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pubmedsum0 | Input: l - arginine ( arg ) , an essential amino acid , is required for normal growth of microbes , plants and animals . deprivation of this amino acid from the culture medium or other sources of nutrition causes serious disturbances in cellular and organ function leading to total destruction . on the other hand , excessive doses of arg also influence cell function , including cell death and cell proliferation . substantial information has been obtained in the past decades on the role of arg in tumour growth and in tumour therapy . arg , an essential amino acid , is required to maintain normal metabolism and proliferation of cells in culture . attempts to influence tumour cell proliferation by changes in amino acid balance were based on such observations . the role of the enzyme arginase , which decreases the amount of arg , was thoroughly investigated in this respect and also used in the therapy of human tumours . according to umeda , the proliferation of both hela cells in vitro and rat novikoff hepatoma in vivo could be decreased by arginase , causing relative arg deficiency . otsuka has shown that an enzyme , very similar to arginase inhibits dna synthesis in normal rat liver . the proliferation promoting activity of l - arg is also underscored by the fact , that arg is converted by arginase to l - ornithine , which is the precursor of various polyamines essential for cell proliferation . wheatley et al. [ 7 - 10 ] analysed the effect of deprivation of eleven essential amino acids on several tumour cell lines and found that apoptotic - like cell death occurs as a consequence of this manipulation . the cell lines died considerably more quickly during arg deprivation than in the absence of any other essential amino acids . moreover , when co - cultures of normal and tumour cells were deprived of arg the normal cells survived and the tumour cells died . according to these observations , lamb and wheatley have also shown , that arg deprivation most probably impairs the control of dna synthesis at the g1 checkpoint , which normally inhibits its initiation of dna synthesis under unfavourable conditions . suggested a possible therapeutic effect of arg - rich diet in malignant disease , in combination with anti - cancer chemotherapy . . found that excess arg combined with doxorubicin chemotherapy extended disease - free interval and survival time of dogs with lymphoma . according to the studies of hester and fee on squamous cell carcinoma in the ch3 / km mousethe mechanism of action of high amounts of arg may be the stimulation of host immune surveillance . however , robinson et al . found that morris hepatoma - bearing rats fed with arg - rich diet did not show any alteration in tumour growth or cytokine production . the role of arg in carcinogenesis has been challenged by the experiments of weinberger et al . who found that high doses of arg glutamate decreased the carcinogenic activity of various acetamine - derivatives in rats . interesting data were reported on arg - induced apoptosis of pancreatic acinar cells both in vitro and in vivo providing a model of acute pancreatitis . the possible therapeutic use of arg against pancreatic acinic cell carcinoma has not been examined yet . arg - rich hexapeptides were identified from peptide libraries that inhibit the interaction of vascular endothelial growth factor to its receptor . these hexapeptides inhibit the proliferation of human umbilical vein endothelial cells and also block the angiogenesis induced by vascular endothelial growth factor in vivo , in the chick chorioallantoic membrane and in the rabbit cornea . one of the hexapeptides blocks the growth and formation of metastases of hm7 human colon carcinoma cells in nude mice . high doses of l - arg , d - arg and dl - arg ( 4005001000 mg / kg body weight intraperitoneally or orally ) were administered to wistar rats bearing subcutaneous yoshida 's sarcoma or to swiss mice bearing subcutaneous ehrlich carcinoma for 915 days ( table 1 ) . d - arg inhibited the growth of yoshida 's sarcoma significantly ( 50 % , p 0.05 ) , when applied in a daily dose of 500 mg / kg , orally . intraperitoneal administration of the same dose to ehrlich carcinoma bearing mice resulted in a 20 % , statistically not significant , inhibition . effect of d - arg , l - arg and dl - arg on the growth of transplantable animal tumours serva ( usa ) , ajinomoto ( japan ) , reanal ( hungary ) animals were sacrificed 24 hours after the last treatment and tumour weight was measured . inhibition or enhancementintraperitoneal ; p. o. peroral ; s. c. subcutaneous ; arg arginine l - arg , however , enhanced the growth of yoshida 's sarcoma , when given intraperitoneally or orally in a dose of 400 mg / kg . the same tendency , namely significant ( 40 % ) enhancement was seen after intraperitoneal treatment ( 400 mg / kg ) of ehrlich carcinoma bearing mice . intraperitoneal application of 500 mg / kg dl - arg to mice , inoculated with ehrlich carcinom | Output: both l - arginine supplementation and deprivation influence cell proliferation . the effect of high doses on tumours is determined by the optical configuration : l - arginine is stimulatory , d - arginine inhibitory . arginine - rich hexapeptides inhibited tumour growth . deprivation of l - arginine from cell cultures enhanced apoptosis . the pro - apoptotic action of no synthase inhibitors , like ng - monomethyl - l - arginine , is manifested through inhibition of the arginase pathway . ng - hydroxymethyl - l - arginines caused apoptosis in cell cultures and inhibited the growth of various transplantable mouse tumours . these diverse biological activities become manifest through formaldehyde ( hcho ) because guanidine group of l - arginine in free and bound form can react rapidly with endogenous hcho , forming ng - hydroxymethylated derivatives . l - arginine is a hcho capturer , carrier and donor molecule in biological systems . the role of formaldehyde generated during metabolism of ng - methylated and hydroxymethylated arginines in cell proliferation and death can be shown . the supposedly anti - apoptotic homozygous arg 72 - p53 genotype may increase susceptibility of some cancers . the diverse biological effects of l - arginine and its methylated derivatives call for further careful studies on their possible application in chemoprevention and cancer therapy . | l - arginine ( arg ) , an essential amino acid , is required for normal growth of microbes , plants and animals . deprivation of this amino acid from the culture medium or other sources of nutrition causes serious disturbances in cellular and organ function leading to total destruction . on the other hand , excessive doses of arg also influence cell function , including cell death and cell proliferation . substantial information has been obtained in the past decades on the role of arg in tumour growth and in tumour therapy . arg , an essential amino acid , is required to maintain normal metabolism and proliferation of cells in culture . attempts to influence tumour cell proliferation by changes in amino acid balance were based on such observations . the role of the enzyme arginase , which decreases the amount of arg , was thoroughly investigated in this respect and also used in the therapy of human tumours . according to umeda , the proliferation of both hela cells in vitro and rat novikoff hepatoma in vivo could be decreased by arginase , causing relative arg deficiency . otsuka has shown that an enzyme , very similar to arginase inhibits dna synthesis in normal rat liver . the proliferation promoting activity of l - arg is also underscored by the fact , that arg is converted by arginase to l - ornithine , which is the precursor of various polyamines essential for cell proliferation . wheatley et al. [ 7 - 10 ] analysed the effect of deprivation of eleven essential amino acids on several tumour cell lines and found that apoptotic - like cell death occurs as a consequence of this manipulation . the cell lines died considerably more quickly during arg deprivation than in the absence of any other essential amino acids . moreover , when co - cultures of normal and tumour cells were deprived of arg the normal cells survived and the tumour cells died . according to these observations , lamb and wheatley have also shown , that arg deprivation most probably impairs the control of dna synthesis at the g1 checkpoint , which normally inhibits its initiation of dna synthesis under unfavourable conditions . suggested a possible therapeutic effect of arg - rich diet in malignant disease , in combination with anti - cancer chemotherapy . . found that excess arg combined with doxorubicin chemotherapy extended disease - free interval and survival time of dogs with lymphoma . according to the studies of hester and fee on squamous cell carcinoma in the ch3 / km mousethe mechanism of action of high amounts of arg may be the stimulation of host immune surveillance . however , robinson et al . found that morris hepatoma - bearing rats fed with arg - rich diet did not show any alteration in tumour growth or cytokine production . the role of arg in carcinogenesis has been challenged by the experiments of weinberger et al . who found that high doses of arg glutamate decreased the carcinogenic activity of various acetamine - derivatives in rats . interesting data were reported on arg - induced apoptosis of pancreatic acinar cells both in vitro and in vivo providing a model of acute pancreatitis . the possible therapeutic use of arg against pancreatic acinic cell carcinoma has not been examined yet . arg - rich hexapeptides were identified from peptide libraries that inhibit the interaction of vascular endothelial growth factor to its receptor . these hexapeptides inhibit the proliferation of human umbilical vein endothelial cells and also block the angiogenesis induced by vascular endothelial growth factor in vivo , in the chick chorioallantoic membrane and in the rabbit cornea . one of the hexapeptides blocks the growth and formation of metastases of hm7 human colon carcinoma cells in nude mice . high doses of l - arg , d - arg and dl - arg ( 4005001000 mg / kg body weight intraperitoneally or orally ) were administered to wistar rats bearing subcutaneous yoshida 's sarcoma or to swiss mice bearing subcutaneous ehrlich carcinoma for 915 days ( table 1 ) . d - arg inhibited the growth of yoshida 's sarcoma significantly ( 50 % , p 0.05 ) , when applied in a daily dose of 500 mg / kg , orally . intraperitoneal administration of the same dose to ehrlich carcinoma bearing mice resulted in a 20 % , statistically not significant , inhibition . effect of d - arg , l - arg and dl - arg on the growth of transplantable animal tumours serva ( usa ) , ajinomoto ( japan ) , reanal ( hungary ) animals were sacrificed 24 hours after the last treatment and tumour weight was measured . inhibition or enhancementintraperitoneal ; p. o. peroral ; s. c. subcutaneous ; arg arginine l - arg , however , enhanced the growth of yoshida 's sarcoma , when given intraperitoneally or orally in a dose of 400 mg / kg . the same tendency , namely significant ( 40 % ) enhancement was seen after intraperitoneal treatment ( 400 mg / kg ) of ehrlich carcinoma bearing mice . intraperitoneal application of 500 mg / kg dl - arg to mice , inoculated with ehrlich carcinom |
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