1-alpha-24-dihydroxyvitamin-d3 and Body-Weight

Active and less toxic vitamin D analogs could be useful for clinical applications. In the present study, we evaluated the toxicity and antitumor effect of two new synthetic analogs of vitamin D, namely PRI-1906 [(24E)-24a-Homo-(1S)-1,25-dihydroxyergocalciferol] and its side-chain unsaturated homo analog PRI-1907.. The toxicity and calcemic activity, as well as antitumor effect of calcitriol analogs was investigated in vivo. The studies were performed in a mouse mammary 16/C cancer model. Since calcitriol and its analogs inhibited 16/C tumor growth only slightly, we applied them in the combined therapy with cyclophosphamide (CY). Moreover, cell cycle analysis and VDR and p27 expression were investigated.. The LD50 values after five daily subcutaneous (s.c.) injections were 7.8, 10.0 and 2.4 microg/kg per day for calcitriol, PRI-1906 and PRI-1907, respectively. The serum calcium level increased to 40, 23 and 63% over the control for these compounds. We also compare the antitumor activity of the PRI-1906 with the calcitriol and previously studied PRI-2191 (1,24-dihydroxyvitamin D3, tacalcitol). Statistically significant inhibition of tumor growth by calcitriol up to the eighth day was observed in all schedules applied. PRI-1906 inhibited the tumor growth at doses 1 and 5 microg/kg per day, and PRI-2191 only at the dose 5 microg/kg per day.. Addition of vitamin D analogs increased the antitumor effect of CY. PRI-1906 exhibited toxicity higher than PRI-2191 but lower than calcitriol and antitumor activity similar to both PRI-2191 and calcitriol. This new analog seems to be a good candidate for the combined treatment of mammary cancer.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Calcitriol; Calcium; Cell Cycle; Cyclophosphamide; Dihydroxycholecalciferols; Ergocalciferols; Female; Lethal Dose 50; Male; Mammary Neoplasms, Animal; Mice; Mice, Inbred C3H; Mice, Inbred DBA; Vitamins

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.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Body Weight; Calcinosis; Calcitriol; Calcium; Cisplatin; Clodronic Acid; Dihydroxycholecalciferols; Drug Therapy, Combination; Female; Lethal Dose 50; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA

Ovariectomy induced a remarkable reduction in the ash content of the femur and histologically a disappearance of the trabecular bone in tibial metaphysis accompanying the decrease of serum calcium level and urinary calcium excretion in young immature rats. Treatment with 1 alpha-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3 and 1,24R-dihydroxyvitamin D3 for 3 months from 7 to 9 months after the ovariectomy dose-dependently increased serum and urinary calcium, bone ash, and histologically partly improved a loss of trabeculae. The 24R,25-dihydroxyvitamin D3 doses, on the other hand, produced no therapeutic effect on the bone disorders in ovariectomized rats, except for the slight effect on the increasing activity of serum calcium.

Topics: Animals; Body Weight; Bone and Bones; Calcitriol; Calcium; Dihydroxycholecalciferols; Female; Hydroxycholecalciferols; Osteoporosis; Ovariectomy; Phosphorus; Rats