks to block angiogenesis; Group MNU + P-MAPA (Group 4): is going to receive an intravesical dose of 5 mg/kg P-MAPA dissolved in 0.3 mL of 0.9% saline for 6 consecutive weeks; Group MNU + P-MAPA + LOSARTAN (Group 5) is going to receive simultaneous treatment with Losartan and P-MAPA according to 3 and 4 groups. After 16 weeks of treatment, the animals will be euthanized and urinary bladders collected and subjected to histopathological analysis, immunohistochemistry, and Western Blotting.(AU)