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

Abstract

Summary A new bisphosphonate, disodium dihydrogen (cycloheptylamino) methylene bisphosphonate monohydrate (YM175), was compared with 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (AHPrBP) and l-hydroxyethylidene-1,1-bisphosphonate (HEBP) in terms of its effect on tumour induced osteolysis using a bladder tumour in mice (MBT-2). 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. Furthermore, it is suggested that bone destruction induced by tumour cell invasion involves at least two mechanisms; osteoclast mediated bone destruction, and direct destruction of bone independent of osteoclasts. Bisphosphonate makes bone less susceptible to the action of both osteoclasts and tumour cells (Nemoto et al., 1992).In this paper, a new more powerful bisphosphonate, YM175 was investigated and compared to both AHPrBP and HEBP using as a model of osteolysis induced by MBT (Soloway, 1977). The tumour has retained the histologic appearance of a poorly differentiated transitional cell carcinoma. TSU-PRI is a cell line derived from a primary adenocarcinoma of the prostate in a 73-year-old man with multiple osteoblastic bone metastases (Nemoto et al., 1988b).Induction of osteolysis MBT-2 cells were transplanted routinely by subcutaneously (SC) inoculation into female C3H/He mice. When the resulting tumour was visible, it was excised aseptically and minced in medium 199. The tumour mince was further disrupted by repeated syringing. A cell suspension containing 106 tumour cells in 0.2 ml medium was inoculated SC over the calvaria of C3H/He mice under ether anaesthesia. The viability of tumour cells were assessed by using trypan blue dye exclusion test. As the tumour cells were inoculated, the needle was used to scratch the bone, which disrupted the periosteum. The same method was used for the induction of osteolysis in the nude mice using TSU-PRI human prostate carcinoma.Radiographic and microscopic examination Tumour-bearing animals were killed under anaesthesia when the tumour grew to cover the calvaria. Tumours were measured with calipers, and the mean tumour diameter was calculated from the equation (L + W) x 0.5, where L is the major and W the minor diameter. The two diameters were measured at right angles to each other. Mice with tumours less than 1Omm in diameter were excluded from analysis. The parietal bones with attached tumour transplants we...

Differential Effect of Doxorubicin and Zoledronic Acid on Intraosseous versus Extraosseous Breast Tumor Growth In vivo

“…It has been clearly shown that several different bisphosphonates can reduce tumor-induced osteolytic bone disease in animal models of a variety of cancers that metastasize to bone, including breast (8,10,32,33), bladder (34,35), and prostate cancer (16, 36 -38) as well as multiple myeloma (11,39,40).…”

Antitumor effects of bisphosphonates

“…Several studies during the past two decades have clearly demonstrated that a variety of bisphosphonates can reduce tumor-induced osteolysis in animal models of breast, [43][44][45][46][47][48][49][50][51][52] prostate, 33,[53][54][55][56][57][58][59][60] and bladder cancer, [61][62][63][64] as well as multiple myeloma. 42,[65][66][67][68][69] By inhibiting osteoclast-mediated bone resorption, bisphosphonates decrease the release of tumor-promoting growth factors from bone and delay the further progression of bone metastases.…”

Hypercalcemia associated with parathyroid hormone-related protein produced by B-cell type primary malignant lymphoma of the kidney

“…Bisphosphonates inhibit osteoclastic bone resorption with little or no effect on the renal reabsorption of Ca [8,10,22]. The substantial effect of bisphosphonate in restoring normocalcemia indicated that the HHM of the patient was caused mainly by increased osteoclastic activity.…”