Lequn Cao

Reduction of tumor growth following treatment with a glutamine antimetabolite

Assessment of arterial-venous differences across transplanted methylcholanthrene-induced sarcomas in rats revealed significant decreases in plasma concentrations of glutamine, serine and glucose. Treatment with the glutamine antimetabolite, acivicin, significantly reduced tumor weights by 65% at the conclusion of the experiment 34 days after tumor induction. These results suggest that glutamine is an essential metabolic substrate for tumor growth and that blockade of glutamine utilization can inhibit the growth of these transplantable sarcomas.

Insulin and acivicin improve host nutrition and prevent tumor growth during total parenteral nutrition

The effect that a 14-day treatment program of total parenteral nutrition (TPN) combined with the glutamine antimetabolite, acivicin, and anabolic hormone, insulin, has on carcass weight and muscle sparing was investigated in tumor-bearing rats. Although TPN resulted in increased carcass weight gain as compared to chow-fed tumor-bearing rats, no savings in gastrocnemius muscle could be demonstrated. The combination of TPN with daily insulin treatment elicited significant increases in both carcass weight and muscle savings, with no alteration in tumor growth. Although combining acivicin with TPN halted tumor growth and increased carcass weight, the change in carcass weight was less than that observed with the insulin-TPN combination. No muscle savings were observed in the acivicin-TPN-treated rats. Yet when acivicin and insulin were combined with TPN, tumor growth was stopped, carcass weight was gained, and muscle mass was saved. Therefore, these experiments suggest that it is possible to add lean body tissue and stabilize tumor growth in rats that receive TPN through anabolic hormone treatment combined with an inhibitor of tumor metabolism.

Hyperammonemia in anorectic tumor-bearing rats

Plasma ammonia concentrations were significantly elevated by 150% in anorectic rats bearing methylcholanthrene sarcomas. Assessment of ammonia levels in blood draining these sarcomas indicated nearly a 20-fold increase as compared with venous blood in control rats, suggesting the tumor mass as the source of this increase in ammonia. Infusing increasing concentrations of ammonium salts produced anorexia and alterations in brain amino acids in normal rats that were similar to those observed in anorectic tumor-bearing rats. Therefore, these results suggest that ammonia released by tumor tissue may be an important factor in the etiology of cancer anorexia.

Reversal of neurochemical aberrations after tumor resection in rats

Assessment of biochemical parameters in methylcholanthrene sarcoma-bearing rats 2 days after the onset of anorexia revealed several biochemical aberrations in blood and brain. Plasma levels of glucose were decreased and lactate concentrations were increased. The plasma and brain amino acid profiles were also greatly altered in these rats, characterized by increased brain concentrations of glutamine and large neutral amino acids. Analysis of regional neurotransmitter and metabolite levels by high-performance liquid chromatography suggested increases in the neuronal activity of dopamine and serotonin in each brain region examined. Surgical removal of the tumors in another group of anorectic tumor-bearing rats was followed by the return of normal feeding within 6 days. Associated with the normalization of food intake was the reversal of these biochemical aberrations in blood and brain. It is hypothesized that the utilization of glutamine and excretion of ammonia by tumor tissue is the precursor of these alterations in brain amino acids and neurotransmitters, which may be causing anorexia.

Clenbuterol treatment increases muscle mass and protein content of tumor-bearing rats maintained on total parenteral nutrition.

Treatment of tumor-bearing (TB) and control rats with the anabolic beta-2 agonist drug clenbuterol (CLE) for 14 days reduced food intake for 4 days initially. Feeding was increased in anorectic TB rats, however, during the last 7 days of drug administration. Since minimal muscle savings were observed in chow-fed TB rats treated with CLE, the anabolic effects of this drug were investigated in a second experiment on TB rats maintained on total parenteral nutrition (TPN). Sixteen days after the subcutaneous transplantation of methylcholanthrene-induced sarcomas rats was begun on a 2-week schedule of TPN. One group of these rats was treated daily for 14 days with CLE, while the remaining rats received injections of saline. Additional groups of TB and nonTB rats were maintained on rat chow for this period and treated with saline. Although TB rats maintained on rat chow or TPN and treated with saline exhibited significantly decreased gastrocnemius muscle weight and protein content, treatment of TB-TPN rats with clenbuterol normalized muscle mass and increased muscle protein content significantly and increased plasma concentrations of branched-chain amino acids. These results indicate that although nutritional support of TB organisms does not result in protein repletion, the addition of an anabolic drug renders the nutritional support highly efficacious.

Response of tumor and host to hyperalimentation and antiglutamine treatments.

In two experiments, treatment of tumor-bearing (TB) rats with the glutamine antimetabolite, acivicin, reduced tumor growth during 14 days of total parenteral nutrition (TPN) that supplied 120% and 130% of the nutritional intake of non-TB control rats. The acivicin treatment or combination of acivicin with TPN produced increased carcass weights and decreased tumor/carcass ratios. Significant muscle saving was observed in TB rats receiving TPN or TPN and acivicin as compared to acivicin-treated TB rats maintained on rat chow. Tumor growth was not stimulated by TPN at 130% of ad libitum. intake with a calorie/nitrogen ratio of 102:1. However, when the calorie/nitrogen ratio was increased to 143:1, tumor growth was increased by TPN at 120% of ad libitum. intake. These results suggest that acivicin may prove useful in the stabilization of tumors in situations where tumor growth may be stimulated, such as during TPN.

Possible role of ammonia in experimental cancer anorexia

Plasma concentrations of ammonia were elevated significantly in tumor-bearing rats prior to the onset of anorexia and continued to increase as the tumor grew and anorexia developed. Associated with this hyperammonemia were elevated levels of brain glutamine and large neutral amino acids (phenylalanine, tyrosine, tryptophan, methionine, histidine). Concentrations of the dopamine metabolites, DOPAC or HVA were elevated in the corpus striatum, nucleus accumbens, hypothalamus and amygdala of anorectic tumor-bearing rats only, while levels of the serotonin metabolite, 5-HIAA, were increased in these brain regions in both anorectic and non-anorectic tumor-bearing rats. Infusing ammonium salts into non-tumor-bearing rats elicited anorexia and alterations in brain amino acid profile and neurotransmitter metabolism that were similar to those observed in anorectic tumor-bearing rats. Therefore, we conclude that ammonia released by tumor tissue may have a direct role in the etiology of experimental cancer anorexia.

Tumor-induced alterations in brain neurotransmitter and plasma ammonia concentrations are normalized twenty-four hours after tumor resection

Tumor-induced anorexia was accompanied by significant elevations in plasma ammonia and lactate and by alteration of the plasma amino acid profile. The brains of anorectic tumor-bearing rats had increased levels of glutamine and most large neutral amino acids. Dopamine and serotonin metabolism were also increased in several brain regions of these rats. Resection of the tumor resulted in the normalization of most of these aberrations in blood and brain within 24 hrs. These results demonstrate a rapid reversal of tumor-induced biochemical alterations shortly after tumor removal and suggest that these aberrations may be secondary to hyperammonemia.

Clenbuterol plus acivicin decrease tumor growth and increase muscle mass in rats maintained on total parenteral nutrition

Two problems associated with supplemental nutrition of tumor-bearing organisms are control of tumor growth and reduction of cachexia. To investigate these problems, rats bearing methylcholanthrene-induced sarcomas were maintained on total parenteral nutrition (TPN) for 10 to 12 days beginning 23 days after tumor inoculation. Combined treatment of one group of these rats with the glutamine antimetabolite, acivicin, and the beta 2-adrenergic agonist, clenbuterol, arrested tumor growth, increased skeletal muscle mass and protein content, increased gut mass, and decreased total plasma lipid levels. Resting energy expenditure and cardiac mass were increased by TPN and were increased further by acivicin plus clenbuterol. These results demonstrate that tumor growth and muscle wasting can be controlled during TPN of tumor-bearing organisms. Therefore, cachectic depletion of lean body tissue may not be obligatory in neoplastic disease.

Brain 3-methoxytyramine varies inversely with blood glucose in decapitated rats ☆

Concentrations of the dopamine metabolite, 3-methyoxytyramine, were decreased significantly in the corpus striatum and nucleus accumbens of rats 30 min after the IP injection of D-glucose (2 g/kg). Conversely, 90 min after the administration of regular insulin (6 U/kg), significant increases in the concentrations of 3-methoxytyramine were observed in these two brain regions. Brain levels of the major metabolites of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid, did not correlate well with blood glucose concentration. The significant negative correlation of blood glucose with striatal and accumbens 3-methoxytyramine suggests an inverse relationship between dopamine metabolism and blood glucose concentration, that may be secondary to decapitation-induced anoxia.