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New therapeutic strategies for non-muscle invasive bladder cancer: effects of BCG and P-mapa immunotherapies on the steroid hormone receptors and reactive oxygen species

Grant number: 12/20706-2
Support type:Regular Research Grants
Duration: February 01, 2013 - January 31, 2015
Field of knowledge:Health Sciences - Medicine - Surgery
Principal Investigator:Wagner José Fávaro
Grantee:Wagner José Fávaro
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Assoc. researchers:Athanase Billis ; Nelson Eduardo Duran Caballero ; Patrick Vianna Garcia ; Priscyla Daniely Marcato Gaspari

Abstract

The low degree of effectiveness of current therapies against the non-muscle invasive bladder cancer (NMIBC) and the progression control and malignancy of tumors in females may be related to modulation of androgen (AR) and estrogens (ERS) receptors in the mechanisms of tissue repair and reactive oxygen species (ROS). In many cancers, the interaction of AR and ERS with ROS potentiates the primary lesion triggering the rapid progression and increasing the chances of malignancy of tumors. The treatment of NMIBC with Bacillus Calmette-Guerin (BCG) has proven effective in reducing recurrence and tumor progression although there are side effects of various intensity from light irritative symptoms to severe systemic reaction. The development of various immunotherapies has become an invaluable therapeutic option. In this context, highlight the P-MAPA which for greater versatility and minimum cytotoxicity revealed through preliminary studies in vivo and in vitro opens a new perspective to combat some types of cancer including NMIBC. The aims of this study will characterize and compare the effects of immunotherapy with BCG and P-MAPA on the steroids receptors in the NMIBC treatment induced in rats and to establish possible action mechanisms of these immunotherapies involving cellular repair pathways, ROS and steroids receptors. For induction of NMIBC, 63 animals will be chemically induced to cancer through a dose of 1.5 mg/Kg of N-methyl-N-nitrosourea (MNU) dissolved in sodium citrate (1M pH 6.0) at 15 days (weeks 0, 2, 4, 6) total of 4 doses. The other 7 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 in 9 groups (7 animals per group). MNU Group (Cancer - Group 2): It will receive intravesical dose of 0.3 mL of 0.9% saline for 6 weeks, MNU + Flutamide Group (Group 3): It will receive subcutaneous injections of 10 mg/Kg of Flutamide each 48h for 6 weeks to block androgen receptor; MNU + Tamoxifen Group (Group 4): It will receive subcutaneous injections of 1mg/kg of tamoxifen each 48 hours for 6 weeks to block the estrogen receptors (ER± and ER²), MNU + BCG Group (Group 5): It will receive a dose of intravesical 40 mg of BCG for 6 weeks consecutive, MNU + P-MAP Group (Group 6):It will receive intravesical dose of 5 mg/Kg of P-MAPA for 6 weeks, MNU + BCG + Flutamide Group (Group 7) will be treated simultaneously with Flutamide and BCG in according to 3 and 5 groups, MNU +BCG + Tamoxifen Group (Group 8): It will be treated simultaneously with BCG and tamoxifen in according to groups 4 and 5, MNU + P-MAPA + Flutamide Group (Group 9): It will be treated simultaneously with P-MAPA and Flutamide in according to 3 and 6 groups; MNU + P-MAPA+ Tamoxifen Group (Group 10): It will be treated simultaneously with P-MAPA and tamoxifen groups according to 4 and 6 groups. After 16 weeks of treatment, the animals will be euthanized and the urinary bladders collected and analyzed for histopathological, immunohistochemical, Western Blotting and serum hormone and tissue levels. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GARCIA, PATRICK VIANNA; FERREIRA SEIVA, FABIO RODRIGUES; CARNIATO, AMANDA POCOL; DE MELLO JUNIOR, WILSON; DURAN, NELSON; MACEDO, ALDA MARIA; DE OLIVEIRA, ALEXANDRE GABARRA; ROMIH, ROK; NUNES, ISEU DA SILVA; NUNES, ODILON DA SILVA; FAVARO, WAGNER JOSE. Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier. BMC CANCER, v. 16, JUL 7 2016. Web of Science Citations: 9.
GARCIA, PATRICK VIANNA; APOLINARIO, LETICIA MONTANHOLI; BOECKELMANN, PETRA KARLA; NUNES, ISEU DA SILVA; DURAN, NELSON; FAVARO, WAGNER JOSE. Alterations in ubiquitin ligase Siah-2 and its corepressor N-CoR after P-MAPA immunotherapy and anti-androgen therapy: new therapeutic opportunities for non-muscle invasive bladder cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY, v. 8, n. 5, p. 4427-4443, 2015. Web of Science Citations: 9.

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