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Translational Therapeutics

Low-dose metronomic cisplatin as an antiangiogenic and anti-inflammatory strategy for cancer

British Journal of Cancer volume 130, pages 336–345 (2024)Cite this article

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Abstract

Background

Conventional chemotherapy is based on the maximum tolerated dose (MTD) and requires treatment-free intervals to restore normal host cells. MTD chemotherapy may induce angiogenesis or immunosuppressive cell infiltration during treatment-free intervals. Low-dose metronomic (LDM) chemotherapy is defined as frequent administration at lower doses and causes less inflammatory change, whereas MTD chemotherapy induces an inflammatory change. Although several LDM regimens have been applied, LDM cisplatin (CDDP) has been rarely reported. This study addressed the efficacy of LDM CDDP on tumour endothelial cell phenotypic alteration compared to MTD CDDP.

Methods

Tumour growth and metastasis were assessed in bladder cancer-bearing mice treated with LDM or MTD gemcitabine (GEM) and CDDP. To elucidate the therapeutic effects of LDM CDDP, the change of tumour vasculature, tumour-infiltrating immune cells and inflammatory changes were evaluated by histological analysis and mRNA expression in tumour tissues.

Results

Tumour growth and bone metastasis were more suppressed by LDM CDDP + MTD GEM treatment than MTD CDDP + MTD GEM. Myeloid­derived suppressor cell accumulation was reduced by LDM CDDP, whereas inflammatory change was induced in the tumour microenvironment by MTD CDDP.

Conclusion

LDM CDDP does not cause inflammatory change unlike MTD CDDP, suggesting that it is a promising strategy in chemotherapy.

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Fig. 1: LDM CDDP + MTD GEM treatment reduces tumour growth and bone metastasis.
Fig. 2: LDM CDDP + MTD GEM treatment normalises tumour vasculature.
Fig. 3: LDM CDDP + MTD GEM treatment facilitates M2 macrophage polarisation and reduced MDSC accumulation.
Fig. 4: LDM CDDP + MTD GEM treatment suppresses inflammatory change of the tumour microenvironment enhanced by MTD GEM chemotherapy.
Fig. 5: LDM CDDP monotherapy has therapeutic effect in orthotopic murine tumour model.

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Data availability

All datasets for this study are available from the corresponding author on request.

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Acknowledgements

We thank Drs. S Tanaka and M Tsuda for providing the UMUC3 and tdTomato-Luc2 gene-transfected UMUC3 cells. We also thank Ms. M Sasaki, Ms. Y Suzuki, and Ms. T Takahashi for their technical assistance with the experiments.

Funding

This research was funded by JSPS Grants-in-Aid for Scientific Research on Integrated Analysis and Regulation of Cellular Diversity Innovative Areas to KH (JP18H05092); JSPS Grants-in-Aid for Scientific Research to NM (JP18K09715 and JP21K10107), HK (JP19K18549), YH (JP18H02891 and JP21H03019) and KH (JP18H02996 and JP21H04840); and Grants from Japan Agency for Medical Research and Development to NM (JP18ck0106198h0003) and KH (JP20ck0106406h0003).

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Authors and Affiliations

  1. Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Hiroshi Kikuchi, Nako Maishi, Cong Li, Masumi Sato, Ryo Takeda, Keita Ishizuka & Kyoko Hida

  2. Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Hiroshi Kikuchi & Nobuo Shinohara

  3. Department of Vascular Biology and Molecular Pathology, Hokkaido University Faculty of Dental Medicine, Sapporo, Japan

    Nako Maishi, Li Yu, Zi Jia, Cong Li, Ryo Takeda & Kyoko Hida

  4. Department of Cardiovascular and Thoracic Surgery, Faculty of Medicine, Hokkaido University, Sapporo, Japan

    Yasuhiro Hida

  5. Advanced Robotic and Endoscopic Surgery, School of Medicine, Fujita Health University, Toyoake, Japan

    Yasuhiro Hida

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  1. Hiroshi Kikuchi
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Contributions

KY and NM conceived of the study and its design. HK, CL, LY, ZJ, MS, RT and KI provided the study data. HK and NM completed the statistical analyses. HK, NM, KH and YH interpreted the results. HK drafted the manuscript. KY, MN, YH and NS critically reviewed the draft manuscript and approved the final version.

Corresponding author

Correspondence to Kyoko Hida.

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The authors declare no competing interests.

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All procedures for animal care and experimentation adhered to institutional guidelines and were approved by the Ethical Committee for Experimental Animal Care of Hokkaido University (18-0050).

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Kikuchi, H., Maishi, N., Yu, L. et al. Low-dose metronomic cisplatin as an antiangiogenic and anti-inflammatory strategy for cancer. Br J Cancer 130, 336–345 (2024). https://doi.org/10.1038/s41416-023-02498-2

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