Abstract

The overall objective of this research is to identify the mechanism(s) whereby dietary restriction of tyrosine and phenylalanine blocks spuntaneous hematogerous metastasis in a variety of rodent neoplasms. The proposed research would complement ongoing clinical trials evaluating the diet as an adjuvant therapy for meloanoma patients. Our preliminary results indicate that this amino acid restriction alters the phenotype of the highly invasive and metastatic B16BL6 melanoma cell line such that it becomes defective in a required invasive function. The major thrust of the proposed research will be to characterize the nature of the induced dietary modulation in variants isolated from lymph node and lung metastases. The extent of the modulation will be assessed by examining tumor cell phenotypes of known importance to the metastatic cascade: the ability of tumor cells to attach to, degrade, and invade through extracellular matrices, and their ability to survive and establish colonies in the lung after intravenous inoculation. We will define the stability of the dietinduced modulation in both in vivo and in vitro environments, and will determine the level of tyrosine and phenyklalanine necessary to block spontaneous hematogenous metastatis of the dietmodified tumor cell variants.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042465-02
Application #
3183833
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Washington State University
Department
Type
Schools of Pharmacy
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164

  Publications

Fu, Y M; Yu, Z X; Pelayo, B A et al. (1999) Focal adhesion kinase-dependent apoptosis of melanoma induced by tyrosine and phenylalanine deficiency. Cancer Res 59:758-65
Pelayo, B A; Fu, Y M; Meadows, G G (1999) Inhibition of B16BL6 melanoma invasion by tyrosine and phenylalanine deprivation is associated with decreased secretion of plasminogen activators and increased plasminogen activator inhibitors. Clin Exp Metastasis 17:841-8
Fu, Y M; Li, Y Q; Meadows, G G (1998) Influence of tyrosine and phenylalanine limitation of cytotoxicity of chimeric TGF-alpha toxins on B16BL6 murine melanoma in vitro. Nutr Cancer 31:1-7
Fu, Y M; Yu, Z X; Ferrans, V J et al. (1997) Tyrosine and phenylalanine restriction induces G0/G1 cell cycle arrest in murine melanoma in vitro and in vivo. Nutr Cancer 29:104-13
Huijzer, J C; McFarland, M; Niles, R M et al. (1996) Phorbol 12-myristate 13-acetate enhances nm23 gene expression in murine melanocytes but not in syngeneic B16-BL6 melanoma variants. J Cell Physiol 166:487-94
Elstad, C A; Thrall, B D; Raha, G et al. (1996) Tyrosine and phenylalanine restriction sensitizes adriamycin-resistant P388 leukemia cells to adriamycin. Nutr Cancer 25:47-60
Uhlenkott, C E; Huijzer, J C; Cardeiro, D J et al. (1996) Attachment, invasion, chemotaxis, and proteinase expression of B16-BL6 melanoma cells exhibiting a low metastatic phenotype after exposure to dietary restriction of tyrosine and phenylalanine. Clin Exp Metastasis 14:125-37
Huijzer, J C; Uhlenkott, C E; Meadows, G G (1995) Differences in expression of metalloproteinases and plasminogen activators in murine melanocytes and B16 melanoma variants: lack of association with in vitro invasion. Int J Cancer 63:92-9
Elstad, C A; Meadows, G G; Aslakson, C J et al. (1994) Evidence for nutrient modulation of tumor phenotype: impact of tyrosine and phenylalanine restriction. Adv Exp Med Biol 354:171-83
Blanckaert, V D; Schelling, M E; Elstad, C A et al. (1993) Differential growth factor production, secretion, and response by high and low metastatic variants of B16BL6 melanoma. Cancer Res 53:4075-81

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