Calcitriol (1,25-dihydroxycholecalciferol) enhances mast cell tumour chemotherapy and receptor tyrosine kinase inhibitor activity in vitro and has single-agent activity against spontaneously occurring canine mast cell tumours

• Published in: Veterinary & comparative oncology Vol. 8; no. 3; pp. 209 - 220
• Main Authors: Malone, E.K, Rassnick, K.M, Wakshlag, J.J, Russell, D.S, Al-Sarraf, R, Ruslander, D.M, Johnson, C.S, Trump, D.L
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.09.2010; Blackwell Publishing Ltd
• Subjects: Animals; anticarcinogenic activity; antineoplastic agents; Antineoplastic Agents - pharmacology; Benzamides; Blotting, Western - veterinary; calcitriol; Calcitriol - adverse effects; Calcitriol - pharmacology; Calcitriol - therapeutic use; Calcium Channel Agonists - adverse effects; Calcium Channel Agonists - pharmacology; Calcium Channel Agonists - therapeutic use; Cell Line, Tumor; cell proliferation; chemotherapy; combination drug therapy; dog diseases; Dog Diseases - drug therapy; Dogs; Dose-Response Relationship, Drug; Drug Synergism; drug toxicity; enzyme inhibitors; Female; Imatinib Mesylate; in vitro model; in vitro studies; in vivo studies; Indoles - pharmacology; Lomustine - pharmacology; Male; mast cells; Mastocytoma - drug therapy; Mastocytoma - pathology; Mastocytoma - veterinary; neoplasms; oncology; oral administration; Piperazines - pharmacology; Protein Kinase Inhibitors - pharmacology; protein-tyrosine kinases; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidines - pharmacology; Pyrroles - pharmacology; receptors; Receptors, Calcitriol - analysis; remission; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Skin Neoplasms - veterinary; small animal; Treatment Outcome; tyrosine kinase; vinblastine; Vinblastine - pharmacology
• ISSN: 1476-5810; 1476-5829
• DOI: 10.1111/j.1476-5829.2010.00223.x

Calcitriol potentiates the effect of multiple chemotherapy agents in a variety of tumour models. In this study, we examine whether calcitriol increases chemotherapy or tyrosine kinase inhibitor in vitro cytotoxicity in canine mastocytoma C2 cells. We also evaluate the in vivo effect of DN101, a highly concentrated oral formulation of calcitriol designed specifically for cancer therapy, as a single-agent therapy in dogs with mast cell tumours (MCTs). Calcitriol exhibits synergistic, antiproliferative activity when used in combination with CCNU, vinblastine, imatinib or toceranib in vitro. The concentrations required for 50% growth inhibition were generally two- to six-fold lower when the drugs were used in combination than when used individually. High-dose oral calcitriol induced remission in 4 of 10 dogs (one complete remission, three partial remissions), although the majority experienced toxicity, necessitating discontinuation of the trial. Further evaluation of calcitriol in combination therapy for dogs with MCTs is warranted.