Glucocorticoids decrease the production of parathyroid hormone-related protein in vitro but not in vivo in the Walker carcinosarcoma 256 rat model.
In 50-90% of cases, humoral hypercalcemia of malignancy (HHM) is due to tumor secretion of parathyroid hormone-related protein (PTHrP). Glucocorticoids are sometimes used as calcium lowering agents and there are in vitro results showing that glucocorticoids diminish PTHrP production. In this study we tested whether the serum-calcium-lowering effect of glucocorticoids is due to decreased PTHrP production by the tumor. As an animal and cell culture model we used the Walker carcinosarcoma (WCS) 256, a rat mammary carcinoma cell line producing PTHrP. In vitro, dexamethasone caused a dose-dependent inhibition of PTHrP production, whereby already 1-5 nmol/L revealed a significant decrease by WCS 256 cells. In contrast to these in vitro results, in WCS 256 tumor-bearing rats, dexamethasone (4 mg/kg body weight on day 4, and 1 mg/kg body weight from day 5 until day 7 after WCS transplantation; circulating dexamethasone levels > 20 nmol/L) did not decrease PTHrP production, PTHrP secretion, serum calcium, or tumor weight in vivo. We conclude that, in this PTHrP-mediated model of humoral hypercalcemia of malignancy, glucocorticoids do not decrease PTHrP production and secretion in vivo and do not show a calcium-lowering effect.
Schilling
T
T
Department of Internal Medicine I, University of Heidelberg, Germany.
Pecherstorfer
M
M
Blind
E
E
Kohl
B
B
Wagner
H
H
Ziegler
R
R
Raue
F
F
D000704:Analysis of Variance; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D002279:Carcinoma 256, Walker / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D005938:Glucocorticoids; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D003907:Dexamethasone; D002118:Calcium