Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The rate of protein synthesis in vivo was assessed in tumor tissue, skeletal muscle, liver, and the whole body of rats bearing either the Yoshida sarcoma or Novikoff hepatoma after 18 days of tumor growth and compared to tumor-free controls. Changes in size of the whole animal and tumor (i.e., growth) were measured, and fractional rates of growth, synthesis, and degradation were estimated. Muscle protein synthesis and whole-body growth were significantly reduced in both groups of tumor-bearing rats after 18 days of tumor growth. In addition to reductions in muscle protein synthesis, whole-body protein synthesis was significantly reduced in the Yoshida tumor-bearing group (587 +/- 36 versus 401 +/- 40 mg/h; mean +/- SEM; control versus Yoshida group, respectively, P less than 0.01). Tumor protein synthesis was not statistically different between the Yoshida tumor (76 +/- 21 mg/h) and the Novikoff tumor (50 +/- 8) after 18 days of growth despite the fact that the Yoshida tumors were significantly larger (33.9 +/- 4.2 g versus 11.9 +/- 1.2 g; P less than 0.01). The fractional synthesis rate (Ks) was, in fact, significantly slower in the Yoshida versus the Novikoff tumor (36.8 +/- 7.6 versus 55.1 +/- 4.8%/day). Tumor growth (Kg) followed first order growth rates for both tumor types (r = 0.945, 0.869; Kg = 17.2 +/- 1.6, 15.5 +/- 1.9%/day; Yoshida and Novikoff, respectively). The fractional degradation rate of tumor protein (Kd) was determined as the difference between the two first order rate constants Ks and Kg. The tumor protein degradation rate was significantly reduced in the Yoshida tumors compared to the Novikoff tumors (19.6 +/- 8.2% versus 39.6 +/- 4.2%/day, respectively). The greater size in the Yoshida sarcoma can be attributed to reduction in fractional protein degradation rather than change in synthesis rates, which supports the theory that some tumors can regulate their growth by alteration in tumor protein degradation rates (J. A. Tayek et al., Cancer Res., 46:5649-5654, 1986).
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PMID:Alterations in whole body, muscle, liver, and tumor tissue protein synthesis and degradation in Novikoff hepatoma and Yoshida sarcoma tumor growth studied in vivo. 334 28

The effect of a calcium antagonist and a physiologic amine on tumor and muscle perfusion was investigated with the aim of improving the preconditions for external hyperthermia treatment of cancer. Nisoldipine (0.04-4.0 mg/kg) and 5-hydroxy tryptamine (5-HT) (0.2-8.0 mg/kg) were administered i.p. in Sprague-Dawley rats bearing Walker 256 carcinoma, Yoshida sarcoma, or a homologous tumor transplant derived from a spontaneous leiomyosarcoma of the uterus. At the maximum dosage used, nisoldipine injection caused a decrease of the regional washout rate of Xenon-133 of 63 +/- 8% (SEM) in the Walker carcinoma and an increase of 80 +/- 41% in the muscle of the hind leg. 5-HT (8 mg/kg) caused a drop of 79 +/- 29% in the Walker carcinoma and only a slight fall of the washout rate in muscle of 14 +/- 4.8%. Tumor-to-muscle uptake ratios of 11C-butanol fell from 5.63 +/- 1.98 to 3.32 +/- 1.21, and from 5.3 +/- 0.56 to 2.98 +/- 0.30, after injection of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT, respectively. Similar reaction patterns and percentage changes were observed in different tumor lines at constant doses of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT. Both drugs representing two different rationales of vasomotor action were able to reduce blood flow specifically in transplanted tumors; nisoldipine increased muscle blood flow and decreased arterial blood pressure, whereas 5-HT acted without substantial systemic effects.
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PMID:Selective drug-induced reduction of blood flow in tumor transplants. 400 92

The pharmacokinetics of intraarterially administered cisplatin (DDP) were studied in three patients with large hepatic tumors, and one patient with a fibrous histiocytoma in the thigh, using an assay sensitive to only those forms of non-protein bound DDP capable of reacting with the nucleophilic ligand diethyldithiocarbamate. Each patient received continuous intravenous and intraarterial infusions at various dose rates, with and without concurrent infusion of the neutralizing agent sodium thiosulfate. Steady-state DDP concentrations were achieved within two hours, and the mean (+/- SEM) plasma clearance at infusion rates of 5-15 mg/m2 per hour was 345 +/- 45 mL/m2 per minute. Apparent plasma clearance did not vary significantly with route of infusion. Based on the plasma clearance, predicted values for the relative advantage of an intraarterial infusion (Rt) were less than two for hepatic infusion; observed values averaged 1.9 +/- 0.5 (+/- SEM). The infusion of thiosulfate did not significantly increase plasma clearance. The mean (+/- SEM) extraction ratio for hepatic infusions was 0.24 +/- 0.09, and for infusion of the peripheral soft tissue sarcoma it was 0.27 +/- 0.03. These data indicate that from the point of view of both the tumor and the systemic circulation there is only a limited pharmacologic advantage for intraarterial infusion of DDP into organs with plasma flows of greater than 350 mL/m2 per minute.
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PMID:Clinical pharmacokinetics of intraarterial cisplatin in humans. 632 76

Previously, Puri et al. (Puri, R. K., M. Ogata, P. Leland, G. M. Feldman, D. Fitzgerald, and I. Pastan. 1991. Cancer Res. 51:3011-3017) have demonstrated that murine sarcoma and colon adenocarcinoma cells express high affinity interleukin-4 receptors (IL-4R) which are internalized after binding to a chimeric ligand consisting of IL-4 and Pseudomonas exotoxin. In the present study, we have tested primary cultures of human renal cell carcinoma (RCC) cells, generated from tumor specimens obtained after nephrectomy, for the expression of IL-4R and their modulation by IL-4. By using iodinated IL-4 in a receptor binding assay, we observed that renal cell carcinoma cells expressed a single class of high affinity IL-4R ranging from 1,425 +/- 207 (mean +/- SEM) to 3,831 +/- 299 (mean +/- SEM) IL-4R molecules/cell with a Kd ranging from 112 +/- 11 pM to 283 +/- 71 pM. Northern blot analysis for IL-4R gene expression, performed with a cDNA probe to IL-4R, revealed that all RCC cells exhibited a single mRNA species of 4 kb. IL-4 downregulated the surface expression of IL-4R on one RCC tumor cell line. The function of IL-4R expression on RCC tumor cells was further determined by investigating the effect of IL-4 on tumor cell growth in vitro and comparing it with IL-4 effect on growth of normal fibroblast and endothelial cell lines. Tumor cell growth, as measured by [3H]thymidine incorporation, was inhibited by IL-4 from 20 to 68% in a dose-dependent manner. A neutralizing antibody to human IL-4 was able to reverse the growth inhibitory effect of IL-4. Normal human fibroblast and endothelial cell lines also expressed high affinity IL-4R, however, IL-4 did not inhibit their growth in vitro. In fact, IL-4 caused modest stimulation of their growth. Taken together, our findings can help develop strategies for the treatment of RCC in which IL-4R may be used as a target for IL-4 itself, for IL-4 toxin therapy or, alternatively, in gene therapy.
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PMID:Expression of high affinity interleukin-4 receptors on human renal cell carcinoma cells and inhibition of tumor cell growth in vitro by interleukin-4. 842 37

The aim of this study was to determine the proliferation rates within the lining layer of the rheumatoid arthritis (RA) synovial membrane (SM) as opposed to the SM of other degenerative and neoplastic joint diseases and to characterize the proliferating cells. 13 RA, 23 osteoarthritis (OA), 21 joint trauma (JT), and 9 synovial sarcoma (SS) specimens were immunostained for Ki-67 and PCNA, silver-stained for nucleolar organizer regions (AgNORs), and double stained with either T-cell- (CD3), macrophage- (CD68), or polymorphonuclear neutrophilic leucocytes (PMN)-markers (CD15). The frequency of PCNA positive synovial lining cells (SLCs) varied from 15.7 +/- 8.7% in RA (mean +/- SEM), 30.97 +/- 4.13% in JT, and 48.55 +/- 3.66% in OA to more than half of all cells in SS (67.2 +/- 3.1%). MIB-1 labeling was observed in 20.0 +/- 8.4% of SS cells., but only in 0.6 +/- 0.2% RA or < or = 1.1% in JT and OA SLCs. Mean AgNOR number per cell ranged from 2.9 +/- 0.1 in JT, 3.6 +/- 0.05 in OA and 4.3 +/- 0.3 in RA to 7.3 +/- 0.3 in SS. Significant differences were observed for Ki-67 and AgNORs, between SS and all other diseases and also between RA and OA (p < 0.01, U-test). In RA, Ki-67 was solely expressed in lymphocytes of germinal centres, but not in macrophages or PMN; in the lining layer expression of Ki-67 was only found in fibroblast-like cells. Our study confirms that T-cell or macrophage proliferation is rare in the RA SM. Also, the proliferation rates of fibroblast-like cells in the RA lining layer are rather low, in particular when compared to a sarcoma in the same anatomical location.
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PMID:[Proliferation of T-cells, macrophages, neutrophilic granulocytes and fibroblast-like cells in the synovial membrane of patients with rheumatoid arthritis]. 906 26

Animal cells release traces of material onto glass or silicon surfaces during adhesion and migration. This little studied phenomenon is a widespread and normal concomitant of cell migration. The paper introduces the study of such material. The traces can be visualised by different microscopic techniques (e.g. TIRF, IRM, CLSM, AFM, SEM). Cell traces typical for different cell lines (NIH 3T3 and L929 mouse fibroblasts, mouse macrophages, mouse sarcoma cells and human osteosarcoma cells) are shown and discussed. There are well organised structures such as different linear and nodular elements as well as patches. Traces can extend up to some hundred micrometers from the cell, but the dimensions of the linear elements are in the submicron range. Cell traces are not identical with focal contacts but can include them. A first classification of basic elements is proposed. It allows an estimation of the total volume and surface in comparison to the donor cell. Higher order structures are discussed and a first insight into the protein composition of traces produced by mouse fibroblasts is given. Our observations, together with the cell adhesion literature suggest that the amount of released material, its extent and chemical and structural properties depend on cell type and physiology as well as other external influences. Cell traces in combination with the adhesion pattern of the donor cell should give information about the activity and physiological status of individual cells, the mechanisms of cell locomotion and the molecular composition of the donor cell membrane. The traces might possibly be used as submicron elements for passive electric characterisation and biotechnological applications.
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PMID:Cell traces--footprints of individual cells during locomotion and adhesion. 979 50

Autologous peripheral blood progenitor cell (PBPC) grafts can be contaminated with tumour cells that potentially give rise to relapse following myeloablative therapy and PBPC transplantation. Adeno-associated virus (AAV)-based vectors produced by a new adenovirus-free technique are a gene delivery system which may be applicable for tumour cell purging. To test for the host range of these vectors, solid tumours of clinical relevance and normal CD34+ PBPC were selected as target cells for an AAV-vector, encoding the green-fluorescent protein (GFP) as the indicator gene. At a multiplicity of infection (MOI) of 100: 79.94% +/- 14.36% (mean +/- SEM) of the connective tissue sarcoma cell line (HS-1) and 64.84% +/- 6.91% of the cervical carcinoma cell line cells (HeLa-RC) expressed GFP while the other cell lines tested (1 ovarian tumour, 1 germ cell tumour, 1 osteosarcoma, 2 small cell lung cancer) ranged between 2.82% and 11.94%. Optimising the transduction protocol by use of higher MOIs of up to 500 and by pretreatment with the tyrosine kinase inhibitor, genistein, resulted in up to 95.97% and 94.10% green-fluorescent HS-1 and HeLa-RC cells, respectively. In contrast, only 1.39% +/- 0.51% of the normal haematopoietic CD34+ progenitor cells expressed GFP at a MOI of 100. The differential infectivity between HS-1 and CD34+ cells was maintained after tumour cell spiking in leucapheresis products. Our observations suggest that AAV-based vectors may prove useful for purging of autologous PBPC grafts from solid tumour cells.
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PMID:Superior gene transfer into solid tumour cells than into human mobilised peripheral blood progenitor cells using helpervirus-free adeno-associated viral vector stocks. 1053 60

Amifostine was investigated for its ability to inhibit spontaneous metastases formation using the well-characterized murine sarcoma, Sa-NH. Amifostine was administered intraperitoneally at a dose of 50 mg/kg every other day for 6 days to C3Hf/Kam mice until tumors reached an average size of 8-8.5 mm in diameter. Amifostine was again administered immediately after surgical removal of the tumor-bearing limbs by amputation, and then once more 2 days later. Twenty-one days later, animals were evaluated for the presence of spontaneously developed pulmonary metastases. Nontumor-bearing control animals were sham treated using the same dosing and surgery schedules. Treatment with amifostine appeared to slightly delay tumor growth, that is, 13 vs. 12 days for tumors to reach an average diameter of 8 mm. Amifostine reduced both the incidence of pulmonary metastases formed in experimental animals from 77% to 57% (p < 0.05), and their average number per animal from 12.8 +/- 5.4 (SEM) to 2.9 +/- 1.1 (SEM). The effect of amifostine exposure on serum levels of the angiogenesis inhibitor angiostatin was also determined using Western blot analysis. Consistent with the antimetastatic effect, exposure of animals to 50 mg/kg of amifostine resulted in a 4-fold enhanced serum level of angiostatin above control levels. This phenomenon occurred in tumor-bearing and nontumor-bearing animals. The effects of amifostine on matrix metalloproteinase (MMP) enzymatic activity was also determined using gelatin zymography. Conditioned growth medium collected from Sa-NH cells grown to confluency was exposed to various concentrations of SH, i.e., 2-[(aminopropyl)amino]ethane-thiol (WR-1065), the active thiol form of amifostine, for either 30 min or 18 hr. WR-1065, as a function of increasing dose and time, inhibited the enzymatic activities of MMP-2 and MMP-9. At a concentration and time of exposure likely to be achieved in vivo, that is, 40 microM and 30 min, MMP-2 and MMP-9 activities were reduced to between 30% and 40% of control values. Consistent with these affects, WR-1065 was also found to be effective in inhibiting the ability of Sa-NH cells to migrate through Matrigel membranes. After an 18-hr exposure under in vitro conditions, WR-1065 at concentrations of 4, 40 and 400 microM, and 4 mM, inhibited Sa-NH migration to 11%, 44%, 81% and 97% of control values, respectively. The abilities of amifostine and its active thiol WR-1065 to stimulate angiostatin production in mice, and to inhibit the MMP enzymatic activities and invasion ability of Sa-NH cells under in vitro conditions, are consistent with the observed antimetastatic effects exhibited against Sa-NH tumors growing in vivo.
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PMID:Inhibition of spontaneous metastases formation by amifostine. 1177 55

Thiol-containing drugs such as WR1065, the free thiol form of amifostine, have been shown to induce a delayed radioprotective effect in both malignant and non-malignant cells. In mammalian cells exposed to a dose as low as 40 microM WR1065, the redox-sensitive nuclear transcription factor kappaB (NFkappaB) is activated, leading to an elevation in the expression of the antioxidant gene manganese superoxide dismutase (SOD2) and a concomitant increase in active SOD2 enzyme levels that peaks 24 to 32 h later. Exposure of cells to ionizing radiation during the period of elevated SOD2 enzymatic activity results in an enhanced radiation resistance. This is seen as an increase in surviving fraction as determined by standard colony formation assays. To determine whether this delayed radioprotection can be maintained over a prolonged period in cells of either malignant or non-malignant origin, both human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were grown to confluence and exposed to 40 muM WR1065 using three administration protocols: (1) daily drug exposure for 10 days followed each day by irradiation with 2 Gy; (2) drug exposure once every 48 h followed by irradiation with 2 Gy 48 h later for 14 days; and (3) drug exposure every 72 h followed by irradiation with 2 Gy 72 h later for 12 days. As a function of each experimental condition, cell numbers and associated SOD2 enzymatic activities were measured at the time of each irradiation. None of the treatment conditions were toxic to either HMEC or SA-NH cells. SOD2 activity was elevated 5.3- and 1.8-fold over background on average for HMEC exposed to 40 microM WR1065 every 24 or 48 h, respectively. Likewise, SOD2 activity was elevated in SA-NH mouse sarcoma cells 7.8- and 4.9-fold after daily exposure to WR1065 or exposure to WR1065 once every 48 h, respectively. Both HMEC and SA-NH cells exhibited enhanced radiation resistance that correlated with the increase in SOD2 activity. The average respective increases in cell survival were 1.33 +/- 0.01 (SEM), 1.23 +/- 0.01 and 1.04 +/- 0.01 for HMEC exposed to WR1065 every 24, 48 and 72 h, respectively, and 1.27 +/- 0.01, 1.18 +/- 0.02 and 1.02 +/- 0.02 for SA-NH cells exposed to WR1065 every 24, 48 and 72 h, respectively. Both the elevation in WR1065-induced SOD2 enzymatic activity and the corresponding increase in radiation resistance were completely inhibited in HMEC and SA-NH cells transfected with human or mouse SOD2 siRNA oligomers and irradiated 24 h later. These data demonstrate that a delayed radioprotective effect can be induced and maintained over a prolonged period in both non-malignant and malignant cells exposed to thiol-containing drugs such as WR1065. For non-malignant cells this represents a novel paradigm for radiation protection. The ability of WR1065 to induce a persistent elevated radiation resistance in malignant cells, however, suggests a new potential concern regarding the issue of tumor protection in patients exposed to thiol-containing drugs.
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PMID:Maintenance of manganese superoxide dismutase (SOD2)-mediated delayed radioprotection induced by repeated administration of the free thiol form of amifostine. 1843 41


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