human
***task***
the task is to summarize an input biomedical literature in six sentences

***input***
the input is a biomedical literature

***output***
the output is the summary of an input biomedical literature in six sentences

***documentation***

***examples***

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 carcinoma had neither inhibitory nor enhancing effect on tumour growth . various pathways of metabolism of this amino acid may explain the mode of action of arg imbalancearg is a highly reactive compound , both as a free amino acid and as a constituent of a protein . the structure of proteins can be altered by specific enzymatic modification of the side chains . one of these protein - modifying reactions is methylation , resulting in the addition of methyl groups to the guanidine residues of arg . methylated arg also occur in free form , possibly resulting from enzymatic hydrolysis of methylated proteins in vivo ( fig . mono - di - and trimethyl arg , hydroxymethyl arg , n - omega - hydroxy l - arg , n - nitro - l - arg methyl ester , nitro - arg were studied regarding the possible effect on cell death and cell proliferation of these compounds . demonstrated that monomethyl arg and dimethyl - arg inhibit significantly the growth of tobacco tissue cultures in concentrations of 10100 ppm in agar nutrient medium , ng - methylated arg added to agar - medium also significantly inhibited the growth of the roots of lettuce seedlings . have shown that ng - hydroxymethyl arg inhibited dose - dependently and significantly the proliferation of ht - 29 human colon carcinoma cells , p - 388 mouse lymphoma cells and pc - 3 human prostate carcinoma as well as k - 562 human erythroleukaemia cells in culture . the cells of the treated cultures showed morphological signs of apoptosis in a high percentage . in our in vivo experimentsthe daily dose of ng - hydroxymethyl arg was 400 mg / kg intraperitoneally , based on previous acute toxicity studies . after 10 days of ng - hydroxymethylated arg treatment complete inhibition of the growth of ehrlich ascites tumour was observed . c57b1 mice , inoculated with lewis lung tumour intramuscularly and made tumour free by amputation of the tumorous leg 10 days after tumour transplantation , were treated for seven days with 400 mg / kg ng - hydroxymethyl arg , daily , intraperitoneally . the average metastasis number in the treated animals was 27 , in the controls 54 . the average volume of the lung nodules was 34 mm in the treated and 50 in the control mice . the anti - proliferative and apoptosis - inducing effect of arg - derivatives was confirmed by the studies of singh et al . who found that n - omega - hydroxy - l - arg inhibited the proliferation of the high - arginase - expressing mdh - mb - 468 cells and induced apoptosis after 48 hours . that n - nitro - arg methyl ester sensitised cells to apoptosis induced by sodium deoxycholate . l - arg , nitro - arg and methyl - arg have been found to induce increase in cytosolic ca concentration in cultured nit - 1 cells , leading to depolarisation of the plasma membrane potential , a phenomenon common during the process of apoptosis . ng - methyl - l - arg n - nitro - l - arg methyl ester , n - hydroxy - l - arg and l - ng - methyl - arg all proved to be inhibitors of nitric oxide synthase . nitric oxide synthase converts l - arg to produce no , which " janus - faced " compound certainly may influence both cell proliferation and cell death . another possible mode of action of methylated and hydroxymethylated arg can be deduced from the fact that these molecules are formaldehyde generators . that ng - hydroxymethyl arg as a biomolecule is one of the compounds that are responsible for the endogenous formaldehyde level . the guanidine group of l - arg can bind one , two or three molecules of ch2o and in the reaction mono - , di - and trihydroxymethylated arg derivatives are formed . arg is suitable to carry the endogenous ch2o in form of hydroxymethyl group in biological systems . although little is known about the demethylation of ng - methylated arg , ng - hydroxymethyl - l - arg generates a direct ch2o - yielding activity , which may be responsible for its apoptotic effect . it has also been shown in our recent experiments that the administration of analytically pure formaldehyde to cell cultures causes dose dependently apoptosis ( 110 g / ml ) or stimulation of dna synthesis and cell proliferation ( 0.10.01 g / ml ) . the calculated quantity of formaldehyde released by demethylation processes from hydroxymethyl arg is in the above mentioned range and the formaldehyde - mediated biological action of this compound has to be taken into consideration . the lysine - arginine antagonism widely shown in nature is also represented in apoptosis resistant cell lines that contain a - to g alteration is the death domain , encoding l - arginine instead of l - lysine in codon 441 . over - representation of the homozygous arg 72 - p53 genotype in cervical carcinoma patients has been reported . did not find increased risk for human papilloma virus - associated cervical tumour development associated with arg 72 - p53 . although data in the literature are pointing to the anti proliferative effect of both arg depletion and supplementation , arg proved to be essential for tumour cell growth . this observation raises the question , whether decreasing the concentration of arg in nutrients and consequently in blood serum or the administration of d - arginine may lead to retardation of tumour growth in humans , too . arg , because of its strong basic guanidine group , plays an important role in molecular interactions in biological systems , such as interaction between arg and formaldehyde , both of which are normal components of cells and biological fluids . as a resultthese functions may also play role in the biological activity of arg and its methylated and hydroxymethylated derivatives . an interesting therapeutic possibility worthy of further investigation may be the administration of methylated and hydroxymethylated arg in order to induce tumour cell death or to prevent tumour cell proliferation .
output:

agent
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 .
***task***
the task is to summarize an input biomedical literature in six sentences

***input***
the input is a biomedical literature

***output***
the output is the summary of an input biomedical literature in six sentences

***documentation***

***examples***

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 carcinoma had neither inhibitory nor enhancing effect on tumour growth . various pathways of metabolism of this amino acid may explain the mode of action of arg imbalancearg is a highly reactive compound , both as a free amino acid and as a constituent of a protein . the structure of proteins can be altered by specific enzymatic modification of the side chains . one of these protein - modifying reactions is methylation , resulting in the addition of methyl groups to the guanidine residues of arg . methylated arg also occur in free form , possibly resulting from enzymatic hydrolysis of methylated proteins in vivo ( fig . mono - di - and trimethyl arg , hydroxymethyl arg , n - omega - hydroxy l - arg , n - nitro - l - arg methyl ester , nitro - arg were studied regarding the possible effect on cell death and cell proliferation of these compounds . demonstrated that monomethyl arg and dimethyl - arg inhibit significantly the growth of tobacco tissue cultures in concentrations of 10100 ppm in agar nutrient medium , ng - methylated arg added to agar - medium also significantly inhibited the growth of the roots of lettuce seedlings . have shown that ng - hydroxymethyl arg inhibited dose - dependently and significantly the proliferation of ht - 29 human colon carcinoma cells , p - 388 mouse lymphoma cells and pc - 3 human prostate carcinoma as well as k - 562 human erythroleukaemia cells in culture . the cells of the treated cultures showed morphological signs of apoptosis in a high percentage . in our in vivo experimentsthe daily dose of ng - hydroxymethyl arg was 400 mg / kg intraperitoneally , based on previous acute toxicity studies . after 10 days of ng - hydroxymethylated arg treatment complete inhibition of the growth of ehrlich ascites tumour was observed . c57b1 mice , inoculated with lewis lung tumour intramuscularly and made tumour free by amputation of the tumorous leg 10 days after tumour transplantation , were treated for seven days with 400 mg / kg ng - hydroxymethyl arg , daily , intraperitoneally . the average metastasis number in the treated animals was 27 , in the controls 54 . the average volume of the lung nodules was 34 mm in the treated and 50 in the control mice . the anti - proliferative and apoptosis - inducing effect of arg - derivatives was confirmed by the studies of singh et al . who found that n - omega - hydroxy - l - arg inhibited the proliferation of the high - arginase - expressing mdh - mb - 468 cells and induced apoptosis after 48 hours . that n - nitro - arg methyl ester sensitised cells to apoptosis induced by sodium deoxycholate . l - arg , nitro - arg and methyl - arg have been found to induce increase in cytosolic ca concentration in cultured nit - 1 cells , leading to depolarisation of the plasma membrane potential , a phenomenon common during the process of apoptosis . ng - methyl - l - arg n - nitro - l - arg methyl ester , n - hydroxy - l - arg and l - ng - methyl - arg all proved to be inhibitors of nitric oxide synthase . nitric oxide synthase converts l - arg to produce no , which " janus - faced " compound certainly may influence both cell proliferation and cell death . another possible mode of action of methylated and hydroxymethylated arg can be deduced from the fact that these molecules are formaldehyde generators . that ng - hydroxymethyl arg as a biomolecule is one of the compounds that are responsible for the endogenous formaldehyde level . the guanidine group of l - arg can bind one , two or three molecules of ch2o and in the reaction mono - , di - and trihydroxymethylated arg derivatives are formed . arg is suitable to carry the endogenous ch2o in form of hydroxymethyl group in biological systems . although little is known about the demethylation of ng - methylated arg , ng - hydroxymethyl - l - arg generates a direct ch2o - yielding activity , which may be responsible for its apoptotic effect . it has also been shown in our recent experiments that the administration of analytically pure formaldehyde to cell cultures causes dose dependently apoptosis ( 110 g / ml ) or stimulation of dna synthesis and cell proliferation ( 0.10.01 g / ml ) . the calculated quantity of formaldehyde released by demethylation processes from hydroxymethyl arg is in the above mentioned range and the formaldehyde - mediated biological action of this compound has to be taken into consideration . the lysine - arginine antagonism widely shown in nature is also represented in apoptosis resistant cell lines that contain a - to g alteration is the death domain , encoding l - arginine instead of l - lysine in codon 441 . over - representation of the homozygous arg 72 - p53 genotype in cervical carcinoma patients has been reported . did not find increased risk for human papilloma virus - associated cervical tumour development associated with arg 72 - p53 . although data in the literature are pointing to the anti proliferative effect of both arg depletion and supplementation , arg proved to be essential for tumour cell growth . this observation raises the question , whether decreasing the concentration of arg in nutrients and consequently in blood serum or the administration of d - arginine may lead to retardation of tumour growth in humans , too . arg , because of its strong basic guanidine group , plays an important role in molecular interactions in biological systems , such as interaction between arg and formaldehyde , both of which are normal components of cells and biological fluids . as a resultthese functions may also play role in the biological activity of arg and its methylated and hydroxymethylated derivatives . an interesting therapeutic possibility worthy of further investigation may be the administration of methylated and hydroxymethylated arg in order to induce tumour cell death or to prevent tumour cell proliferation .
output:
