The Inhibition by Aspirin and Indomethacin of Osteolytic Tumour Deposits and Hypercalcaemia in Rats with Walker Tumour, and its Possible Application to Human Breast Cancer

Abstract

Summary.-Walker carcinosarcoma cells cause in vitro osteolysis which may be inhibited by aspirin. In the rat, this tumour produces osteolytic bone deposits and hypercalcaemia, both of which can be prevented by aspirin and indomethacin, whereas soft tissue tumour deposits are unaffected by these drugs. Some human breast tumours cause in vitro osteolysis which may be inhibited by aspirin.PATIENTS with breast cancer frequently develop abnormalities in their calcium metabolism, which are usually associated with osteolytic bone metastases (Galasko and Burn, 1971) and are caused by excessive mobilization of calcium from the skeleton. This raises the possibility that the mechanism for this skeletal calcium mobilization, and the ability of tumour deposits to develop into destructive bone deposits, may both depend on the ability of tumour cells to produce osteolytic substances.To investigate this hypothesis, we have used an in vitro organ culture system of neonatal mouse bone which releases calcium in response to known osteolytic substances. We have found that some, but not all, human breast carcinomata when added to the organ culture caused increased calcium release from the bones and that this osteolysis could be inhibited by aspirin.To test whether these in vitro observations were relevant to the in vivo behaviour of tumours, it was necessary to develop a suitable animal tumour model. For this, we chose the intra-aortic injection of Walker carcinosarcoma cells into the rat, because this tumour has been reported to cause hypercalcaemia (Raue et al., 1972) These were cultured for a further 3 days under the same conditions as for the preliminary period, during which time calcium passed from the bone into the medium. At the end of the culture period the 45Ca in the medium, and remaining in the bone, was estimated using a Packard scintillation counter. The

In vitro osteolytic activity of human breast carcinoma tissue and prognosis

“…This destruction is probably mediated by release of osteolytic substances from tumour cells. Using in vitro organ culture (Reynolds, 1968) we previously reported that 23/38 primary human breast carcinomas showed significant osteolytic activity (Powles et al, 1976) mediated, at least in part, by prostaglandins (Dowsett et al, 1976;Powles et al, 1973;Goodson et al, 1974). Early clinical follow-up appeared to indicate that patients whose tumours produced the greatest in vitro osteolytic activity had the greatest risk of bone metastases (Powles et al, 1976).…”

Prostaglandin E production and hypercalcaemia in rats bearing the Walker carcinosarcoma

“…This animal model is often used to study the pathogenesis of hypercalcaemia in breast cancer; the Walker carcinosarcoma was derived from a spontaneously developed tutmour of the rat mammary gland (Minne et al, 1975). At least two candidates have been proposed as mediators of this type of hypercalcaemia: a parathyroid hormone (PTH)-like compound (Minne et al, 1975(Minne et al, , 1978 and a prostaglandin, most likely PGE2 (Powles et al, 1973;Spiro & Mundy, 1979).…”

Timing of indomethacin in the control of prostaglandins, osteoclasts and bone destruction produced by VX2 carcinoma in rabbits

“…THERE IS much evidence that the development of skeletal metastases is associated with the ability of cancer cells to form prostaglandins (Powles et al, 1973;Bennett et at., 1975Bennett et at., , 1977Voelkel et al, 1975;Galasko & Bennett, 1976). Furthermore, prostaglandin-synthesis inhibitors of the aspirin type inhibit the following: hypercalcaemia and osteolysis in rats with the Walker tumour (Powles et al, 1973); hypercalcaemia in patients with various non-haematological tumours (Seyberth et al, 1975); osteolysis and osteoclast proliferation in rabbits bearing the VX2 carcinoma (Galasko & Bennett, 1976).…”

“…Furthermore, prostaglandin-synthesis inhibitors of the aspirin type inhibit the following: hypercalcaemia and osteolysis in rats with the Walker tumour (Powles et al, 1973); hypercalcaemia in patients with various non-haematological tumours (Seyberth et al, 1975); osteolysis and osteoclast proliferation in rabbits bearing the VX2 carcinoma (Galasko & Bennett, 1976). However, in these experiments treatment with prostaglandin-synthesis inhibitors was started at the time of tumour inoculation, unlike the timing of therapy that would be feasible in man.…”