Prostaglandin E production and hypercalcaemia in rats bearing the Walker carcinosarcoma

Abstract

Summary.-The hypothesis that there is prostaglandin-mediated hypercalcaemia associated with the Walker carcinosarcoma in the rat was tested by measuring PGE production during the development of the hypercalcaemia, and determining the effects of inhibition of prostaglandin synthesis on serum calcium concentration. Parathyroid hormone (PTH) activity was estimated by the determination of the serum concentration of immunoreactive PTH. There was a 3-fold increase in the urinary excretion of 7oa-hydroxy-5, 1 -diketotetranor -prostane -1,16-dioic acid (PGE-M), a major urinary metabolite of the E prostaglandins from basal levels. Treatment with indomethacin, a potent inhibitor of prostaglandin synthesis, did not lower serum calcium concentrations with two different doses (1-6 mg/kg/day orally and 5 mg/kg/day i.m.); effective inhibition of prostaglandin synthesis was demonstrated by the suppression of PGE-M excretion rates below basal levels. Serum concentrations of immunoreactive PTH were not significantly altered by either tumour growth or indomethacin. Dexamethasone (0 5 mg/kg/day i.m.) attenuated both the increased urinary excretion of PGE-M and the rise in serum calcium concentration, suggesting that one or several lipoxygenase products might be the actual mediators of the hypercalcaemia. We conclude that the hypercalcaemia in the rat with Walker carcinosarcoma is probably not mediated by E-prostaglandins and probably not by any other product of the cyclo-oxygenase pathway. The increased PGE turnover may be considered as a biochemical marker of tumour load, but not as an indicator of a prostaglandin-mediated hypercalcaemia.

Factors associated with humoral hypercalcemia of malignancy stimulate adenylate cyclase in osteoblastic cells.

“…Cells from the hypercalcemic variant of Walker tumor were derived from explant cultures of the tumor that was kindly provided by Dr. R. Martodam of the Procter and Gamble Co., Cincinnatti, OH. All rats carrying these tumors subcutaneously developed hypercalcemia in the range of [13][14][15][16][17][18] mg/dl (10)(11)(12). Cells were grown in Dulbecco's modified Eagle medium supplemented with 10% (vol/vol) fetal calf serum (FCS), penicillin, 100 U/ml, and streptomycin, 100 ug/ml, and were incubated at 370C in a humidified 5% CO2, 95% air atmosphere.…”

Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.

“…In the short-term study, the six subjects took 60 mg of prednisone by mouth at 0800 on two consecutive days. Twenty-four-hour urine collections were obtained before and on the first day of drug treatment and heparinized whole blood was obtained 0,1,2,4,8,24, and 30 hr after the first dose.…”

“…In the short-term study, the six subjects took 60 mg of prednisone by mouth at 0800 on two consecutive days. Twenty-four-hour urine collections were obtained before and on the first day of drug treatment and heparinized whole blood was obtained 0,1,2,4,8,24, and 30 hr after the first dose.Plasma prednisone and prednisolone concentrations were measured by HPLC (16). The completion of all urine collections obtained in the study was inferred from the close similarity of total creatinine in the four collections obtained from each subject.…”

“…Almost all have been performed in animals. These experiments, with rare exception (5), have failed to demonstrate a suppressive effect (6)(7)(8)(9)(10)(11)(12)(13)(14)(15), even in the face of unequivocal inhibition of eicosanoid formation in vitro (10). We have designed a study to evaluate the effects of therapeutic doses of glucocorticoids on the synthesis of eicosanoids in vivo in humans.…”