Hua-Tang Zhang

The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo

Vascular endothelial growth factor (VEGF) is known to occur as at least six differentially spliced variants, giving rise to mature isoforms containing 121, 145, 165, 183, 189 and 206 amino acids. However, little is yet known concerning the in vivo activities of this differential splicing. Stably transfected MCF-7 breast carcinoma cells were constructed that secreted comparable amounts of the 121, 165 or 189 isoforms. Rabbit corneal angiogenesis assays showed the VEGF121 transfectant to have much greater angiogenic activity than the 165 or 189 expressing MCF-7 cells. While the VEGF121-expressing MCF-7 cells were reproducibly more tumorigenic than the control transfectants, this was not the case with the VEGF165- or VEGF189-expressing cells. More surprising was the observation that VEGF189 located to the nucleus, consistent with the presence of a highly conserved nuclear localization sequence in exon 6a that is expressed in VEGF189 but not 121 or 165. It was concluded that the VEGF121 isoform is both more angiogenic and tumorigenic than are the 165 and 189 isoforms. This is probably due to the ability of the 121 isoform, unlike the 165 and 189 isoforms, to freely diffuse from the cells producing it.

Breast cancer angiogenesis — new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting

SummarySeveral groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGFβ1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suraminin vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize.New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.

Anti-angiogenic therapies in cancer clinical trials.

Strategies involving vasculature have widely been acknowledged to have therapeutic potential in the management of cancer and other diseases. Based on a large body of evidence from preclinical studies and early clinical trials there is considerable optimism that anti-angiogenesis and vascular targeting will be a major clinical therapy. This review considers some 30 anti-angiogenic and vascular targeting agents that are currently in cancer clinical trials and highlights specific problems relating to the assessment of the activity of these agents in patients, trial design, potential toxicities and resistance mechanisms.

Therapeutic inhibition of angiogenesis

Angiogenesis, or the growth of new blood vessels, has, in recent years, become an area of intense scientific research. The primary reason for this has been the realization that angiogenesis plays a key role in many common pathologies, and that its inhibition could have profoound implications in the treatment of these disorders. A substantial number of anti-angiogenic agents have now been identified; however, none has, as of yet, achieved widespread acceptance in the clinic. Many agents have been identified as the result of clearly defined research programs, such as the inhibitors of the vascular endothelial growth factor transmembrane tyrosine kinase receptors, but many other simply by screening. The purpose of this article is to reveiw the wealth of information available on known anti-angiogenic agents and to assess their future potential.

Angiogenic Polypeptides in Breast Cancer: Expression of Mrna’s in Primary Human Tumours, MCF-7 Cell Transfection and Xenograft Models

Screening of 84 primary human breast carcinomas for the mRNA expression of seven angiogenic polypeptides showed that the most commonly expressed and/or the most highly expressed when compared to normal breast tissue were vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor/thymidine Phosphorylase (PDECGF/TP)1. The neurokines midkine (MK) and pleiotrophin were also fairly commonly expressed in tumour but not normal tissue (unpublished data from this group and ref. 1).