Effect of protein-intake on tumor-growth and host survival in tumor-bearing animals

Nutritional repletion of the tumor-bearing host remains controversial. The present study was performed to determine the effect of protein intake on tumor growth and host survival in tumor-bearing animals. Forty-three female C2H mice with subcutaneous mammary tumor implants (MA 16/C) were randomized to receive standard protein diet or an isocaloric, protein-depleted diet ad libitum per os. Body weight and tumor volume were measured throughout the study and ail animals were maintained on these diets until death. Body weight was significantly greater in animals receiving standard protein intake compared to those given the protein-depleted diet. However, tumor growth was significantly stimulated and host survival reduced in animals given standard protein diet compared to animals maintained on protein-depleted diet. Thus, exogenous protein intake preferentially benefitted tumor versus host anabolism in this animal model with significant reduction in host survival.     

Biochemical modulation of tumor-growth, metastasis and host metabolism

Exogenous nutrients, hormones and metabolites can significantly alter tumor growth, metastasis, and host nutritional status. Arginine, serine and methionine are critical amino acids required for protein, DNA and RNA synthesis and, thus, for cellular proliferation. To determine the effect of these specific amino acids on host metabolism, primary tumor growth and metastasis, 48 Lewis rats bearing the mammary adenocarcinoma MAC-33 were randomized to receive similar diets with 3% supplements of serine, arginine, methionine or glycine (control). After 25 days on each diet, animals were sacrificed to determine primary tumor biochemical composition and growth kinetics, number of lung metastases and carcass weight. A significant reduction in lung metastases occurred with serine and methionine supplementation (p<0.01) with no significant change in primary tumor size. However, increased mortality (p<0.001) and low carcass weight (p<0.05) were found in the methionine group indicating significant host toxicity. Serine-supplemented animals had a mortality rate and carcass weight comparable to the control group. Arginine supplementation had no effect on primary tumor growth, metastasis or carcass weight; however, increased mortality was observed in this group compared to controls. These results suggest that serine supplementation selectively supports host growth and inhibits metastasis in tumor-bearing animals. This study demonstrates the potential to differentially effect host and tumor growth with exogenous amino acid supplements.     

Effect of protein-intake on dihydrofolate-reductase activity of host and tumor-tissues

Although previous laboratory research has found that methotrexate toxicity is significantly increased by protein depletion, the cause of this phenomenon is unclear. Protein depletion can potentially increase methotrexate toxicity by altering methotrexate pharmacokinetics, changing levels of its target enzyme, dihydrofolate reductase, or by other mechanisms. To determine the specific effect of protein malnutrition on dihydrofolate reductase activity of tumor and host tissues, 30 Lewis/Wistar rats with subcutaneous mammary tumor implants (AC-33) were randomized to receive a standard protein diet (22.0% protein; 4.20 kcal/g) or protein-depleted diet (0.03% protein; 4.27 kcal/g) ad libitum per os. At sacrifice, specific activity of dihydrofolate reductase was determined in critical host target tissues (bone marrow, liver, gastrointestinal mucosa) and tumors. Our results indicate a differential effect of protein depletion on dihydrofolate reductase activity of tumor and various host tissues. Protein depletion reduced enzyme activity in bone marrow and tumors to 50% and 85%, respectively, of levels found in animals receiving standard protein intake (p<0.05). In contrast, dihydrofolate reductase activity in liver was unchanged and in gastrointestinal mucosa was increased to 136% with protein depletion compared to standard protein intake. Thus, increased myelosuppression from methotrexate in depleted animals may result, in part, from reduced dihydrofolate reductase activity in bone marrow. Other mechanisms must be implicated to account for increased hepatic or gastrointestinal toxicity observed in the protein-depleted, tumor-bearing host.     

Biochemical and biologic effects of somatostatin therapy on tumor-growth and host metabolism

Somatostatin has been shown to have direct antiproliferative activity against various animal and human tumors and may be useful for long-term treatment of cancer patients. However, the metabolic effects of long-term somatostatin therapy have not been studied in the tumor-bearing host. It is known that somatostatin inhibits growth hormone and insulin secretion, and has inhibitory functions at all levels of the gastrointestinal tract. These properties may be especially detrimental to the tumor-bearing host which already suffers the cachectic effect of malignancy. This study examined the effect of the long-term somatostatin analogue octreotide (SMS) on host and tumor tissues in rats bearing a mammary adenocarcinoma (MAC-33). In vitro studies demonstrate that SMS (10-1000 ng/ml) has no direct effect on tumor cell proliferation in this model. Thirty female tumor-bearing Lewis rats were randomized to two groups. The treatment group received 175 mu g/kg SMS injections ip twice daily for 25 days; the placebo group received saline injections by the same route and schedule. Biochemical studies revealed a significant increase in tumor and liver protein/DNA ratio and decreased skeletal muscle protein/DNA content as a result of SMS treatment. These alterations in tumor and muscle composition are indicative of tumor growth and host catabolism. Biologic parameters demonstrated no significant change in carcass weight, tumor weight, or tumor metastasis from SMS treatment. Thus, a discordance is found between gross biologic parameters (indicating no significant effect of SMS) and more subtle biochemical indices (indicating progressive tumor growth and muscle protein catabolism). SMS therapy may produce adverse biochemical effects on host muscle which simulate cachexia when used chronically in the tumor-bearing host.     

Differential-effects of omega-3 and omega-6 Fatty-acids on primary tumor-growth and metastasis

The amount and type of dietary lipid can significantly influence spontaneous tumor development and tumor progression. To determine the effect of fish oil (rich in omega-3 polyunsaturated fatty acids) and corn oil (rich in omega-6 polyunsaturated fatty acids) on primary tumor growth, metastasis and carcass weight, 45 female Lewis/Wistar rats with subcutaneous mammary tumor implants (MAC-33) were randomized to 1 of 3 diets with 30% lipid consisting of: (i) corn oil alone, (ii) combined 50%:50% corn oil:fish oil, or (iii) fish oil alone. Primary tumor weight was significantly reduced in animals which were fed fish oil or corn oil alone compared to animals given combined corn oil:fish oil diet. Biochemical analysis (protein, DNA, RNA) of the primary revealed no difference between dietary groups. Cell cycle analysis of the primary tumor showed no difference in percent G(0)-G(1), S, G(2)-M or growth fraction (% S + G(2)-M) between dietary groups. In contrast, lung metastasis, was reduced in animals fed the combined corn oil:fish oil diet. Thus, dietary, lipid intake can significantly influence primary tumor growth and tumor metastasis. Differential effects of omega-3 and omega-6 polyunsaturated fatty acids occur on primary tumor growth and development of distant pulmonary metastases in this animal model.     

Reduction of methotrexate toxicity with improved nutritional status in tumor-bearing animals

The administration of chemotherapy in clinical situations is limited frequently because of the associated toxicity to normal bone marrow cells, gastrointestinal epithelium, and other host tissues. Although nutritional support has been advocated to reduce chemotherapy-related toxicity in cancer patients, few studies substantiate this clinical impression. The current study was performed to determine the role of nutritional status and enteral nutrient intake as determinants of methotrexate (MTX) toxicity in a well-controlled, tumor-bearing animal model. After subcutaneous mammary tumor (AC-33) inoculation, 56 female Lewis/Wistar rats were assigned randomly to one of the following two nutritional regimens for 14 days: (1) protein-depleted chow (PC) (0.03% protein; 4.27 kcal/g) or (2) standard chow (RC) (22.0% protein; 3.50 kcal/g). After 7 days of dietary control, all animals received one of three weight-adjusted doses of MTX (5, 10, or 20 mg/kg intramuscularly [IM] ) or placebo. All animals received leucovorin rescue (0.6 mg IM) at 6 and 24 hours after MTX injection. Improved nutritional status was associated with a significant reduction in objective measures of MTX-related morbidity and mortality. At low doses of MTX (5 and 10 mg/kg), the mean duration of clinical signs of toxicity (i.e., hair loss, lethargy, and diarrhea) and severity of leukopenia were greater in protein-depleted (PD) animals. With high-dose MTX (20 mg/kg), mortality was increased significantly in PD animals (100%) compared with well-nourished animals (0%). Equivalent tumor response was observed in PD and well-nourished animals. Thus, improved nutritional status by enteral nutrition reduced the morbidity and mortality associated with MTX significantly in this tumor-bearing animal model.     

Growth hormone and experimental cancer cachexia

Plasma levels of growth hormone (GH) and the effect of GH treatment have been evaluated in adult nongrowing sarcoma-bearing mice (C57BL/6J). Prepubertal tumor-bearing mice, tumor-bearing hypophysectomized Sprague-Dawley rats, and malnourished non-tumor-bearing animals served as additional groups of study and control animals. Adult sarcoma-bearing mice showed an increase in plasma levels of GH early following tumor implantation. GH levels increased further with tumor progression. The anorexia and the state of malnutrition in sarcoma-bearing mice were the major factors behind increased GH levels. Muscle wasting and body composition in the tumor-bearing host were not improved by GH treatment at doses that increased growth rate in normal growing mice with intact pituitaries or partially normalized growth rate in hypophysectomized rats. Exogenous GH supported tumor growth and host body growth to the same extent in hypophysectomized rats. Exogenous GH in excess of endogenous GH did not stimulate tumor growth further. It is suggested that increased GH production in a tumor-bearing host acts in concert with other hormones to stimulate endogenous substrate mobilization and in tumor-bearing animals to prevent substrate deficiency and hypoglycemia. On the basis of this conclusion, it is unlikely that GH supplementation to a freely eating tumor-bearing host will support replenishment of host tissues.     

Body composition changes in rats with experimental cancer cachexia: improvement with exogenous insulin

Exogenous insulin treatment has been shown to improve food intake and host weight of cachectic tumor-bearing (TB) rats, but the composition of the host weight gain has not been quantitated. Sixty-six Fischer 344 rats were randomized to seven groups: early nontumor-bearing (NTB) (n = 10) who underwent compositional analysis (CA) on the day the methylcholanthrene sarcoma was implanted in TB rats; pretreatment-NTB (n = 10) and pretreatment-TB (n = 10) who underwent CA 25 days later when rats began treatment with saline or insulin; and finally saline-treated NTB (n = 9), saline-treated TB (n = 9), insulin-treated NTB (n = 9), and insulin-treated TB (n = 9), who underwent CA following 5 days of treatment with daily saline or neutral protamine hagedorn insulin 2 units/100 g. Body weight and food intake were measured daily. For compositional analysis, the tumor was separated from the host in TB rats and the entire rat in NTB animals was homogenized, lyophilized and analyzed for fat, water, protein, potassium, chloride, and sodium. The tumor was processed in a similar fashion. In response to insulin, NTB rats ate significantly more food, and had an increase in body weight gain. Compositional analysis of insulin-treated NTB rats indicated a slight, but insignificant, increase in body fat and a similar insignificant decrease in body protein. TB rats ate significantly less than NTB rats during the 5-day experimental period, and insulin treatment significantly increased food intake to levels similar to NTB animals. Compositional analysis indicated that the tumor-bearing state resulted in a significant decrease in total host water, protein, fat, potassium, sodium, and chloride. Insulin administration resulted in preservation of host nitrogen, fat, potassium, sodium, and chloride in cachectic tumor-bearing rats. Insulin treatment did not affect tumor dry weight or composition. The results suggest that exogenous insulin, can preserve normal host composition of TB rats during cachectic decline.     

Effects of reciprocal changes of diets differing in fat content on pulmonary metastasis from the 13762 rat mammary tumor

The effect of changing the amount of polyunsaturated fat in the diet of aged female Fischer 344 rats at the time of tumor implant on metastasis from the 13762 transplantable mammary tumor was studied. Three experiments were performed. (a) Retired breeders, maintained on standard commercial chows until 10 to 12 mo of age, were transferred to high fat (HF, 23% corn oil) or low fat (LF, 5% corn oil) diets for 4 wk; at tumor implant, half of each group were kept on their original diets, while half were changed to the other diet (i.e., HF----HF, HF----LF, LF----LF, LF----HF). (b) Aged virgins, 14 to 16 mo old, were fed HF and LF diets from weaning; at tumor implant, the LF group stayed on the LF diet, while half the HF group remained on the HF diet and half were changed to LF. (c) Retired breeders were fed Purina rodent chow (5% mainly saturated fat) until tumor implant when they were placed on either the HF or LF diets. Six wk after tumor implant, all rats were necropsied, and the extent of pulmonary metastasis was determined. Data were expressed as volume of pulmonary metastases. In Experiment 1, animals maintained on a HF diet or changed to a HF diet at implant had significantly more pulmonary metastases than those animals kept on a LF or changed to a LF diet. Likewise in Experiment 2, pulmonary metastasis was less in rats which were fed a HF diet from weaning and then changed to LF at tumor implant than in the animals maintained on a HF diet both before and after tumor implant. Finally, in Experiment 3, when rats were changed from Purina rodent chow to either the HF or LF diet at tumor implant, there was no significant difference in the extent of pulmonary metastasis between the two groups; in both, the extent of metastasis was comparable to that seen in animals maintained on the LF corn oil diet. Data on metastasis were also examined in light of body weight, growth of the primary tumor, and food disappearance. These results suggest that the amount of fat consumed by aged rats after tumor implant is an important determinant of the extent of pulmonary metastasis from the 13762 mammary tumor. However, a period of prefeeding the semipurified diets appears to be required in order for the HF corn oil diet to stimulate metastasis in this system.     

Insulin reversal of cancer cachexia in rats

The anabolic effects of exogenous neutral protamine hagedorn insulin on tumor-bearing (TB) and non-tumor-bearing (NTB) rats were examined. Exogenous insulin (2 units/100 g/day) produced similar hypoglycemia in TB and NTB rats. Food intake and body weight gain were significantly increased by insulin in NTB rats. In TB rats in an early stage of cachexia, insulin increased food intake and host weight (total body weight minus tumor weight). In TB rats with severe cachexia, insulin increased food intake and stabilized host weight when untreated TB controls were not eating and were losing weight. When daily insulin administration was started at an early stage of tumor growth and continued until death, there was again significant enhancement of host weight and food intake. Heart and adrenal weights were significantly reduced in insulin-treated TB animals. Tumor growth was not stimulated by insulin treatment. Survival time was slightly reduced in TB rats treated with long-term insulin. Survival time in TB rats randomized to insulin during late cachectic decline was not different from untreated TB controls. Insulin did not have any measurable effect on energy expenditure or the motor activity compartment of energy expenditure in either TB or NTB rats. Insulin treatment can reverse experimental cancer cachexia. It is a nutritional therapy which preferentially feeds the host over the tumor. As yet, its beneficial effects have not prolonged survival of tumor-bearing animals.     

Antitumor effect of cepharanthin--mechanism of the antimetastatic effect on Lewis lung carcinoma (3LL)

The antitumor activity of cepharanthin against Lewis lung carcinoma (3LL) primary tumor and its pulmonary metastases was evaluated. Oral administration of cepharanthin to tumor-bearing mice at a daily dose of 5 mg/kg resulted in inhibition of 3LL primary tumor growth, preferential suppression of pulmonary metastases, and prolongation of survival time. The antimetastatic effect was not observed when tumor-bearing mice were treated with some blockers of immunocompetent cells, e.g. carrageenan or monoclonal anti-Thy 1.2 antibody. In ex vivo experiments, cepharanthin was also shown to augment the activities of murine alveolar macrophages and splenic natural killer (NK) cells. These results suggest that the antitumor or antimetastatic effect of cepharanthin might be expressed through host defense mechanisms, including macrophages, T lymphocytes and/or NK cells.     

Effect of dietary fat on human breast cancer growth and lung metastasis in nude mice

Results from epidemiological studies have generally indicated an association of dietary saturated animal fats with human breast cancer risk. Some studies, however, have suggested a similar association for some polyunsaturated vegetable fats shown to promote both rodent mammary carcinogenesis and metastasis. This study was performed to evaluate the effects of corn oil on growth and metastasis of MDA-MB-435 human breast cancer cells, which have a propensity for metastasis. Corn oil is rich in the omega-6 fatty acid linoleic acid. Fifty-eight female athymic nude mice (NCr-nu/nu) were fed a high-fat diet (23% wt/wt corn oil; 12% linoleic acid) or a low-fat diet (5% wt/wt corn oil; 2.7% linoleic acid). Seven days after diets were started, tumor cells (1 x 10(6) were injected into a mammary fat pad. The time to appearance of solid tumors and the tumor size were recorded. After 15 weeks, the study was terminated, and autopsies were performed to determine the weight of the primary tumor and the extent of metastasis. The latent interval for tumor appearance in the animals fed the high-fat diet was shorter than that in the low-fat diet group, and the tumor growth rate in the high-fat diet group showed a small but statistically significant increase compared with the low-fat diet group. Primary tumors developed in 27 of the 29 mice on the high-fat diet and in 21 of the 29 on the low-fat diet. Of the mice with palpable primary tumors, 18 of 27 in the high-fat diet group and eight of 21 in the low-fat diet group had macroscopic lung metastases. The extent of metastasis in the high-fat diet group was independent of the primary tumor weight, but only those in the low-fat diet group with primary tumors weighing more than 2 g developed metastases. These results suggest that a high-fat diet rich in omega-6 polyunsaturated fatty acid can enhance metastasis of human breast cancer cells in this mouse model. The findings support the need for further study of the relationship between dietary polyunsaturated fats and breast cancer risk and for experiments to determine the effect on metastasis of only a 50% difference in fat intake--the dietary goal of the proposed clinical trials of low-fat dietary intervention in breast cancer patients.     

Stimulatory effect of high polyunsaturated fat diet on lung metastasis from the 13762 mammary adenocarcinoma in female retired breeder rats

The effect of a high-fat (HF) diet (23% corn oil) on the growth and metastasis of the 13762 mammary tumor in Fischer 344 retired breeder (RB) and young virgin (YV) female rats was studied. The RB (10-12 mo old) and YV (8 wk old) rats were fed the HF or low-fat (LF) diet (5% corn oil) prior to and following tumor implantation for a total of at least 10 weeks. The growth rate of the primary tumor in the intact RB and YV was not affected by the HF diet. In RB rats ovariectomized 4 weeks prior to tumor implantation, the tumor grew significantly faster in the HF group as compared to the LF group. The total volume of metastatic tumor nodules in the lungs of the HF groups was significantly higher than that in the the lungs of the LF groups in both the intact and ovariectomized RB. In the YV, there was no difference in pulmonary metastatic burden between the HF and LF groups. The weights of the HF intact and ovariectomized RBs were higher than those of the LF animals. However, when pulmonary metastatic tumor burden was compared to body weight at implant or at sacrifice, there was no significant correlation in either the HF or LF groups. These results suggest that an HF diet enhanced the growth of pulmonary metastases in the intact and ovariectomized RB but not the YV rats and that the effect of the HF diet on pulmonary tumor burden cannot be attributed entirely to increased body weight.     

Growth-promoting Effect of Retinoic Acid in Transplantable Pituitary Tumor of Rat

MtT/F84 grew well in Fischer rats (F344), but tumor growth was promoted in hyperestrogenized rats. Effects of dietary retinoic acid (RA) on tumor growth, estrogen receptor (ER) and serum growth hormone (GH) level were examined. Tumor latency became shortened, and tumor take and weight were promoted by all- trans RA at dosages of 50 and 200 mg/kg basal diet, but not dose-dependently. ER level was elevated in tumor of RA-treated rats, whereas the retinoic acid-binding protein level remained unchanged. RA also elevated incorporation of 5-bromo-2'-deoxyuridine, a thymidine analogue, into DNA of tumor cells. Average serum GH level was increased in tumor-bearing rats treated with RA and was well correlated with tumor weight. RA may directly affect ER level and enhance estrogenic action, resulting in promotion of tumor growth, or it may act independently for tumor growth and elevation of serum GH level.     

Growth-promoting effect of retinoic acid in transplantable pituitary tumor of rat

MtT/F84 grew well in Fischer rats (F344), but tumor growth was promoted in hyperestrogenized rats. Effects of dietary retinoic acid (RA) on tumor growth, estrogen receptor (ER) and serum growth hormone (GH) level were examined. Tumor latency became shortened, and tumor take and weight were promoted by all-trans RA at dosages of 50 and 200 mg/kg basal diet, but not dose-dependently. ER level was elevated in tumor of RA-treated rats, whereas the retinoic acid-binding protein level remained unchanged. RA also elevated incorporation of 5-bromo-2'-deoxyuridine, a thymidine analogue, into DNA of tumor cells. Average serum GH level was increased in tumor-bearing rats treated with RA and was well correlated with tumor weight. RA may directly affect ER level and enhance estrogenic action, resulting in promotion of tumor growth, or it may act independently for tumor growth and elevation of serum GH level.     

原发瘤切除对荷人骨肉瘤裸鼠血管生成和肺转移的影响

目的 研究原发瘤切除对骨肉瘤血管生成和肺转移的影响,并探讨其可能的机制及临床意义.方法 用细胞悬液法构建倚人骨肉瘤裸鼠模型,分为实验组(切除原发瘤)、截肢对照组(不切除原发瘤的截肢手术)和空白对照组.用酶联免疫吸附试验(ELISA)法,检测手术前后裸鼠血清中血管内皮生长因子(VEGF)和内皮抑素的表达水平.用HiCN法检测裸鼠体内Matrigel胶体中血红蛋白浓度.应用膨胀压片计数法和组织切片苏木素-伊红对比染色法,观察肿瘤肺部转移灶的情况.结果 手术后实验组血清中的VEGF和内皮抑素浓度较空白对照组和截肢对照组有明显的下降,且内皮抑素下降幅度更大[VEGF分别为(71.43±9.15)pg/ml、(115.81±4.38)pg/ml和(111.68±12.26)ps/ml(P<0.01);内皮抑素分别为(40.77±5.41)ng/ml、(123.18±5.94)ng/ml和(128.06±4.52)ng/ml(P<0.01)];实验组、空白对照组和截肢对照组Matrigel小体中血红蛋白浓度分别为(36.55±2.35)g/L、(16.84±1.15)g/L和(16.29±1.10)g/L(P<0.01).实验组、空白对照组和截肢对照组的肺转移率分别为80.0%、40.0%和35.0%,差异有统计学意义(P<0.05).结论 原发瘤切除可使荷人骨肉瘤裸鼠体内的VEGF和内皮抑素比例失衡,有利于肿瘤血管生成和肺转移,故原发瘤切除后及时抑制肿瘤血管生成,对降低骨肉瘤肺转移有重要意义.     

Interaction of dietary fat and protein on pancreatic carcinogenesis in Syrian golden hamsters

The role of interactions between dietary fat and protein in experimental pancreatic cancer was determined in Syrian golden hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Two levels of corn oil [4.5 and 18 g/385 kilocalorie (kcal)] were fed with each of two levels of casein (9 g/385 kcal and 36 g/385 kcal), either before or after a single sc injection of BOP (10 mg/kg body wt) at 8 weeks of age. Control diet was fed at other times (9 g corn oil and 18 g casein/385 kcal). The pancreatic ductular carcinoma incidence and multiplicity (average No. of tumors/tumor-bearing animals) increased as dietary fat and protein levels rose in hamsters fed the four diets after carcinogen treatment. Enhanced carcinogenesis by high-fat (HF) diets occurred only in hamsters fed the high-protein (HP) level, and protein effects were seen only with the HF diets. The low-fat-low-protein (LF-LP) diet inhibited pancreatic carcinogenesis among the hamsters given the four diets before BOP treatment. Pancreatic adenoma yields were elevated in hamsters given either HF or HP diets following BOP treatment, by comparison with the low levels. However, when diets were fed before BOP treatment, an increased yield occurred with the rise in protein, but the yield was reduced in males with the increase in fat. Acinar cell nodules were observed primarily in hamsters fed LP levels after BOP, and their multiplicity was highest in those given the HF diet. The interaction between dietary fat and protein demonstrated the interdependence of the effects of these two nutrients on pancreatic carcinogenesis in hamsters.     

Role of insulin in development of cancer cachexia in nongrowing sarcoma-bearing mice: special reference to muscle wasting

This study evaluated whether altered insulin metabolism is a key factor behind weight loss during sarcoma growth in nongrowing mice (C57BL/6J). Fasted sarcoma-bearing mice had decreased blood glucose concentrations but unchanged levels of insulin, compared with those in pair-weighed and freely fed controls. During refeeding, insulin levels were inappropriately low for the degree of glycemia in sarcoma-bearing mice compared with those of pair-weighed and freely fed controls. Injections ip of glucose to tumor-bearing animals resulted in insulin levels comparable to postabsorptive values in healthy control animals, indicating that hypoinsulinemia in freely eating tumor-bearing animals was due to a reduced glycemic sensitivity for pancreatic insulin release. Insulin supplementation at doses [4 IU/100 g (body wt)] that increase body fat in normal animals could not protect the tumor-bearing host from progressive loss of body fat or lean tissues. Exogenous insulin in excess of endogenous insulin production did not stimulate tumor growth. Nitrogen and RNA-DNA content were significantly decreased in the quadriceps muscle of tumor-bearing mice. This reduction was independent of altered insulin levels and could not be prevented by exogenous insulin. The depressed capacity of protein synthesis in extensor digitorum longus (EDL) muscle could be entirely attributed to the state of malnutrition in tumor-bearing animals. The sensitivity and responsiveness of protein synthesis in EDL muscles to insulin were normal in tumor-bearing mice, regardless of whether exogenous insulin exerted its effect in vivo or in vitro. This study confirms insulin resistance for glucose metabolism in an experimental sarcoma animal model. Such changes are concluded to be secondary to anorexia and necessary to counteract hypoglycemia. In non-growing sarcoma-bearing mice, malnutrition and anorexia account entirely for depressed muscle protein synthesis, which is not explained by insulin resistance at the translational level. Insulin metabolism is not a key factor behind progression of wasting in sarcoma-bearing mice, but anorexia is.     

Effects of enteral and parenteral nutrition on tumor response to chemotherapy in experimental animals

The effects of oral and intravenous nutrition on host and tumor responses to graded doses of methotrexate (MTX) were evaluated in 150 adult Sprague-Dawley rats. All animals were inoculated with Walker-256 carcinosarcoma and were fed a regular diet for ten days before assigning them to three dietary groups. Group I (n = 64) received a constant intravenous infusion of 30% dextrose-5% amino acids (IVH), group II (n = 64) received an identical solution orally ad libitum, and group III (n = 22) received a regular diet ad libitum. Animals in groups I and II were then divided into three subgroups each that received either 20 mg/kg, 40 mg/kg, or 60 mg/kg of MTX intramuscularly. Ten days later, all surviving animals were killed. Animals fed the 30% dextrose-5% amino acid diet orally and given 20 mg/kg and 40 mg/kg of MTX lost slightly less body weight when compared with their IVH counterparts. In the 60 mg/kg treatment group, orally fed animals lost 52 gm of body weight compared with 23 gm in IVH animals. IVH rats given 20 mg/kg and 40 mg/kg of MTX demonstrated significant inhibition of tumor growth and decreased tumor weight/body weight ratios when compared with orally fed rats. No improvement in tumor response to 60 mg/kg of MTX was observed, however, when IVH animals were compared with orally fed rats. In a second study, nutrient intake was maintained at a constant level by intravenous infusion in one group and intrajejunal infusion in another group of tumor-bearing rats. Host and tumor responses to 20 mg/kg of MTX were similar in both groups of animals.     

Response of tumor-bearing rats to high-fat total parenteral nutrition

Total parenteral nutrition (TPN) solutions fed to tumor-bearing rats have been shown to affect host and tumor metabolism. This study was initiated to evaluate the effect of two intravenous nutrient regimens on carcass and organ composition as well as tumor composition and growth. Thirty Sprague-Dawley rats were implanted with Walker 256 carcinosarcoma and randomly assigned to one of three diet groups: (1) A, a glucose-based TPN formula; (2) B, a lipid-based TPN formula, isocaloric to A; and (3) C, a purified powdered diet fed ad libitum. Equal assignments were made for non-tumor-bearing controls. Tumor-bearing rats infused with diet B had the highest amount of carcass and organ fat as well as the lowest carcass and organ protein. Tumor composition paralleled carcass composition, but tumor weight and density did not differ among dietary groups. Tumor weight to body weight ratios were highest in the group fed diet B. These data indicate that although tumor growth remains unchanged, alterations in body and tumor composition are effected by a high fat TPN solution.