Toxicity and antineoplastic effect of (24R)-1,24-dihydroxyvitamin D3 (PRI-2191)
| Autor: | Kuśnierczyk H, Wieslaw Szelejewski, Janusz Madej, Adam Opolski, Andrzej Kutner, Stanisław Dzimira, Marzena Pełczyńska, Joanna Wietrzyk |
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| Rok vydání: | 2004 |
| Předmět: |
Male
medicine.medical_specialty Calcitriol Clinical Biochemistry chemistry.chemical_element Antineoplastic Agents Adenocarcinoma Calcium Pharmacology Biochemistry Median lethal dose Lethal Dose 50 Mice Endocrinology Oral administration Internal medicine medicine Vitamin D and neurology Animals Molecular Biology Cisplatin Mice Inbred C3H Tacalcitol business.industry Body Weight Organic Chemistry Calcinosis Mammary Neoplasms Experimental Mice Inbred C57BL chemistry Mice Inbred DBA Toxicity Dihydroxycholecalciferols Drug Therapy Combination Female Clodronic Acid business medicine.drug |
| Zdroj: | Steroids. 69:629-635 |
| ISSN: | 0039-128X |
| DOI: | 10.1016/j.steroids.2004.05.015 |
| Popis: | Many efforts have been made to obtain active and less toxic Vitamin D analogs for new clinical applications. The results of previous studies demonstrated the efficacy and safety of topical treatment of psoriasis with one of these analogs, 1,24-dihydroxyvitamin D(3), tacalcitol (1,24-(OH)(2)D(3)). In the present study, we evaluated the toxicity and antitumor effect of this analog. Lethal toxicity of 1,24-(OH)(2)D(3) after s.c. injection was significantly lower than that of calcitriol. No significant differences were observed in the toxicity of the analogs when administered p.o. Calcium levels in the serum of mice treated with calcitriol were significantly higher (111%) than those in mice treated with 1,24-(OH)(2)D(3) (89%) at 5 day after the first s.c. (10 microg/kg/day) administration in comparison to the control (healthy, untreated animals). Oral administration increased the calcium level by 78% for calcitriol and only to 47% over the control for 1,24-(OH)(2)D(3). Parallel administration of clodronate prevented the calcitriol- and 1,24-(OH)(2)D(3)-induced lethal toxicity and also prevented increase in calcium levels. Single therapy with calcitriol did not affect tumor growth in the 16/C mouse mammary cancer model. In contrary, 1,24-(OH)(2)D(3) alone reduced tumor volume to 41% of control. Cisplatin alone did not affect growth of 16/C tumor in these conditions. The growth of tumors in the presence of cisplatin was inhibited by 1,24-(OH)(2)D(3) but not by calcitriol. Interestingly, the inhibition of tumor growth in cisplatin-treated mice by 1,24-(OH)(2)D(3) was greater, than that observed in mice treated with this analog alone. In conclusion, 1,24-(OH)(2)D(3) revealed higher antitumor and lower calcemic activity and toxicity than calcitriol. Application of biphosphonates along with Vitamin D analogs is sufficient to overcome the calcemic and toxic side effects of the proposed treatment. |
| Databáze: | OpenAIRE |
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