The extracellular matrix plays an important role in many physiological processes. We have identified >20 angiogenic sites in the
extracellular matrix protein laminin-1. The most potent sites are A13 (RQVFQVAYIIIKA) and C16 (KAFDITYVRLKF), which are present in homologous NH(2)-terminal domains of the alpha 1 and gamma 1 chains, respectively. We reported recently that a scrambled C16 sequence, C16S (DFKLFAVTIKYR), acts as an antagonist to both
peptides. Here, we have identified a stronger antiangiogenic
peptide, C16Y (C16S with a T to Y substitution), with potent activity in several
biological assays including
tumor growth. C16Y is more potent in promoting endothelial cell attachment and inhibiting attachment to
laminin-1 than either C16 or C16Y. Disruption of tube formation by C16Y is also observed at concentrations at least five times lower than C16S. The minimal active sequence was found to be DFKLFAVY. C16Y is more potent in blocking C16-induced chick chorioallantoic membrane angiogenesis than C16S.
Tumor growth studies on the chick chorioallantoic membrane showed that C16Y reduces
breast cancer cell growth without affecting cell proliferation. This result suggests that angiogenesis is being inhibited by the
peptide. In vivo animal studies demonstrated that C16Y treatment significantly reduced
tumor growth and decreased
tumor vessel number, as compared with controls, additionally suggesting that angiogenesis was affected. These results indicate that we have identified a more potent antiangiogenesis inhibitor
peptide that may be used as a therapeutic to treat
cancer.