Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The application of recombinant DNA technology to the production of tumor necrosis factor has resulted in the availability of large quantities of a highly purified protein product. This product has been evaluated extensively in preclinical studies, which have documented a direct cytostatic and cytotoxic effect on human tumor cells, as well as a variety of immunomodulatory effects on various immune effector cells, including neutrophils, macrophages, and T cells. In addition, a number of anti-infective and metabolic effects have been documented. In addition to its in vitro effects, rTNF has been shown to have antitumor activity in vivo in preclinical studies involving both transplantable murine tumors and human tumor xenografts. Such observations have led to the evaluation of rTNF as a potential antineoplastic agent in humans. Both single- and multiple-dose phase I studies have confirmed that rTNF can be safely administered to patients with advanced malignancies in a dose range associated with anticancer effect without concomitant serious toxicities such as shock and cachexia. The most commonly observed clinical toxicities include constitutional symptoms, such as fever, chills, headache, and fatigue, and toxicities, which can be at least partially controlled with concomitant administration of nonsteroidal anti-inflammatory drugs, such as acetaminophen and meperidine. Hypotension, which occurs at high doses administered by short intravenous infusion, can usually be prevented by prehydration with intravenous fluids or otherwise controlled by the administration. An intense local inflammatory reaction at the injection site as well as thrombocytopenia appear to be the dose-limiting toxicities after subcutaneous and intramuscular administration. Neurologic toxicity is infrequent, except following continuous intravenous infusion, where it may manifest as transient focal neurologic deficits or seizure. Prolonged administration of rTNF at higher doses may be associated with transient, subclinical decreases in diffusing capacity. Patients with underlying cardiopulmonary disease should be excluded from rTNF therapy in future clinical studies until the end-organ toxicities of this agent are better defined. For at least one preparation of rTNF there appears to be no evidence for the formation of antibodies to rTNF in patients who receive multiple administrations of the agent. Pharmacokinetic studies have shown a relatively rapid clearance following intravenous infusion with a half-life of 15 to 30 min and dose-dependent pharmacokinetics. rTNF can be detected in the serum following intramuscular or subcutaneous injection at only relatively high doses, suggesting a decreased bioavailability with the routes of administration. Early phase I studies defined tolerable dose ranges for each route of administration and began to explore immunomodulatory and metabolic effects of rTNF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Recombinant human TNF-alpha: preclinical studies and results from early clinical trials. 155 Aug 75

In the past few years tumor necrosis factor (TNF), also known as cachectin, has been isolated, cloned and now human recombinant TNF is available. This cytokine has numerous actions, which can be divided into four groups: 1) antitumor function; 2) immunomodulating activity and function in the inflammatory response; 3) effects on metabolism; 4) other functions. TNF was first identified for its anticancer activity; it is able to induce hemorrhagic necrosis in subcutaneously implanted tumors, due to the induction of free radicals in tumor cells and to vascular damage. It can also activate T-lymphocytes to become lymphokine-activated killer cells (LAK cells) against tumors. TNF also plays an important role in the inflammatory response: it mediates many of the immunologic features of T-cell function and of infection, and is essential in septic shock. TNF is a cause of the hypertriglyceridemia and the cachexia that characterize chronic infections and neoplasms. In vitro this cytokine causes growth of vascular endothelial cells; this observation suggests that it could have an atherogenic role. In in vivo experiments severe hepatic ischemia-reperfusion injury results in TNF release with subsequent local and systemic injury that was significantly reduced by anti-TNF antiserum pretreatment. Thus, TNF could be a cause of ischemic tissue damage. In conclusion, while TNF is known to play many roles, the intercellular network of the cytokines is not yet sufficiently understood and so we are only just beginning to comprehend the full implication of this important molecule in both histology and pathology.
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PMID:[Tumor necrosis factor: a cytokine with multiple actions]. 156 77

In this report we describe an experimental model of cachexia that fulfills the criteria of an early effect with a small tumor mass not related to the growth rate of the tumor, and progressive wasting of muscle and fat without a detectable loss of appetite. C-26.IVX is a cell line derived from murine colon-26 adenocarcinoma which retains the transplantability of the original tumor and induces true cachexia in syngeneic hosts. Evidence is presented to support a role for interleukin (IL-6) as a cachectic factor in the development of cancer cachexia in this model system. Thus, increasing levels of IL-6 in C-26.IVX-bearing mice correlate with the development of cachexia. If the primary tumors were resected, mice gained weight and the levels of IL-6 in the serum were reduced significantly. Moreover, monoclonal antibody to murine IL-6 (but not anti-tumor necrosis factor antibody) was able to significantly suppress the development of key parameters of cachexia in tumor bearing mice.
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PMID:Evidence for the involvement of interleukin 6 in experimental cancer cachexia. 156 7

Paraneoplastic syndromes are caused by factors produced by cancer cells that often act at a site distant from both the primary site and its metastases. These syndromes are estimated to occur in only 7% to 15% of patients with cancer and are diagnoses of exclusion. If the definition of paraneoplastic syndrome is broadened to include indirect effects of the tumor such as cachexia or the anemia of chronic disease, the incidence is much higher. Lung cancer, particularly small cell lung cancer, is the most common malignancy causing paraneoplastic syndromes. This review focuses on recently published literature on paraneoplastic syndromes associated with lung cancer, including humoral hypercalcemia of malignancy, autoimmune paraneoplastic neurologic syndromes, neuromuscular disorders, and cancer cachexia. It includes advances in both molecular biology and immunology, and in clinical investigation.
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PMID:Paraneoplastic syndromes in lung cancer. 159 5

The cause of cancer cachexia is unclear. Tumors may be competing with the host for ingested nutrients or may be releasing some factor that actively inhibits energy utilization. To explore these questions, plasma was sterilely collected and pooled from 103 terminally cachectic Fischer 344 rats implanted with an experimental sarcoma. Control plasma was collected in similar fashion from 138 nontumor-bearing rats (NTBP). Plasma from tumor-bearing rats (TBP) or NTBP was continuously infused in a randomized, blinded fashion for 4 days into 20 normal rats. During infusion, food intake and nitrogen excretion were measured daily. At sacrifice, body weight and organ masses were determined. Rats receiving TBP demonstrated an immediate and profound anorexia compared with those receiving NTBP. Total food intake during treatment was 31.2 +/- 3.3 (g +/- SEM) in the TBP group versus 48.2 +/- 2.8 in the NTBP group (P less than 0.001 by t test). Likewise, the total decline in body weight was greater in the TBP group as compared with the NTBP group (-35.2 +/- 3.4 versus -14.6 +/- 4.0, P less than 0.001). Mean daily nitrogen balance during treatment was negative in the rats receiving TBP (-14.5 +/- 20.1 mg +/- SEM) while remaining highly positive in the rats receiving NTBP (110.7 +/- 19.3, P less than 0.002). Finally, cardiac and gastrocnemius muscle masses were decreased, while hepatic mass was unaffected. These data demonstrate that the syndrome of cancer-associated cachexia is transmissible in plasma and therefore may be mediated by a circulating molecule or molecules. Identification and purification of the molecule(s) responsible for this effect would have obvious clinical benefits.
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PMID:Cancer cachexia is transmissible in plasma. 159 73

Among 625 patients with squamous cell carcinoma and 134 patients with adenocarcinoma of the esophagus and cardia, a one stage resection was performed upon 375 patients of the squamous carcinoma group (excluding pharyngolaryngoesophagectomy) and 92 patients in the adenocarcinoma group. The patients formed the basis of the current analysis. Male to female ratio was 7:1 for those with squamous carcinoma compared with 3.6:1.0 for those with adenocarcinoma (p = 0.037). Most squamous carcinomas were located in the middle one-third (56.3 percent) and lower one-third (33.0 percent) of the esophagus. Adenocarcinomas were predominantly found at the cardia (91.3 percent) and lower one-third (6.5 percent). Postoperatively, respiratory complications occurred in 34.4 percent of patients in the group with squamous carcinoma and in 19.6 percent of patients in the group with adenocarcinoma (p = 0.01). Cardiac complications occurred in 28.3 percent of patients in the group with squamous carcinoma and in 16.3 percent of patients in the group with adenocarcinoma (p = 0.03). Anastomotic leaks were uncommon for both groups (4.3 and 5.4 percent, respectively). Anastomotic recurrence occurred in 6.1 and 7.6 percent of patients, respectively. Respiratory complications, malignant cachexia and sepsis accounted for most of the deaths in the hospital. The 30 day mortality rates for patients with squamous carcinoma and adenocarcinoma were comparable (4.8 and 6.5 percent, respectively) (p = 0.33). After 30 days, mortality rates differed significantly (11.7 and 3.3 percent, respectively) (p = 0.026). The overall hospital mortality rates, however, were comparable (16.5 and 9.8 percent, respectively) (p = 0.14). The overall five year survival rate for both groups was 15 percent. For patients with squamous carcinomas, the five year survival rate after curative resection was 31 percent compared with 5 percent for palliative resection. For patients with adenocarcinomas, the respective five year survival rates were 35 and zero percent. It was concluded that the two types of tumor differ significantly in the incidence of postoperative morbidity, but mortality and the long term survival rates were similar.
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PMID:A comparison of outcome after resection for squamous cell carcinomas and adenocarcinomas of the esophagus and cardia. 163 32

Tumour necrosis factor (TNF) is a pleiotropic cytokine with activities that extend beyond its antitumour effect. There is now increasing evidence that TNF can be either constitutively produced or induced in human tumours. Tumour cells may also lead to TNF induction in normal cells. Experimental studies implicate TNF in processes that contribute to cancer progression. These range from stimulation of cancer growth and metastasis, to metabolic and haematological disturbances, e.g. cancer cachexia, anaemia, and hypercalcaemia. Future cancer therapies may therefore involve neutralisation of TNF activity in cancer patients.
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PMID:Tumour necrosis factor: roles in cancer pathophysiology. 164 92

The effect of the polyunsaturated fatty acids eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) on host body weight loss and tumor growth has been investigated in mice bearing a cachexia-inducing colon adenocarcinoma, the MAC16. EPA effectively inhibited both host weight loss and tumor growth rate in a dose-related manner with optimal effects being observed at a dose level of 1.25 to 2.5 g/kg. At these concentrations host body weight was effectively maintained, and there was a delay in the progression of growth of the tumor, such that overall survival was approximately doubled in EPA-treated animals, using the criteria dictated by the United Kingdom Coordinating Committee for the welfare of animals with neoplasms. Even when tumor growth resumed, weight loss did not occur. Animals bearing the MAC16 tumor showed a decreased protein synthesis and an increased degradation in skeletal muscle. Treatment with EPA significantly reduced protein degradation without an effect on protein synthesis. The effect of GLA on both host body weight loss and tumor growth was much less pronounced than that of EPA, with an effect only being seen at a dose of 5 g/kg, at which some toxicity was observed. In vitro studies showed that while EPA was effective in inhibiting tumor-induced lipolysis, GLA was ineffective in this respect. However, prostaglandin E1, which is formed from GLA in vivo, showed partial reversal of tumor-induced lipolysis and probably accounted for the anticachectic effect of GLA. These results suggest that EPA as the pure fatty acid should be considered for clinical investigation as both an anticachectic and antitumor agent, since prior work has shown that the other major component of fish oil docosahexaenoic acid is without pharmacological activity in this system.
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PMID:Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover. 165 78

A request by the Institutional Animal Care and Use Committee for an alternative to death as an end point in a cancer research project using a rat brain 9L tumor cell model led to a search for reliable criteria for predicting time of death in this type of experiment. These experiments evaluated the therapeutic effectiveness of radiation alone, continuous intracerebral infusions of 5-iodo-2-deoxyuridine (IUDR) alone, and a combination of both therapies. We found that a characteristic pattern of body weight changes occurs after injection of 9L tumor cells into the brain ventricles or parenchyma. The initial phase was characterized by a loss of body weight which appeared to be related to surgery and, in the irradiated groups, to the subsequent doses of radiation under anesthesia on days 4, 6, and 7. After this initial phase (phase 1), a second period of weight change (phase 2) which was characterized by an overall gain of body weight interrupted temporarily in 76 out of the 149 rats by reversible episodes of weight loss of 1 to 5 days duration. The length of this phase 2 weight gain period was significantly extended by XRT-IUDR treatment in the rats with intraparenchymal tumors. The third and final phase consisted of a period of irreversible weight loss which may be related to cachexia. The third phase was similar in duration for control, XRT, IUDR and XRT-IUDR groups of rats and had a mean length of 9.8 +/- 0.27 days.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Time of death of CNS tumor-bearing rats can be reliably predicted by body weight-loss patterns. 165 69

The anabolic beta 2-agonist cimaterol was used in conjunction with supplemental nutrition to reverse cancer-induced cachexia and malnutrition in tumor-bearing rats. Cimaterol was administered to tumor-bearing rats receiving total parenteral nutrition or enteral nutrition for 10 days, beginning 2 weeks after subcutaneous transplantation of methylcholanthrene sarcoma. A significant increase occurred in both muscle weight and muscle protein in animals receiving cimaterol in conjunction with either enteral or parenteral feeding, compared to food fed tumor-bearing animals. Muscle protein content was increased significantly by 16% in cimaterol-treated rats maintained on parenteral nutrition and by 11% in cimaterol-treated enterally fed rats compared with the respective tumor-bearing controls. Urinary concentrations of 3-methylhistidine, an estimation of muscle turnover or catabolism, were significantly reduced in both tumor-bearing groups treated with cimaterol compared to 3-methylhistidine levels of the untreated tumor-bearing groups. The anabolic effects of cimaterol were expressed in the presence of a large tumor burden resulting in reversal of muscle depletion and muscle breakdown regardless of the route of supplemental nutrition. Thus, beta 2-agonists may be considered as a possible therapy for cancer cachexia.
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PMID:Reversal of cancer cachexia in rats by cimaterol and supplemental nutrition. 168 93


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