التفاصيل البيبلوغرافية
| العنوان: |
In vitro and in vivo evaluation of combined calcitriol and cisplatin in dogs with spontaneously occurring tumors. |
| المؤلفون: |
Rassnick, Kenneth M., Muindi, Josephia R., Johnson, Candace S., Balkman, Cheryl E., Ramnath, Nithya, Wei-Dong Yu, Engler, Kristie L., Page, Rodney L., Trump, Donald L. |
| المصدر: |
Cancer Chemotherapy & Pharmacology; Oct2008, Vol. 62 Issue 5, p881-891, 11p, 5 Charts, 4 Graphs |
| مصطلحات موضوعية: |
TUMORS, CANCER cells, CISPLATIN, ANTINEOPLASTIC agents, ALKYLATING agents |
| مستخلص: |
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. 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. 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. 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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |