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Tumor-Suppressing, Immunostimulating, and Hepatotoxic Effects of Immunostimulatory RNA in Combination with Dacarbazine in a Murine Melanoma Model

  • MOLECULAR CELL BIOLOGY
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Abstract

Melanoma is one of the most aggressive tumors and is accompanied by the induction of local and systemic inflammatory responses. Combinations of chemotherapeutic agents with immunotherapy are therefore commonly used for melanoma treatment. A B16 melanoma model was used to study the tumor suppressive, immunostimulating, and hepatotoxic effects of a combination of a small double-stranded immunostimulatory RNA (isRNA) with 3'-trinucleotide overhangs and the cytotoxic drug dacarbazine compared with respective monotherapies. The drugs efficiently suppressed the tumor growth and acted synergistically. Histological and immunohistochemical examinations of tumor nodes showed that the combination of isRNA and dacarbazine significantly decreased mitotic activity and more efficiently increased apoptosis in tumor tissue as compared with either monotherapy. Regardless of the treatment regimen, signs of immune activation were observed in the spleen, including an increase in the number and diameter of lymphoid follicles and the volume density of the white pulp. Destructive changes were detected in the livers of nontreated animals with B16 melanoma. Administration of isRNA in combination with dacarbazine did not cause any additional damage to liver parenchyma, while stimulating regenerative processes in hepatic tissue of tumor-bearing animals.

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ACKNOWLEDGMENTS

We are grateful to M.I. Meshchaninova and A.G. Ven’ya-minova (Institute of Chemical Biology and Fundamental Medicine) for isRNA synthesis.

Funding

This work was supported by the Russian Science Foundation (project no. 19-74-30011) and by the Russian State Funded Budget Project of ICBFM SB RAS (project no. AAAA-A17-117020210024-8).

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Authors and Affiliations

  1. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk, Russia

    A. V. Sen’kova, I. A. Savin, T. O. Kabilova, M. A. Zenkova & E. L. Chernolovskaya

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  1. A. V. Sen’kova
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  2. I. A. Savin
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  3. T. O. Kabilova
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  4. M. A. Zenkova
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Correspondence to A. V. Sen’kova.

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Conflict of interests. The authors declare that they have no conflict of interest.

Statement on the welfare of animals. Experiments with animals followed the guidelines established by The Directive 2010/63/EU of the European Parliament and the Council of 22 September 2010 and were approved by the Ethics Committee at the Institute of Cytology and Genetics (Novosibirsk, Russia; Minutes no. 22.11 dated May 30, 2014).

Additional information

Translated by T. Tkacheva

Abbreviations: isRNA, immunostimulating RNA; TGS, tumor growth suppression; CI, combination index; DT, doubling time.

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Sen’kova, A.V., Savin, I.A., Kabilova, T.O. et al. Tumor-Suppressing, Immunostimulating, and Hepatotoxic Effects of Immunostimulatory RNA in Combination with Dacarbazine in a Murine Melanoma Model. Mol Biol 54, 233–242 (2020). https://doi.org/10.1134/S0026893320020144

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