1-25(oh)2-16-ene-23-yne-d3 and Hypercalcemia

To compare the effects of vitamin D analogs versus calcitriol on serum levels of Ca, P and parathyroid hormone (PTH). A compound better than calcitriol should increase the Ca x P product less than calcitriol for an equivalent decrease in PTH levels.. Biological activity of 4 vitamin D analogs, 1,25-(OH)(2)-16ene- D(3) (RO(1)), 1,25-(OH)(2)-16ene-23yne-D(3) (RO(2)), 1,25-(OH)(2)-26,27-hexafluoro-16ene-23yne-D(3) (RO(3)) and 1,25-(OH)(2)-16ene-23yne-26,27-hexafluoro-19nor-D(3) (RO(4)) was tested vs. calcitriol in parathyroidectomized rats. In a second set of experiments, the effects of RO(2), RO(4) and calcitriol were studied in 5/6 nephrectomized rats with secondary hyperparathyroidism.. In parathyroidectomized rats, all analogs (250 pmol/day) led calcemia to rise after 7 days. In uremic rats, all treatments reduced PTH levels. RO(4) revealed toxicity. RO(2) was as effective as calcitriol in suppressing PTH in a dose dependent manner. Mean plasma ionized calcium did not change from baseline to day 14 and day 28 on RO(2) (250 or 500 pmol/day) whereas it increased significantly on RO(2) (1,000 pmol/day) and calcitriol (125 or 250 pmol/day). Increasing the dose of calcitriol led Ca x P to rise more dramatically than increasing the dose of RO(2), which appears to have a wider therapeutic window than calcitriol.. 1,25-(OH)(2)-16ene-23yne-D(3) (RO(2)) may represent a novel candidate for the treatment of renal osteodystrophy in humans.

Topics: Animals; Calcitriol; Calcium; Hypercalcemia; Hyperparathyroidism, Secondary; Injections, Intraperitoneal; Male; Parathyroid Hormone; Phosphorus; Phosphorus, Dietary; Rats; Rats, Wistar; Uremia

To investigate the effectiveness of the vitamin D analogues 1,25-(OH)(2)-16-ene-23-yne vitamin D(3) (16,23-D(3)) and 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)) in inhibiting retinoblastoma growth in large tumors in a xenograft model and with prolonged use in a transgenic model.. For the large-tumor study, the xenograft athymic mouse/human retinoblastoma cell (Y-79) model was used. Subcutaneous tumors were allowed to grow to an average volume of 1600 mm(3). Systemic treatment with 1 of the vitamin D analogues or with vehicle (control groups) was carried out for 5 weeks. For the long-term study, transgenic beta-luteinizing hormone-large T antigen (LHbeta-Tag) mice were systemically treated with 1 of the 2 compounds or vehicle (control groups) for up to 15 weeks. Tumor size and signs of toxicity were assessed.. In the large-tumor study, tumor volume ratios for the 1alpha-OH-D(2) and 16,23-D(3) groups were significantly lower than those for controls (P<.002). No significant differences in tumor volume were seen between the 1alpha-OH-D(2) and 16,23-D(3) groups (P =.15). In the long-term study, the 1alpha-OH-D(2) group showed significantly smaller tumor size compared with its control (P<.001). No significant difference was seen between the 16,23-D(3) group and its control. Some toxic effects related to hypercalcemia were seen in both studies.. In athymic mice in the large-tumor study, both 1alpha-OH-D(2) and 16,23-D(3) were effective in inhibiting tumor growth compared with controls. In the long-term study, 1alpha-OH-D(2) inhibited tumor growth but 16,23-D(3) did not. Effective doses of both compounds caused hypercalcemia and a significant increase in mortality. Clinical Relevance Use of 1alpha-OH-D(2) inhibited tumor growth in large tumors and with long-term treatment compared with controls. Because of hypercalcemia-related toxic effects seen in the present experiments, in clinical trials, serum calcium levels should be carefully monitored. This analogue may require use with drugs that lower serum calcium levels or use of relatively lower doses or skipped doses. The ideal alternative solution would be to identify vitamin D analogues that retain the antineoplastic action without the calcemic activity.

Topics: Animals; Antineoplastic Agents; Calcitriol; Disease Models, Animal; Ergocalciferols; Hypercalcemia; Mice; Mice, Nude; Mice, Transgenic; Retinal Neoplasms; Retinoblastoma; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and of two synthetic analogs, 1,25S,26-tri-hydroxy-delta 22-vitamin D3 (1,25,26(OH)3-22ene-D3, Ro 23-4319) and 1,25-dihydroxy-delta 16-23yne-vitamin D3 (1,25(OH)2-16ene-23yne-D3, Ro 23-7553) on cell growth was evaluated by determination of [3H]thymidine incorporation into DNA of human colon adenocarcinoma-derived Caco-2 cells. The extent of growth inhibition by the vitamin D compounds varied between 20-40% (at 10(-8) M), depending on particular growth conditions of Caco-2 cells as well as on the molecular structure of the vitamin D sterols. In confluent, i.e., rather quiescent cells, all three vitamin D compounds were equipotent in suppressing growth. In rapidly dividing log phase cells, 1,25(OH)2-16ene-23yne-D3 or 1,25,26(OH)3-22ene-D3 were ten or five times, respectively, more efficient than 1,25(OH)2D3. A substantial effect on induction of the colonocyte differentiation marker alkaline phosphatase was only elicited by 1,25(OH)2-16ene-23yne-D3. The ability of the vitamin D compounds to raise intestinal calcium absorption was evaluated by determination of 45Ca2+ accumulation in embryonic chick duodenal explants. In this assay, both synthetic analogs were less effective than 1,25(OH)2D3 by a factor of 20. The intrinsic bone resorbing activities of the vitamin D analogs were compared in organ-cultured neonatal mouse calvariae. The most effective antiproliferative compound, 1,25(OH)2-16ene-23yene-D3, stimulated calcium release from cultured bones at concentrations less than 10(-11) M, and was thus ten times more potent than 1,25(OH)2D3 and hundred times more than 1,25,26(OH)3-22ene-D3.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bone Resorption; Calcitriol; Calcium; Cell Differentiation; Cell Division; Colonic Neoplasms; Humans; Hydroxycholecalciferols; Hypercalcemia; Intestinal Absorption; Mice; Tumor Cells, Cultured