Campus Bio-Medico University, Rome, Italy
*E-mail: b.vincenzi@unicampus.it
We read with interest the review written by K. D. Miller et al. [1]. We found that the authors failed to describe the antiangiogenic properties of the bisphosphonate family. Recent evidence suggests that bisphosphonates have antitumor activity. The anticancer properties of these molecules may be partially attributed to an antiangiogenic effect. Most of the knowledge about this effect is derived from preclinical studies with the amino-bisphosphonate zoledronic acid. Wood et al. reported that zoledronic acid produced a dose-dependent inhibition of cell proliferation in human umbilical vein endothelial cells [2]. This effect counteracts stimulation by fetal calf serum, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). The same investigators have demonstrated that zoledronic acid is able to reduce vessel sprouting in cultured aortic rings and in the chicken egg chorioallantoic membrane assay [2]. Moreover, in a subcutaneous murine growth factor implant model, zoledronic acid strongly inhibited the angiogenic response induced by bFGF and VEGF [3].
The INSERM research group has recently demonstrated that zoledronic acid clearly inhibits angiogenesis both in bone and prostate tissues in a murine model [4]. Furthermore, for the first time in humans, our research group showed a significant decrease of circulating VEGF levels in patients with advanced solid cancer and bone metastases receiving a single dose of pamidronate administration. VEGF decrease was already significant on day 1 after a single pamidronate infusion (90 mg), and the reduction persisted on day 7 [5]. Similarly to our previous study, we performed an additional test (unpublished data) to confirm in vivo the potential antiangiogenic properties of a single zoledronic acid infusion (4 mg) in cancer patients with bone metastases. Differently from pamidronate, zoledronic acid induced a more prolonged decrease in serum VEGF levels lasting 21 days from the infusion. Moreover, zoledronic acid was able to induce a significant, though transient, decrease in serum platelet-derived growth factor levels. The angiogenic cytokine reduction in both the studies was unquestionably achieved as a consequence of the bisphosphonate infusion, because any patients who received radiotherapy, chemotherapy, immunotherapy, steroids or hormonotherapy during the 4 weeks before study accrual were considered ineligible.
Although these findings should be confirmed in larger studies, we suggest the inclusion of the bisphosphonates in the list of molecules with antiangiogenic properties. Future clinical trials should be performed to evaluate the safety and efficacy of bisphosphonates in association with other antiangiogenic compounds and anticancer drugs in cancer patients.
B. Vincenzi*, D. Santini, L. Rocci & G. Tonini
Campus Bio-Medico University, Rome, Italy (*E-mail: b.vincenzi@unicampus.it)
References
1. Miller KD, Sweeney CJ, Sledge GW. The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era. Ann Oncol 2003; 14: 2028.
2. Wood J, Bonjean K, Ruetz S et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002; 302: 10551061.
3. Wood J, Schnell C, Green JR. Zoledronic acid, a potent inhibitor of bone resorption, inhibits proliferation and induces apoptosis in human endothelial cells in vitro and is anti-angiogenic in a murine growth factor implant model. Proc Am Soc Clin Oncol 2000; 19: 664 (Abstr 2620).
4. Fournier P, Boissier S, Filleur S et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002; 62: 65386544.
5. Santini D, Vincenzi B, Avvisati G et al. Pamidronate induces modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 2002; 8: 10801084.