In vitro and in vivo evaluation of combined calcitriol and cisplatin in dogs with spontaneously occurring tumors.
OBJECTIVE
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.
Rassnick
Kenneth M
KM
Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Box 31, Ithaca, NY 14853, USA. kmr32@cornell.edu
Muindi
Josephia R
JR
Johnson
Candace S
CS
Balkman
Cheryl E
CE
Ramnath
Nithya
N
Yu
Wei-Dong
WD
Engler
Kristie L
KL
Page
Rodney L
RL
Trump
Donald L
DL
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002117:Calcitriol / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000453:epidemiology; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000453:epidemiology; D006402:Hematologic Diseases / Q000139:chemically induced / Q000453:epidemiology; D007275:Injections, Intravenous; D009369:Neoplasms / Q000188:drug therapy* / Q000662:veterinary*; D013778:Tetrazolium Salts; D013844:Thiazoles; D014815:Vitamins / Q000008:administration & dosage
D000970:Antineoplastic Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D014815:Vitamins; C022616:thiazolyl blue; D002117:Calcitriol; D002945:Cisplatin