Evidence for the uptake of a vitamin D analogue (OCT) by a human carcinoma and its effect of suppressing the transcription of parathyroid hormone-related peptide gene in vivo
| Autor: | Kenji Kumaki, Koichi Endo, Etsuro Ogata, Kyoko Katsumata, Hiroyuki Ohkawa, Yasushi Uchiyama, Fumihiko Ichikawa, Kyoji Ikeda |
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| Rok vydání: | 1994 |
| Předmět: |
Male
medicine.medical_specialty Transcription Genetic Calcitriol Mice Nude Biology Biochemistry Calcitriol receptor Mice Transcription (biology) In vivo Internal medicine Gene expression medicine Animals Humans Tissue Distribution RNA Messenger Molecular Biology Messenger RNA Parathyroid hormone-related protein Parathyroid Hormone-Related Protein Proteins Promoter Cell Biology Neoplasm Proteins Gene Expression Regulation Neoplastic Pancreatic Neoplasms Endocrinology Hypercalcemia medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 269:32693-32699 |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/s0021-9258(18)31690-9 |
| Popis: | The present study was undertaken to clarify the pharmacokinetics of 22-oxa-1,25-dihydroxyvitamin D3 (22-oxa-1,25-(OH)2D3, OCT), a vitamin D3 analogue with little calcemic activity, and its effect on the transcription of parathyroid hormone-related peptide (PTHRP) gene in nude mice bearing a human carcinoma (FA-6) associated with humoral hypercalcemia. FA-6 tumor expressed vitamin D receptor (VDR) mRNA, and its nuclear extract contained a specific and saturable 1,25-(OH)2D3 binding activity. Although [3H]OCT administered intravenously into FA-6 tumor-bearing nude mice was cleared from the circulation more rapidly than [3H]1,25-(OH)2D3, the uptake of [3H]OCT into the tumor tissue, relative to the radioactivity in the circulation, was greater than that of [3H]1,25-(OH)2D3. Intravenous or oral administration of OCT reduced the steady-state levels of PTHRP mRNA in FA-6 tumor, and nuclear run-off assays demonstrated that the effect of OCT on PTHRP gene expression occurred at a transcriptional level. RNase mapping analysis revealed that both upstream and downstream promoters of the human PTHRP gene were down-regulated by OCT. Finally, OCT exerted a preventive as well as therapeutic effect on cancer-associated hypercalcemia with a marked prolongation of the survival time in tumor-bearing animals. These results suggest that OCT is effectively taken up by a VDR-positive human carcinoma in vivo and has a therapeutic potential for cancer-associated hypercalcemia through suppression of PTHRP gene transcription. |
| Databáze: | OpenAIRE |
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