Given that the inhibition of angiogenesis may be of value in the treatment of neoplasms, concern has been raised that the administration of angiogenic growth factors could lead to development of tumors. There are neither in vitro nor in vivo data to suggest that either VEGF or FGF increases the risk of neoplastic growth and/or metastases, although longer-term follow-up will be required to address this issue in clinical trials. In our own experience with 88 subjects who have undergone VEGF gene transfer for critical limb ischemia, the cumulative 7-yr incidence of cancer was limited to two patients with bladder cancer and one with liver and brain metastases from unknown primary (107). It was interesting to note that in the VIVA Trial that there was a greater incidence of tumors in the placebo group compared to the VEGF group. This highlights the fact that the age group receiving such therapy will develop some unrelated tumors. Because of the theoretical risk of neoplastic growth, one must be vigilant about the possibility of cancer in patients treated with these angiogenic growth factors. In addition, concerns regarding the development of angiomata were raised in studies involving mice or rats treated with transduced myoblasts or supraphysiological doses of plasmid DNA respectively. Importantly, no other preclinical or clinical reports, including those using adenoviral vectors, have described this complication (108,109).
It is theoretically possible that VEGF may exacerbate proliferative and/or hemorrhagic retinopathy in patients with diabetes in view of the high VEGF levels demonstrated in the ocular fluid of patients with active proliferative retinopathy leading to loss of vision (110). To date, this adverse effect of therapeutic angiogenesis has not been observed. The local delivery of naked plasmid DNA encoding for VEGF-1 or VEGF-2 to more than 100 patients (one third with diabetes and/or remote ret-inopathy) treated at our institution with up to 4-yr follow-up did not affect the visual acuity or fundoscopic findings as evidenced by serial funduscopic examinations pre- and post-gene transfer by an independent group of retinal specialists.
Experiments in transgenic mice engineered to overexpress VEGF ± angiopoietin have demonstrated the lethal permeability-enhancing effects of VEGF (111). However, even though VEGF has been reported to cause local edema, which manifests as pedal edema in patients treated with VEGF for critical limb ischemia, it responds well to treatment with diuretics (44). As previously described, hypotension has been observed in therapies with recombinant proteins particularly when used systemi-cally and in higher doses (112,113). This is believed to be a result of the fact that VEGF upregulates NO synthesis. This complication, however, has never been described following gene transfer in either animals or humans (114,115).
Moulton et al. recently observed that when hypercholesterolemic, apolipoprotein E-deficient mouse models were treated with inhibitors of angiogenesis (endostatin or TNP-470), there was significant regression of plaque areas and inhibition of intimal neovascularization (116). This and other studies raised concern regarding the potential for VEGF and other proangiogenic therapies to promote atherosclerosis (92,117,118). However, data available from four separate animal studies and two clinical studies of human subjects fail to support the notion that accelerated atherosclerosis is a likely consequence of administering angiogenic cytokines (48-51,119,120). The outcome is quite the opposite, in that administration of VEGF led to a statistically significant reduction in intimal thickening due to accelerated reendothelialization, thereby refuting the notion that acceleration of atherosclerosis will be a consequence of VEGF-induced stimulation of angiogenesis.
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