Influence of tyrosine and phenylalanine limitation of cytotoxicity of chimeric TGF-alpha toxins on B16BL6 murine melanoma in vitro.
Previous research in animals supports the use of tyrosine and phenylalanine (Tyr-Phe) restriction as an adjuvant to the treatment of cancer. In this regard, dietary restriction of Tyr-Phe specifically inhibits the growth of B16BL6 melanoma tumors, dramatically suppresses spontaneous hematogenous metastasis, and modulates the sensitivity of these tumor cells to growth factors. Two chimeric toxins, HB-TGF alpha-PE4EKDEL and TGF alpha-PE4EKDEL, were examined for their toxicity against the B16BL6 melanoma cell line, and the ability of Tyr-Phe limitation to modulate the potential of these toxins was examined. Tyr-Phe limitation significantly enhanced the cytotoxic effects of HB-TGF alpha-PE4EKDEL approximately 10-fold toward B16BL6 melanoma, and free heparin diminished the cytotoxicity of HB-TGF alpha-PE4EKDEL. Although TGF alpha-PE4EKDEL is cytotoxic to this cell line, Tyr-Phe limitation did not effect the cytotoxicity of this toxin. Tyr-Phe limitation inhibited the synthesis and secretion of heparin-binding proteins but did not alter the expression of surface heparan sulfate proteoglycans. These data suggest that cell surface heparan sulfate proteoglycan is a target for binding and execution of the cytotoxicity of HB-TGF alpha-PE4EKDEL and that augmentation of cytotoxicity by Tyr-Phe limitation is due to the inhibition of heparin-binding protein production.
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman 99164-6510, USA.
Y M
YM
Fu
Y Q
YQ
Li
G G
GG
Meadows
D000818:Animals; D000970:Antineoplastic Agents; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003470:Culture Media; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006493:Heparin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D010649:Phenylalanine / Q000008:administration & dosage*; D011509:Proteoglycans / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D003470:Culture Media; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha; C036090:heparin proteoglycan; D014443:Tyrosine; D010649:Phenylalanine; D004815:Epidermal Growth Factor; D006493:Heparin