| Clinical Applications of Angiogenic Growth Factors and Their Inhibitors. |
Contributed by C. Yap SACB/Roche Corporate Symposium Speaker
: Associate Professor Jerry Yeo Kiang Teck,
Director, Clinical Chemistry and Endocrinology
Laboratories Date : Thursday 22/6/2000 Time : 5:30 pm Venue : Pathology Lecture Theatre, Singapore General Hospital A/Prof Jerry Yeo Kiang Teck shared his experiences in the research and development in angiogenic factors and anti-angiogenic factors with SACB members. "Implanted tumours in animal models elicit angiogenesis (the development of blood vessels), "suggesting that tumours can secrete diffusible activators" said Prof Yeo. Vascular endothelial growth factors (VEGF) and vascular permeability factors (VPF) were discovered in the 1980’s. VEGF is upregulated by hypoxia and tightly correlated to the increase in tumour burden. A study showed that negative cytology but positive VEGF results in 6 patients could be explained by the fact that VEGF from malignant cells attached to the peritoneal cavity were released into the effusion. VEGF is found in breast, gastric, colorectal, hepatobiliary and pancreatic, esophageal and lung solid tumours, and shows great promise as a tumour marker. It is a bioactive molecule and may be used to assess the aggressiveness of certain cancers. VEGF also shows prognostic value as those with higher levels tend to have lower survival rates. Knowledge of these angiogenesis factors has allowed us to study endogenous angiogenic inhibitors. Inhibitors such as angiostatin and endostatin may inhibit metastatic growth by primary tumours and can thus be used as new weapons against cancer as they can prevent neovascularization. Results from preliminary trials involving anti-angiogenic agents such as TNP, batimastat (first generation), marimastal (second generation), pentosan polysulfate, angiostatin, endostatin and a g b 3 antagonists, have been encouraging. "Tumour cells mutate and become resistant to cancer drugs" said Prof Yeo "but the target cells of endogenous angiogenic inhibitors are not the tumour cells but the endotheliel cells which are normal so the chances of mutation are slim". The role of VEGF in diabetic retinopathy remains unclear. In patients with diabetic retinopathy, VEGF is produced locally and is detectable in the vitreous humour of the eye but not in the serum. Prof Yeo discussed the role of therapeutic angiogenesis in coronary arterial disease. Animal models and clinical trials illustrated the use of recombinant formulations of growth factors, such as injections of bFGF and VEGF165, and arterial gene transfer, to expedite and/or augment collateral artery development in myocardial and hind limb ischemia. It appears that the use of bFGF and VEGF165 may be a double-edged sword as they have the ability to induce angiogenesis and enhance coronary flow but may also cause vascular malformation as a result. Prof Yeo concluded his lecture by telling the audience that the current challenges of gene therapies are the long term benefits of VEGF in the heart, whether angiogenesis can augment the contractile function of the heart, and if other vascular abnormalities or tumorigenesis may develop in the long run. |
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