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Intravesical Thalidomide boosts bacillus Calmette-Guérin (BCG) in non-muscle invasive bladder cancer treatment

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Abstract

The aim of this study was to explore the efficacy of intravesical Thalidomide (immunomodulatory, anti-inflammatory and anti-angiogenic) added to BCG using an immune competent autochthonous orthotopic NMIBC animal model. Female Fischer 344 rats, 7 weeks of age, received every 2 weeks for four times, a dose of 1.5 mg/kg of N-methyl-N-nitrosourea (MNU) intravesically. The rats were randomized into four groups (n = 10 per group) to receive intravesical treatment once a week for 6 weeks as follows: control (0.2 ml vehicle), BCG (2 × 106 CFU of Connaught strain in 0.2 ml), Thalidomide (20 mg/kg in 0.2 ml) and BCG-Thalidomide in 0.2 ml. At week 15, bladders were collected for histopathology, cell turnover index by immunohistochemistry and immunoblotting quantification of 4E-BP1 and p70S6K1 for downstream mTOR proliferation signaling and HIF and VEGF for angiogenesis pathway. Thalidomide-BCG association showed a trend for normal histopathology and down-regulation of cell turnover, p70S6K1, HIF-1 and VEGF. 4E-BP1 was up-regulated by treatment, especially in the Thalidomide groups, supporting that its regulation occurs independently of p70S6K1 on mTOR pathway in NMIBC. Intravesical BCG-Thalidomide might represent a significant increment in NMIBC treatment, suggesting p70S6K1, HIF-1 and VEGF as potential molecular target candidates in a clinically relevant immune competent NMIBC model.

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Abbreviations

NMIBC:

Non-muscle invasive bladder cancer

BCG:

Bacillus Calmette-Guérin

IMiDs:

Immunomodulatory Thalidomide analogs

MNU:

N-Methyl-N-nitrosourea

BSA:

Bovine serum albumin

HRP:

Horseradish peroxidase

VEGF:

Vascular endothelial growth factor

HIF:

Hypoxia-inducible factor

mTOR:

Mammalian target of rapamycin

4E-BP1:

Elongation-initiation factor 4E-binding protein 1

p70S6K1:

p70S6 kinase-1

p:

Phosphorylated

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Acknowledgements

Funding was provided by CAPES, Brazil (Grant No. BEX 14679/13-2), and CNPq Research Productivity, Brazil (Grant No. 302622/2015-2).

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Authors and Affiliations

  1. Urologic Oncology Department, Pontifical Catholic University of Campinas (PUC-Campinas), Av. John Boyd Dunlop, s/n, Campinas, São Paulo, CEP: 13060-904, Brazil

    Amilcar C. de Mattos & Leonardo O. Reis

  2. UroScience and School of Medical Sciences, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil

    Gabriela R. Passos, Juliana A. Camargo, Karen L. Ferrari, Mário J. A. Saad & Leonardo O. Reis

Authors
  1. Gabriela R. Passos
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  2. Juliana A. Camargo
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  3. Karen L. Ferrari
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  4. Mário J. A. Saad
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  5. Amilcar C. de Mattos
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  6. Leonardo O. Reis
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Contributions

GRP helped in data collection, data analysis and manuscript writing; JAC and KLF collected and analyzed the data and wrote the manuscript; ACM collected and analyzed the data and edited the manuscript; MJAS contributed to manuscript editing and funding acquisition; and LOR helped in project development, funding acquisition, manuscript editing and supervision.

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Correspondence to Leonardo O. Reis.

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All the authors declare that they have no conflict of interest.

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Passos, G.R., Camargo, J.A., Ferrari, K.L. et al. Intravesical Thalidomide boosts bacillus Calmette-Guérin (BCG) in non-muscle invasive bladder cancer treatment. Med Oncol 35, 3 (2018). https://doi.org/10.1007/s12032-017-1067-2

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