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Editorial |
Massachusetts General Hospital, Boston, Massachusetts
Introduction
Bone metastases are a major cause of morbidity for patients with many types of cancer including multiple myeloma, breast cancer, prostate cancer, and other solid tumors. The clinical complications of bone metastases include pain, fracture, spinal cord compression, and hypercalcemia of malignancy. Although there are important differences in the biology of bone metastases from different cancer types, osteoclast activation is the major mechanism for all tumor-mediated bone destruction.
Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and play an important role in the supportive care of patients with bone metastases. Several bisphosphonates (clodronate, pamidronate, and zoledronic acid) improve clinical outcomes for patients with multiple myeloma and metastatic breast cancer. Zoledronic acid decreases the risk of skeletal complications for patients with prostate cancer and other solid tumors including lung cancer and renal cell carcinoma.
Bisphosphonates inhibit osteoclast-mediated bone resorption by several mechanisms. Etidronate and clodronate are metabolized into cytotoxic analogues of ATP. More potent nitrogen-containing bisphosphonates (risedronate, pamidronate, and zoledronic acid) inhibit farnesyl diphosphate synthase, a key enzyme in the mevalonate pathyway, and decrease prenylation of essential GTP-binding proteins. Bisphosphonates also increase osteoblast secretion of an inhibitor of osteoclast recruitment and transforming growth factor-ß, a signal for osteoclast apoptosis.
In this issue of Clinical Cancer Research, Alvarez et al. (1)
report the properties of bisphosphonates in a rat mammary carcinoma model of tumor-mediated osteolysis. Alendronate, pamidronate, and risedronate prevented tumor-mediated bone destruction in this model. In contrast, proliferation of the rat mammary cells in vitro was relatively resistant to bisphosphonates in vitro with IC50 
33.6 µM. Was the broad protective effect against tumor-mediated osteolysis due to inhibition of osteoclasts alone? The study was not designed to address this question, although considerable preclinical evidence suggests that antitumor effects of bisphosphonates contribute to their biological activity.
Development and progression of bone metastases involve tumor cell adhesion to bone, invasion, new blood vessel formation, and proliferation. Preclinical studies suggest that bisphosphonates inhibit each of these steps (2 , 3) .
Adhesion and Invasion
Bisphosphonates inhibited adhesion of breast and prostate cancer cells to mineralized and unmineralized matrices in vitro. Bisphosphonates also inhibited invasion through extracellular matrices. The relative ability of various bisphosphonates to inhibit tumor cell adhesion and invasion parallels their antiresorptive potency. Some of these activities are observed at very low bisphosphonate concentrations (10-12 to 10-6 M), suggesting that inhibition of adhesion and invasion are among the most potent biological effects of bisphosphonates. Maximum inhibition of adhesion and invasion was achieved at bisphosphonate concentrations similar to the peak plasma concentrations from clinical studies.
Angiogenesis
Zoledronic acid inhibited the proliferation of human umbilical vein endothelial cells in vitro. In rodents, zoledronic inhibited basic fibroblast growth factor-induced angiogenesis and testosterone-induced revascularization of the ventral prostate gland. Zoledronic acid also inhibited tumor-induced angiogenesis in a mouse myeloma model.
Proliferation/Survival
Several in vitro studies have shown that bisphosphonates inhibited proliferation and promoted apoptosis of myeloma, breast, and prostate cancer cell lines in a concentration-dependent and time-dependent manner. The concentrations necessary to inhibit proliferation and promote apoptosis (5–2000 µM) exceeded the peak plasma concentrations from clinical studies, although these concentrations may be achieved locally in bone. Zoledronic acid had synergistic effects with standard anticancer drugs in multiple myeloma, breast cancer, and prostate cancer cell lines.
Do these antitumor properties contribute to the clinical efficacy of bisphosphonates in cancer patients? Some studies suggest that bisphosphonates have clinically important antitumor activity (4) . Clodronate and pamidronate confer a survival advantage to certain groups of patients with multiple myeloma. Similar data have been reported for pamidronate in women with metastatic breast cancer. Some but not all studies suggest that adjuvant clodronate prevents metastases and improves survival in women with breast cancer. These clinical observations and preclinical evidence of antitumor activity provide a compelling basis to further study the antineoplastic efficacy of bisphosphonates in cancer patients. All marketed bisphosphonates have been developed based on their antiresorptive potency. The characterization of antitumor properties distinct from osteoclast inhibition raises the possibility that future drug development may identify new compounds with enhanced antitumor activity and greater clinical efficacy.
FOOTNOTES
Requests for reprints: Matthew R. Smith, MD, Massachusetts General Hospital, Cox 640, 100 Blossom Street, Boston, Massachusetts 02114. E-mail: smith.matthew{at}mgh.harvard.edu
Received 8/ 4/03; accepted 8/ 5/03.
REFERENCES
Key Article
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