Dietary Protein And Amino Acids

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It is not possible to establish recommendations for cancer prevention based upon dietary protein level or source. Dietary protein can increase, decrease, or have no effect on tumorigenesis in various tumor models, suggesting that protein may exert very specific mechanisms of action that are unique to each target tissue and initiating agent (42,147-149).

Very little research has focused on the role of dietary protein or amino acids in tumor angiogenesis. One mechanism whereby dietary protein intake may influence angiogen-esis is via dietary intake of the amino acid L-arginine, and subsequent modulation of nitric oxide (NO) production. NO is synthesized from L-arginine by the enzyme family, NO synthase (NOS). Recent investigations revealed that the NOS pathway is frequently upregulated in solid tumors of experimental animals (150-153), and the expression of different isoforms of NOS has been characterized in several tumor systems (150152,154). The synthesis of NO by endothelial cells is blocked by L-arginine analogs such as N™-mono-methyl-L-arginine (L-NMMA) and Lm-nitro-L-arginine methyl ester (L-NAME); D-isomers are ineffective. Systemic administration of L-NAME to rabbits bearing corneal implant blocked VEGF-, but not bFGF-induced angiogenesis (155). Furthermore, L-NAME was very effective in blocking angiogenesis induced by VEGF-transfected MCF-7 breast cancer cells (155). Stimulation of monocytes with LPS in absence of L-arginine greatly reduced their production of angiogenic activity; the NOS

inhibitors L-NMMA and L-NAME reduced the angiogenic activity, suggesting that this enzyme has a key role in controlling the pathway of angiogenesis (156). In another model of angiogenesis, rat microvascular endothelial cells grown in three-dimensional collagen gels exhibited extensive tube formation in presence of TGF-B1, which was blocked by NOS inhibitors (157). Excess L-arginine in this model reversed the inhibitory effect of L-NAME on vascular tube formation (157).

The connection between NO and enhanced vascular permeability in solid tumors was explored, and found to be suppressed by NO synthatase inhibitors and augmented following the administration of L-arginine (153). The ability of VEGF and bFGF to enhance vascular permeability and tone is also coupled to NO production and blocked by NOS inhibitors (153, 159-161). Another potential mechanism whereby dietary arginine and NO may modify angiogenesis is via upregulation of urokinase-type plasminogen activator and participation in matrix degradation (162). These studies clearly indicate that increased NO within tumors may enhance angiogenic pathways, as well as vascular permeability and blood flow. How changes in dietary arginine and metabolic antagonists, such as L-lysine, may modulate NO synthesis and alter tumor vascular tone, blood flow, and angiogenesis, remains to be clearly defined.

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