Bisphosphonates as inhibitors of tumor angiogenesis

An estimated 10 million Americans over the age of 50 years old suffer from osteoporosis and a further 32.9 million have low bone mass, placing them at an increased risk for developing this condition. As described in the “Focus on Metabolic Diseases” section of this edition of TherapeuticAdvances, since their launch the bisphosphonates have become the most effective means of limiting bone loss (for a review of osteoporosis therapeutics click here).

Many patients with cancer develop metastases to bone, which affects quality of life and contributes to the morbidity of the disease. Following their approval for the treatment of osteoporosis, bisphosphonates were also approved for the treatment and prevention of fractures related to metastatic disease. Clinical trials of zoledronic acid for example have shown that it can reduce markers of bone resorption by 40% to 60% in patients with multiple myeloma and breast, prostate, and lung cancers. More recently researchers have demonstrated that bisphosphonates have direct antitumor effects.

N-bisphosphonates inhibit farnesyl diphosphate synthase resulting in reduced isoprenylation of key regulatory proteins such as Ras, Rac, Rho, cdc42 and contributing to the inhibition of proliferation and stimulation of apoptosis in cultured human cancer cells. In addition, bisphosphonate treatment interferes with breast cancer cell adhesion to bone matrix, and inhibits cell migration and invasion. More recently researchers at Novartis have demonstrated that zoledronic acid is also a potent inhibitor of angiogenesis.

Angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. Both stimulators and inhibitors of angiogenesis are being developed, with primary interest being focussed on the use of inhibitors to prevent the growth of tumors (Click here for an analysis of angiogenesis-related approaches to oncology). This is based on the concept that cells in the center of the tumor receive inadequate levels of oxygen and nutrients by diffusion alone once they extend past a critical volume of 2 cubic millimeters and instead rely on neovascularization for further growth.

Early observations that bisphosphonates are able to inhibit angiogensis were made using non-tumoral angiogenesis assays. More recently Hamma-Kourbali et al have reported that the novel bisphosphonate, BP7033 inhibited the density of endothelial cells in xenografts of the human cancer cell line, A431. This effect was related to an inhibition of endothelial cell chemotaxis, proliferation and tube formation. In addition to having direct effects on endothelial cell function, BP7033 also reduced the secretion by A431 cells of two pro-angiogenic mediators, VEGF and MMP-2 by 60-80%. Ras signaling is related to the expression of both MMP-2 and VEGF and as predicted by earlier studies, BP7033 prevented the post translational processing of Ras offering an explanation for the anti-angiogenic properties of this bisphosphonate.

This study further demonstrates the potential of bisphosphonates in the treatment of cancer and demonstrates for the first time that anti-cancer efficacy of this class involves both the direct and indirect inhibition of angiogenesis.

Entry date Tuesday, December 16, 2003

Adapted from Hamma-Kourbali et al, Biochem Biophys Res Commun. 2003 Oct 24;310(3):816-23.