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In vitro and in vivo evaluation of combined calcitriol and cisplatin in dogs with spontaneously occurring tumors

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Abstract

Purpose

Calcitriol potentiates cisplatin-mediated activity in a variety of tumor models. We examine here, the effect of calcitriol and cisplatin pre-clinically and clinically in canine spontaneous tumors through in vitro studies on tumor cells and through a phase I study of calcitriol and cisplatin to identify the maximum-tolerated dosage (MTD) of this combination in dogs with cancer and to characterize the pharmacokinetic disposition of calcitriol in dogs.

Methods

Canine tumor cells were investigated for calcitriol/cisplatin interactions on proliferation using an MTT assay in a median-dose effect analysis; data were used to derive a combination index (CI). Cisplatin was given at a fixed dosage of 60 mg/m2. Calcitriol was given i.v. and the dosage was escalated in cohorts of three dogs until the MTD was defined. Serum calcitriol concentrations were quantified by radioimmunoassay.

Results

In vitro, CIs < 1.0 were obtained for all combinations of calcitriol/cisplatin examined. The MTD was 3.75 μg/kg calcitriol in combination with cisplatin, and hypercalcemia was the dose-limiting toxicosis. The relationship between calcitriol dosage and either C max or AUC was linear. Calcitriol dosages >1.5 μg/kg achieved C max ≥ 9.8 ng/mL and dosages >1.0 μg/kg achieved AUC ≥ 45 h ng/mL.

Conclusions

Calcitriol and cisplatin have synergistic antiproliferative effects on multiple canine tumor cells and high-dosages of i.v. calcitriol in combination with cisplatin can be safely administered to dogs. C max and AUC at the MTD 3.75 μg/kg calcitriol exceed concentrations associated with antitumor activity in a murine model, indicating this combination might have significant clinical utility in dogs.

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Acknowledgments

This work was supported by grants (NCI and DOD Grants CA67267, CA95045, and PCRP050202) and The Sprecher Institute for Comparative Cancer Research, Cornell University. The authors thank Dr. Lili Tian, Associate Professor of Biostatistics, University of Buffalo, for assistance with statistical analysis.

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Authors and Affiliations

  1. Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Box 31, Ithaca, NY, 14853, USA

    Kenneth M. Rassnick, Cheryl E. Balkman & Rodney L. Page

  2. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Josephia R. Muindi, Candace S. Johnson, Wei-Dong Yu & Kristie L. Engler

  3. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Nithya Ramnath & Donald L. Trump

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  1. Kenneth M. Rassnick
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  2. Josephia R. Muindi
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Correspondence to Kenneth M. Rassnick.

Additional information

This article was presented in part as a poster presentation at the 13th Workshop on Vitamin D, Victoria, British Columbia, Canada, 8–12 April 2006.

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Rassnick, K.M., Muindi, J.R., Johnson, C.S. et al. In vitro and in vivo evaluation of combined calcitriol and cisplatin in dogs with spontaneously occurring tumors. Cancer Chemother Pharmacol 62, 881–891 (2008). https://doi.org/10.1007/s00280-008-0678-x

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