Biological activities of prostaglandin analogues and metabolites on bone in organ culture

Abstract

PROSTAGLANDINS, especially the E-series, are potent stimulators of bone resorption in several in vitro systems^1–4. Studies with two experimental tumours (HSDM₁ mouse fibrosarcoma and VX₂ rabbit carcinoma) have indicated that excessive synthesis and secretion of prostaglandin E₂ (PGE₂) by the neoplastic cells is associated with and seems likely to be responsible for the hypercalcaemia observed in these tumour-bearing animals^2,5–8. A similar hypercalcaemic syndrome occurs in some patients with cancer, is associated with excessive PGE₂ metabolite excretion in urine and is reversed at least in part by treatment with aspirin-like drugs^9,10. Finally, intravenous infusion of PGE₂ in intact, unanaesthetised rats causes an increase of plasma calcium concentration¹¹. The most straightforward interpretation of these findings is that PGE₂ is secreted by certain tumour cells into plasma in such quantity that the steady-state plasma concentration of PGE₂ is sufficiently high to stimulate osseous target cells to resorb bone. An alernative interpretation is that unmeasured intermediates in arachidonic acid metabolism or PGE₂ metabolites have sufficient bone resonption-stimulating activity to be the agent acting on bone cells. This hypothesis gains a degree of support from knowledge that some prostaglandin metabolites have longer half lives in plasma than PGE₂ itself¹². We have now measured the biological activities of several endoperoxide analogues and PGE₂ metabolites in a bone culture assay system and compared their potencies with that of PGE₂.