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

Cancer Chemother Pharmacol. 2008 Oct;62(5):881-91. doi: 10.1007/s00280-008-0678-x. Epub 2008 Feb 2.

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 microg/kg calcitriol in combination with cisplatin, and hypercalcemia was the dose-limiting toxicosis. The relationship between calcitriol dosage and either Cmax or AUC was linear. Calcitriol dosages >1.5 microg/kg achieved Cmax > or = 9.8 ng/mL and dosages >1.0 microg/kg achieved AUC > or = 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. Cmax and AUC at the MTD 3.75 microg/kg calcitriol exceed concentrations associated with antitumor activity in a murine model, indicating this combination might have significant clinical utility in dogs.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Area Under Curve
  • Calcitriol / administration & dosage
  • Cell Line, Tumor
  • Cisplatin / administration & dosage
  • Dog Diseases / drug therapy*
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Hypersensitivity / epidemiology
  • Gastrointestinal Diseases / chemically induced
  • Gastrointestinal Diseases / epidemiology
  • Hematologic Diseases / chemically induced
  • Hematologic Diseases / epidemiology
  • Injections, Intravenous
  • Neoplasms / drug therapy*
  • Neoplasms / veterinary*
  • Tetrazolium Salts
  • Thiazoles
  • Vitamins / administration & dosage

Substances

  • Antineoplastic Agents
  • Tetrazolium Salts
  • Thiazoles
  • Vitamins
  • thiazolyl blue
  • Calcitriol
  • Cisplatin