Development, characterization and imaging of bone metastasis mouse models -
Year: 2009
Type: dissertation
Abstract: Bone metastasis is an incurable disease considerably decreasing quality of life of patients with metastatic tumors of particularly breast, prostate, lung and kidney. The vicious cycle of bone metastasis is a multi step process in which tumor cells, osteoclasts, osteoblasts, the organic bone matrix and other factors are involved. Combination therapies that target different steps of the cycle could be especially effective in inhibiting growth of osteolytic bone metastases. However, current therapies are palliative and mostly target either tumor cells or osteoclasts. Thus, to develop therapy options and better understand the biology of breast and renal cell cancer (RCC) bone metastasis, it is crucial to develop new animal models. In this thesis, we have established a new experimental model of RCC bone metastasis by intracardiac (i.c.) inoculation of human 786-O/luciferase cells in athymic nude mice. The animals developed extensive osteolytic bone destruction as monitored by radiography and micro-CT scans within 10 weeks. The bone destruction observed was comparable to clinical settings and mainly occurred in hind limbs, forelimbs and the spine. To increase the bone-metastatic potential of the 786-O cell line and make the model suitable for evaluating compounds, an in vivo selection was done yielding a subclone causing osteolytic lesions in 7 weeks. To conclude, this model provides a reliable reproduction of the clinical situation and allows for designing effective treatments by better understanding the molecular mechanisms of RCC bone metastasis. In addition, the effect of sagopilone on tumor-induced osteolysis and tumor burden in athymic nude mice inoculated i.c. with MDA-MB-231(SA)/luciferase human breast cancer cells was examined. Imaging modalities (bioluminescent imaging, micro- CT, radiography) were evaluated for their use to monitor therapeutic effects in preclinical models of bone metastasis. Sagopilone, a novel, fully synthetic epothilone, inhibits the growth of breast cancer cells in vitro and in vivo. In this thesis its potency was determined in treatment models simulating the adjuvant (preventive) and metastatic (therapeutic) settings in the clinic. The study demonstrated that sagopilone significantly inhibited tumor burden and bone destruction compared with vehicle group and reduced tumor-induced cachexia and paraplegia. In the therapeutic model, sagopilone treatment significantly lowered the number of activated osteoclasts, and significantly reduced osteolytic lesion area, bone volume loss and bone resorption compared with vehicle treatment, while simultaneously inhibiting tumor burden. In this setting, sagopilone showed superior efficacy compared to paclitaxel. In vitro assays confirmed that sagopilone inhibited osteoclast differentiation and activation without cytotoxic effects and more efficiently than paclitaxel. Finally, the effect of sagopilone on osteoclasts was confirmed in vivo using a mouse model of ovariectomy (OVX)-induced osteoporosis. OVX mice treated with sagopilone showed higher trabecular bone density compared to OVX mice without treatment. Consequently, sagopilone appears to inhibit the vicious cycle of bone metastasis at both the tumor growth and bone resorption stages, suggesting the possibility for substantial benefit in the treatment of patients with breast cancer at risk from bone metastases or with bone lesions already present as well as possibly in other diseases with increased bone resorption.
Author: Strube, Anne-Kathrin
Language: English
Topic: Bone health and treatments
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1617263620