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Targeting bone metastasis and hypercalcemia
Most cancer patients are not killed by their primary tumors but succumb to metastatic disease. The most common human cancers--lung, breast, and prostate--frequently spread to bone, causing suffering and morbidity through pain, fractures, and nerve compression syndromes.
Tumor cells enter bones through blood and lymphatic vessels. In order to establish bone metastases, they have to influence bone metabolism. Most breast cancers that spread to bone express high levels of parathyroid hormone related protein, or PTHrP, a molecule that promotes bone breakdown. Scientists believe that the bone breakdown caused by PTHrP starts a vicious cycle: cross-talk between the tumor cells and the osteoclasts, cells that specialize in breaking down bone, ultimately leads to more and more bone loss and more and more aggressive growth of the tumor.
Consistent with this scenario, inhibition of osteoclast activity not only decreases bone lesions but also reduces tumor burden in animals. Preliminary results from human patients treated with bisphosphonates, a group of drugs also used to prevent and treat osteoporosis, suggest that the same might be true in humans.
An article in the November 18 issue of the Journal of Clinical Investigation focuses on direct inhibition of PTHrP, the molecule that is believed to play a critical role in starting the vicious cycle in most breast cancers that metastasize to bone.
Wolfgang Gallwitz and colleagues (of Osteoscreen Ltd in San Antonio, Texas)
identified two compounds that inhibit PTHrP production in human breast
cancer cells. In animal models, the compounds did reduce metastatic bone
breakdown, and compared favorably with bisphoshonates. The mode of act
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Contact: Brooke Grindlinger, PhD
science_editor@the-jci.org
212-342-9006
Journal of Clinical Investigation
19-Nov-2002