Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The intriguing observation has been made that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptors are present in tissues not involved in calcium homeostasis and that 1,25(OH)2D3 exerts an antiproliferative, differentiation-promoting action in a variety of cancer cell lines, including cells of the large intestine. It was therefore deemed of interest to study 1,25(OH)2D3 expression and biological activity in a murine model of colon carcinogenesis. Colon carcinogenesis was induced in male rats by the sequential administration of 1,2-dimethylhydrazine dihydrochloride (DMH). Levels and binding characteristics of 1,25(OH)2D3 receptors were assessed in control and DMH-treated rat colonic mucosal high-speed supernatants. In concurrent studies, 1,25(OH)2D3 was administered (s.c., 400 ng/rat) prior to, together with and after DMH challenge and the activity of ornithine decarboxylase (ODC), a growth-related DMH-induced enzyme, was determined in colonic cytosols. Serum Ca2+ levels were measured concurrently. Rats submitted to identical treatment schedules were killed 10 weeks after termination of DMH administration and the whole colon was opened and examined for tumors. The results show that (i) rat colonic mucosa possesses a single class of high-affinity 1,25(OH)2D3 receptors; (ii) DMH administration provokes a marked reduction (50%) in 1,25(OH)2D3 binding sites without affecting Kd values; (iii) DMH administered concurrently with 1,25(OH)2D3 suppressed the vitamin D-induced hypercalcemia and restored serum Ca2+ concentrations to basal levels; and (iv) 1,25(OH)2D3 delivered prior to DMH challenge obliterated the typical DMH-induced early colonic ODC activity peak and markedly reduced (50%) the number of colon adenocarcinomas. The present findings indicate that a colon-specific potent carcinogen interferes with the biological expression of 1,25(OH)2D3 and that vitamin D administered prior to a carcinogenic insult is able to reduce significantly the incidence of colon tumors, presumably acting as an antiproliferative or differentiation-promoting agent.
 ...
PMID:A protective role of 1,25-dihydroxyvitamin D3 in chemically induced rat colon carcinogenesis. 133 76

Topical application of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3], an active form of vitamin D3, was previously shown to inhibit the induction of ornithine decarboxylase (ODC) and tumor promotion by tumor promoters in mouse skin. In the present study, this observation in skin was extended to other tissues, such as the stomach, colon, and liver, using 1 alpha-hydroxyvitamin D3 [1 alpha (OH)D3], which is converted to 1 alpha,25(OH)2D3 in the liver without hormonal control and thus evokes the systemic effects, if any, of 1 alpha,25(OH)2D3. When mice were given 1 alpha (OH)D3 at a dose of 5 micrograms by gastric tube, their plasma level of 1 alpha,25(OH)2D3 increased to a peak of about 18-fold the normal level after 12 h, followed by hypercalcemia (about 14 mg/dl), which reached a peak on Days 2 to 3. In 1 alpha (OH)D3-treated mice, induction of epidermal ODC by 12-O-tetradecanoylphorbol-13-acetate was markedly inhibited, the inhibition being maximal 2 to 4 days after 1 alpha (OH)D3 administration. ODC induction in the glandular stomach mucosa of rats by NaCl, a tumor promoter in stomach carcinogenesis, was also inhibited dose and time dependently by 1 alpha (OH)D3. Similarly, 1 alpha (OH)D3 treatment of rats markedly inhibited the induction of ODC in the colon mucosa by deoxycholate, a tumor promoter of colon carcinogenesis, and of ODC in the liver by phenobarbital, a promoter of liver carcinogenesis. These results suggest that an active form of vitamin D3 has a systemic inhibitory effect on induction of ODC activity by tumor promoters.
 ...
PMID:Systemic inhibition of tumor promoter-induced ornithine decarboxylase in 1 alpha-hydroxyvitamin D3-treated animals. 362 Nov 89

1 alpha,25-Dihydroxyvitamin D3 [1 alpha,25(OH)2D3], a hormonally active form of vitamin D3, was found to inhibit the promotional phase of 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis in female Sencar mice. Topical application of 1 alpha,25-(OH)2D3 once a week at a dose of 1 micrograms or less, a tolerable dose from hypercalcemia, dose dependently inhibited tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). When 1 micrograms of 1 alpha,25(OH)2D3 was applied 30 min before 5 micrograms of TPA, the times required for 50 and 100% tumor incidence were delayed about 2.5 and 7 weeks, respectively, and the number of tumors per mouse was decreased by 25-30%. This inhibitory effect was more pronounced when examined by a two-stage promotion protocol, in which a single application of 5 micrograms of TPA (Stage I) was followed by repeated applications of 5 micrograms of mezerein once a week for 19 weeks (Stage II). When 1 alpha,25(OH)2D3 at 1 micrograms was applied at Stage I + II or Stage II, tumor formation was markedly suppressed, resulting in decrease of about 70-80% in the incidence and 87-90% in the number of tumors per mouse. Application of 1 alpha,25(OH)2D3 at Stage I only did not inhibit tumor formation, indicating that 1 alpha,25(OH)2D3 specifically inhibited Stage II promotion. These results are in good agreement with the previous and present findings that 1 alpha,25(OH)2D3 inhibited induction of epidermal ornithine decarboxylase by TPA and mezerein. The possibility that 1 alpha,25(OH)2D3 suppressed tumor promotion by killing initiated cells rather than inhibiting promotion was ruled out by an experiment in which TPA was applied to the 1 alpha,25(OH)2D3 alone-treated animals.
 ...
PMID:Inhibition of tumor promotion in mouse skin by 1 alpha,25-dihydroxyvitamin D3. 384 Apr 12