Clinical genitourinary cancer · 2017
Intravesical Immunomodulatory Imiquimod Enhances Bacillus Calmette-Guérin Downregulation of Nonmuscle-invasive Bladder Cancer.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Camargo Juliana A, Passos Gabriela R, Ferrari Karen L, Billis Athanase, Saad Mário J A, Reis Leonardo O
Аннотация
BACKGROUND: The Toll-like receptor (TLR)2/4 agonist bacillus Calmette-Guérin (BCG), although not failure proof, has been the most efficient immunomodulatory treatment of immunogenic nonmuscle-invasive bladder cancer (NMIBC) for > 40 years. We investigated the role of the immunomodulatory molecule TLR7 agonist imiquimod through the BCG key receptors TLR2/4 and the main downstream molecules of the mammalian target of rapamycin pathway in NMIBC treatment.
MATERIALS AND METHODS: A total of 40 Fischer-344 rats, 7 weeks old, received 4 doses of 1.5 mg/kg N-methyl-N-nitrosourea intravesically on weeks 0, 2, 4, and 6 for cancer induction. At week 8, the rats were randomized into 4 groups (10 per group) and treated intravesically once a week for 6 weeks: control (0.2 mL of vehicle); BCG (2 × 106 colony-forming units Connaught strain in 0.2 mL); imiquimod (20 mg/kg in 0.2 mL), and associated treatment BCG plus imiquimod in 0.2 mL. The bladders were extracted and analyzed for histopathology, immunohistochemistry, cell proliferation (Ki-67), apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling [TUNEL]), and immunoblotting for TLR2, TLR4, p-P70S6K, and p-4E-BP1 proteins.
RESULTS: The histopathology results showed that BCG and imiquimod decreased bladder tumorigenesis compared with the control group, with a proliferation decrease (Ki-67) and an apoptosis increase (TUNEL). BCG upregulated TLR2/4, imiquimod upregulated TLR4, and both downregulated P70S6K1.
CONCLUSION: Imiquimod is able to efficiently decrease bladder carcinogenesis through upregulation of TLR7/4 and downregulation of P70S6K1 protein, generating new perspectives to boost BCG effects in the future.
MATERIALS AND METHODS: A total of 40 Fischer-344 rats, 7 weeks old, received 4 doses of 1.5 mg/kg N-methyl-N-nitrosourea intravesically on weeks 0, 2, 4, and 6 for cancer induction. At week 8, the rats were randomized into 4 groups (10 per group) and treated intravesically once a week for 6 weeks: control (0.2 mL of vehicle); BCG (2 × 106 colony-forming units Connaught strain in 0.2 mL); imiquimod (20 mg/kg in 0.2 mL), and associated treatment BCG plus imiquimod in 0.2 mL. The bladders were extracted and analyzed for histopathology, immunohistochemistry, cell proliferation (Ki-67), apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling [TUNEL]), and immunoblotting for TLR2, TLR4, p-P70S6K, and p-4E-BP1 proteins.
RESULTS: The histopathology results showed that BCG and imiquimod decreased bladder tumorigenesis compared with the control group, with a proliferation decrease (Ki-67) and an apoptosis increase (TUNEL). BCG upregulated TLR2/4, imiquimod upregulated TLR4, and both downregulated P70S6K1.
CONCLUSION: Imiquimod is able to efficiently decrease bladder carcinogenesis through upregulation of TLR7/4 and downregulation of P70S6K1 protein, generating new perspectives to boost BCG effects in the future.
Предметные рубрики MeSH
Adjuvants, ImmunologicAdministration, IntravesicalAnimalsBCG VaccineCell ProliferationDrug SynergismFemaleGene Expression Regulation, NeoplasticImiquimodMethylnitrosoureaRandom AllocationRatsRats, Inbred F344Ribosomal Protein S6 Kinases, 70-kDaToll-Like Receptor 2Toll-Like Receptor 4Treatment OutcomeUrinary Bladder NeoplasmsXenograft Model Antitumor Assays