The effect of zoledronic acid and osteoprotegerin on growth of human lung cancer in the tibias of nude mice

Abstract

The pathogenesis of bone metastases may require the activation of osteoclasts by tumor-secreted factors, which promote important interactions with the bone microenvironment. We utilized an intratibial model of bone metastasis with bioluminescent imaging (BLI) to measure the effect of osteoclast inhibition on the interaction of human lung cancer cells with bone, and on tumor growth. Mice were injected with luciferase-transduced tumor cells (HARA, human pulmonary squamous carcinoma) and divided into three groups: (1) untreated, (2) twice weekly treatment with the bisphosphonate zoledronic acid (ZOL), or (3) osteoprotegerin (OPG). Histomorphometry and imaging were used to evaluate tumor burden, and parameters of osteoclast activity. Mice in the treated groups had increased bone density and decreased osteoclast numbers in nontumor-bearing tibiae. There was greater than 60% reduction in mean tumor volume in both treatment groups when evaluated by histomorphometry (P = 0.06 [OPG], P = 0.07 [ZOL]). However, bioluminescent imaging failed to show a reduction in tumor burden due to wide variability in the data. Osteoclast numbers along tumor-associated bone were significantly increased compared to tumor-free bone, and were not reduced by either treatment. Plasma calcium concentration was increased in all groups. Plasma tartrate-resistant acid phosphatase 5b was reduced in both treatment groups. Plasma PTHrP was significantly increased in the untreated tumor-bearing group, but was not significantly different in the two treatment groups compared to normal mice. OPG or ZOL did not change tumor cell proliferation, but ZOL increased HARA cell apoptosis. OPG and ZOL reduced tumor growth in the tibiae of treated mice, however, PTHrP production by HARA cells may have resulted in a high concentration in the bone microenvironment, partially overriding the antiosteoclast effects of both OPG and ZOL.

Bisphosphonates regulate cell proliferation, apoptosis and pro-osteoclastic expression in MG-63 human osteosarcoma cells

“…All of these findings suggest the potential involvement of the RANK/RANKL/OPG axis in osteosarcoma (28). OPG would decrease tumor burden and select plasma parameters of tumor burden and bone resorption by inhibiting osteoclastic bone resorption and tumor growth in an intratibial injection model of bone metastasis of a human pulmonary squamous cell carcinoma (29).…”

Impact of Chemotherapy on Hypercalcemia in Breast and Lung Cancer Patients

“…The administration of zoledronic acid to malignant hypercalcemic mice would lead to a decreased in osteoclast cell i.e., increased in bone density and decreased in hypercalcemia, but not decrease in PTHrP production by tumor cells, and have no impact on tumor cell proliferation (Tannehill-gregg, 2006). Thus, reduction of PTHrP level associated with the use of chemotherapy and bisphosphonates (such as pamidronate or zoledronic acid) combination is mainly caused by the chemotherapy itself rather than by bisphosphonates, since chemotherapy caused the changes in the cancer cell proliferation.…”

A Novel Bioluminescent Mouse Model and Effective Therapy for Adult T-Cell Leukemia/Lymphoma

“…RV-ATL-luc cells expressing luciferase were generated using a lentiviral vector as previously described (23). Following transduction, the cells were incubated at 37jC for 1 h and washed twice with RPMI 1640 before i.p.…”