Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Postmenopausal osteoporosis is caused mainly by a deficiency of oestrogen with rapid bone loss. To target oestrogen to the bone effectively, we have synthesized and evaluated the effects of a novel hybrid compound of oestrogen and bisphosphonate, SM-16896. The tissue distribution pattern and pharmacological potential are reported. Although the affinity for calf uterine oestrogen receptor was very low (IC50: 73.3 microM; 1/25000 of that of 17beta-oestradiol (2.84 nM)), SM-16896 showed oestrogenic activity. SM-16896 (1 microM) induced a 4.5-fold transcriptional activity in rat osteosarcoma UMR-106 cells compared with vehicle-treated control, when we used the expression vector for human oestrogen receptor and a CAT reporter plasmid containing an oestrogen-responsive element. The distribution of SM-16896 after a subcutaneous administration to 7-week-old female rats was examined by radioluminography using 3H-labelled SM-16896. At 30 min after the administration, significant radioactivity was detected in the bone. At 24 h after administration, a high level of radioactivity was detected in the bone, but in the uterus it was only at a background level. Daily subcutaneous administration of 0.5 mgkg(-1) SM-16896 for 12 weeks (five times per week) to 13-week-old ovariectomized rats suppressed the ovariectomized-induced reduction in bone mineral density. A bone mineral density ratio of 120% was maintained compared with sham-operated rats, whereas a relatively low suppression of uterine weight was observed (about 50% loss compared with sham-operated rats). In the same experiment, the implantation of a 17beta-oestradiol time-release pellet (0.25 mg/pellet/90 days) almost completely suppressed the reduction of both the bone mineral density and uterine tissue weight. It is likely that the effect of SM-16896 on bone was due to its oestrogenic activity, since 1.0 mgkg(-1) SM-18108, the bisphosphonate moiety of this compound, had no effect on bone in 7-week-old ovariectomized rats. The results suggest that SM-16896, a bisphosphonate-conjugated oestrogen, showed a preference profile in the uterus and bone due to its characteristic distribution pattern compared with the natural oestrogen analogue 17beta-oestradiol. Thus, bisphosphonate-conjugated oestrogens have the potential to improve patient compliance in oestrogen therapy by minimizing adverse effects and reducing the frequency of medication.
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PMID:Tissue distribution and pharmacological potential of SM-16896, a novel oestrogen-bisphosphonate hybrid compound. 1071

Although numerous clinical studies have demonstrated the beneficial effect of preventing postmenopausal bone loss in elder women by long-term estrogen administration, effects of estrogen at the cellular level still remain unclear. Efforts to determine the precise role of bone cells in estrogen-mediated pathways are often hampered by the lack of suitable cell culture models. Presuming that sex steroids have a direct, stimulating effect on bone cells in vitro, we investigated the influence of 17beta-estradiol, testosterone and 1,25(OH)2D, on cell proliferation and differentiation using four established human osteosarcoma (HOS) cell lines of different gender of the donors (male origin: MG 63, HOS 58; female origin: SaOS 2, TE 85). These cell lines are believed to represent different stages of osteogenic maturation. Thus, the aim of this study was to clarify if possible responses to sex steroids are related to gender or osteogenic commitment of the individual cell culture. HOS cells were cultured in six-well plates and underwent hormone treatment (1 nM and 10 nM 17beta-estradiol. 0.1 nM and I nM testosterone and 1 microM 1,25(OH)2D3) for 48 h hours. Cell proliferation was determined by measuring total cell numbers. Cell function was studied by measuring alkaline phosphatase activity and secreted osteocalcin. In this study, estrogen significantly increased proliferation of both one male (MG 63) and one female (SaOS 2) cell line, but decreased proliferation of the female HOS TE 85 cell line significantly. Testosterone treatment had a positive effect on proliferation of only one female cell line (SaOS 2). A significant increase of alkaline phosphatase activity in SaOS 2 and HOS 58 cells and of osteocalcin levels in SaOS 2 cells was detected following estrogen treatment. Administration of 1.25(OH)2D3 was followed by an increased cell proliferation in HOS 58, MG 63 and SaOS 2. Significant gender-related differences could not be demonstrated. In conclusion, response to hormonal treatment with sex steroids is not related to the gender of the osteosarcoma cell line, but rather depends on its osteoblastic commitment.
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PMID:Sex steroids and bone metabolism: comparison of in vitro effects of 17beta-estradiol and testosterone on human osteosarcoma cell lines of various gender and differentiation. 1102 55