Zoledronic Acid -a Multiplicity of Anti-Cancer Action

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Abstract:

Bisphosphonates (BPs) are inhibitors of bone-resorption and have become the current standard of care for preventing skeletal complications associated with bone metastases. Among BPs, zoledronic acid (ZOL) has the strongest activity of anti-bone resorption and shows diverse direct anti-cancer effects in vitro. Some chemical and biological characteristics of ZOL indicate the potential for in vivo growth inhibition and the mechanisms responsible for the observed anti-cancer effects are beginning to be elucidated. ZOL inhibits farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. Consequently, it inhibits the prenylation of small G-proteins such as Ras, Rap1, Rho and Rab, reduces the signals they mediate, and thereby prevents the growth, adhesion/spreading, and invasion of cancer cells. ZOL, which has a high affinity for mineralized bone, rapidly localizes to bone, resulting in therapeutically effective local concentrations for the cancer cells in bone. ZOL also blocks osteolysis and osteoclastgenesis, thus preventing the release of various growth factors which are abundantly stored in bone. Moreover, ZOL stimulates γδ T cells, which play important roles in innate immunity against cancer. In addition, ZOL is also a potent inhibitor of angiogenesis, probably due to the modification of various angiogenic properties of endothelial cells. Furthermore, ZOL synergizes with a variety of anticancer agents including chemotherapeutic drugs, molecular targeted agents, and other biological agents. Based on these potential anti-cancer properties, several clinical trials have been initiated to test the combination of ZOL and other agents. The accumulated encouraging evidence to date indicate that ZOL is an attractive anti-cancer agent which promises to be the next exciting therapy for patients with various cancers.

Keywords: angiogenesis; bisphosphonate; bone metastasis; cancer; osteoclast; zoledronic acid; γδo T-cell

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986707781389600

Affiliations: Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.

Publication date: August 1, 2007

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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