Establishment of a Model to Evaluate Inhibition of Bone Resorption Induced by Human Prostate Cancer Cells in Nude Mice

Abstract

A model system of human prostate carcinoma in nude mice for searching out a method to protect the bone from cancer cells is described, in which the transplanted human prostate cancer cells were inoculated subcutaneously over the calvaria in nude mice after the periosteum wa disrupted. The tumor induced osteolysis associated with osteoclast proliferation accompanied with reactive new bone formation. This osteolysis was evaluated by measuring the increased area of bone resorption by its reduced opacity to X-ray, and histology. Etidronate disodium, a diphosphonate derivative, at a dose of three mg./kg. and 10 mg./kg. s.c. protected the bone by decreasing the extent of osteolysis as judged by the above criteria. This inhibition was obtained with no apparent effect on the growth of the tumor. These results are discussed in light of recent clinical work, showing that this animal model is a useful tool to test the effect of new drugs against osteolysis of cancer as well as to study the biology of local interaction between bone and cancer cell.

Osteoprotegerin inhibits prostate cancer–induced osteoclastogenesis and prevents prostate tumor growth in the bone

“…However, while important gains in understanding the role of osteoclastic activity have been made for osteolytic tumors, the importance of osteoclastic activity in the development of prostate cancer skeletal metastatic lesions has received little attention because of their overall osteoblastic radiographic appearance. Yet, despite the radiographic appearance, it is clear from histological evidence that prostate cancer metastases form a heterogeneous mixture of osteolytic and osteoblastic lesions (2,(20)(21)(22)(23). In fact, histomorphometric analysis of metastatic lesions reveals that osteoblastic metastases form on trabecular bone at sites of previous osteoclastic resorption, suggesting that bone resorption is required for subsequent osteoblastic bone formation (2).…”

Advances in the use of bisphosphonates in the prostate cancer setting

“…29 Early animal work in the 1980s demonstrated that the bisphosphonates clodronate and etidronate inhibited tumour-mediated osteolysis induced by implanted prostate cancer cells. [30][31][32] A later exciting development came when in vitro work established that bisphosphonates also act directly on tumour cells themselves. They have been shown to inhibit cell proliferation and viability, and induce apoptosis in a number of cancer cell lines, including prostate cancer.…”

Inhibition by a new bisphosphonate (YM175) of bone resorption induced by the MBT-2 tumour of mice

“…With regard to experimental model systems of neoplasmassociated local osteolysis, tumour-bone interactions using calvaria of the mice were extensively studied by our group (Nemoto et al, 1986;Nemoto et al, 1987;Nemoto et al, 1988a;Nemoto et al, 1988b). In one of the recent studies, suggestive evidence was obtained that our system might be suitable for studying the biology of local interaction between bone and cancer cells.…”

“…The method consisted of inoculating tumour cells subcutaneously (SC) (Fleisch et al, 1969;Fleisch & Felix, 1979;Fleisch, 1983). Inhibition of tumour induced osteolysis by bisphosphonates has been noted in animal and human studies (Jung et al, 1981; VanHoltenVerzantvoort et al, 1987;Morton & Howell, 1988).With regard to experimental model systems of neoplasmassociated local osteolysis, tumour-bone interactions using calvaria of the mice were extensively studied by our group (Nemoto et al, 1986; Nemoto et al, 1987;Nemoto et al, 1988a;Nemoto et al, 1988b). In one of the recent studies, suggestive evidence was obtained that our system might be suitable for studying the biology of local interaction between bone and cancer cells.…”