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PubMed1996

Glucocorticoids decrease the production of parathyroid hormone-related protein in vitro but not in vivo in the Walker carcinosarcoma 256 rat model.

In 50-90% of cases, humoral hypercalcemia of malignancy (HHM) is due to tumor secretion of parathyroid hormone-related protein (PTHrP). Glucocorticoids are sometimes used as calcium lowering agents and there are in vitro results showing that glucocorticoids diminish PTHrP production. In this study we tested whether the serum-calcium-lowering effect of glucocorticoids is due to decreased PTHrP production by the tumor. As an animal and cell culture model we used the Walker carcinosarcoma (WCS) 256, a rat mammary carcinoma cell line producing PTHrP. In vitro, dexamethasone caused a dose-dependent inhibition of PTHrP production, whereby already 1-5 nmol/L revealed a significant decrease by WCS 256 cells. In contrast to these in vitro results, in WCS 256 tumor-bearing rats, dexamethasone (4 mg/kg body weight on day 4, and 1 mg/kg body weight from day 5 until day 7 after WCS transplantation; circulating dexamethasone levels > 20 nmol/L) did not decrease PTHrP production, PTHrP secretion, serum calcium, or tumor weight in vivo. We conclude that, in this PTHrP-mediated model of humoral hypercalcemia of malignancy, glucocorticoids do not decrease PTHrP production and secretion in vivo and do not show a calcium-lowering effect.

Analysis of Variance↗
PubMed1997

The effect of clenbuterol and recombinant erythropoietin on tumor growth and the anemia caused by the Walker 256 carcinosarcoma.

In patients with advanced cancer, anemia is a common complication indicative of a poor prognosis. Attempts to alleviate this have met with mixed success and interventions including erythropoietin often fail to elicit an appropriate response. We have used rats implanted with the Walker 256 carcinosarcoma as a model of non-responsive anemia. This study demonstrates that the provision of recombinant erythropoietin in the presence of clenbuterol, a beta2 agonist, attenuates both the cancer induced anemia and the growth of the tumor in this model. We hypothesize that this treatment relieves the tumor induced inhibition of hematopoiesis, which allows for not only an increase in hematocrit but an increased immunosurveillance resulting in tumor suppression.

Adrenergic beta-Agonists↗
PubMed1998

Carcinosarcomas (malignant mixed mullerian tumors) of the female genital tract: comparative molecular analysis of epithelial and mesenchymal components.

Female genital tract carcinosarcomas (FGTCS) are biphasic neoplasms composed of an admixture of malignant epithelial and mesenchymal elements. Histogenesis of FGTCS centers on two theories: (1) simultaneous formation of independent tumors (biclonal theory), (2) multidirectional differentiation of a single neoplasm (monoclonal theory). In an attempt to resolve this histogenetic controversy, we determined the presence, specific genotype, and timing of p53 mutational change in each component of FGTCS using a topographic genotyping (TG) approach. We selected 43 FGTCS from the files of Magee-Womens Hospital, Pittsburgh, and initially immunostained them for p53 protein. Strong p53 immunopositivity was detected in 35 (82%) of 43 tumors. Subsequently, topographic genotyping (TG) was performed on a subset of nine immunopositive tumors with sufficiently distinct malignant components to enable effective sampling. All nine tumors showed point mutations in p53 exons 5 through 8. In each case, the identical point mutational genotype was present in both components. Furthermore, in all nine cases mutations were present with loss of the wild-type allele. P53 gene mutation is a frequent event in progression of FGTCS. Of importance, both p53 mutation and allelic loss occur before the differentiation into separate epithelial and mesenchymal malignant components. These molecular findings strongly support monoclonal, multidirectional histogenesis of FGTCS.

Base Sequence↗
PubMed1993

Characterization of calcium transport in the luminal and the basolateral membrane from kidney cortex of hypercalcemic rats bearing the Walker 256 carcinosarcoma.

The Walker 256 (W256) carcinosarcoma did not significantly modify calcium uptake by brush border membrane (BBM) vesicles in the kidney of the host rat, compared with that in membranes isolated from control animals. However, it showed a tendency to increase at near equilibrium in W256 tumor-host rats, associated with a decreased BBM protein content. ATP-dependent calcium influx by basolateral membrane (BLM) vesicles from W256 tumor-bearing rats was also increased compared with that in control BLM. This stimulation was due to a decreased Km for calcium. Passive calcium permeability or the Na+/Ca2+ exchanger were unchanged in BLM from W256 tumor-host rats compared with control BLM. Pre-stimulation of control rat cortical tubules with either 10(-7) M parathyroid hormone-related protein (PTHrP) (1-34) or 10(-4) M N6,2'-O-dibutiryl cyclic AMP before BLM isolation, did not modify the ATP-dependent calcium uptake by BLM vesicles compared with control membranes. However, our results do not rule out that the stimulated ATP-dependent calcium influx in BLM from W256 tumor-host rats could be mediated by the interaction among PTHrP and other humoral factors. Our findings suggest a possible mechanism for the increased renal calcium reabsorption in this animal model for humoral hypercalcemia of malignancy.

Adenosine Triphosphate↗
PubMed1998

Protrusion, contraction and segregation of membrane components associated with passive deformation and shape recovery of Walker carcinosarcoma cells.

We mimicked essential elements of the cortical-contraction model of cell locomotion by exposing Walker carcinosarcoma cells to passive deformation and to hydrostatic pressure changes within micropipettes followed by shape recovery after release. Protrusion, contraction and segregation of cell surface membrane components were observed. Regardless of the initial shape (spherical, polarized with lamellipodia or blebs) cells tended to produce blebs during uptake into the pipette and during and after release from the pipette, but usually not during the short time they were held within the pipette. Bleb formation depended on the deformation stress, extracellular hydrostatic pressure and cell structure (initial shape). In polarized cells, blebs were much more readily induced at the front as compared to the tail. Cells undergoing large deformations formed constriction rings and large hyaline caps. Deformation resulted in segregation of membrane components. Equatorial constriction rings divided the cell into two parts which differed with respect to Con A binding and their role in shape recovery. Spherical and polarized cells usually recover the respective initial shape. Polarized cells reacquired the same type of protrusions (blebs or lamellipodia) which they exhibited before deformation. Shape recovery of spherical cells was characterized by a rapid recoil by about 20% followed by a slow asymptotic recovery.

Animals↗
PubMed1998

Regulation by calcium of the synthesis of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in Walker 256 carcinosarcoma cells: comparison with synthesis regulation from renal phenotype cells (LLC-PK1).

The aim of this work was to study the regulation by calcium of the synthesis of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) in Walker 256 carcinosarcoma (W256) cells compared to renal phenotype LLC-PK1 cells. We have detected synthesis of 1,25(OH)2D3 and 24,25(OH)2D3 in W256 cells. Levels of 1,25(OH)2D3 in W256 were similar to those of LLC-PK1 cells. Levels of 24,25(OH)2D3 were higher in W256 than in LLC-PK1 cells. High levels of calcium inhibited 1,25(OH)2D3 synthesis in LLC-PK1 cells but not in W256 cells.

24,25-Dihydroxyvitamin D 3↗
PubMed1977

Aprotinin and growth of Walker 256 carcinosarcoma in the rat.

Growth of the Walker 256 carcinosarcoma implanted within various sites in Spraque-Dawley rats was investigated in animals receiving twice daily i.p. injections of the antiprotease aprotinin. Although administration of aprotinin partially attenuated the growth and lethality of i.p. tumour, no effect of aprotinin was found on intramuscular tumour development. Furthermore, we were unable to demonstrate unequivocal growth inhibition by aprotinin of lung tumour colonies from i.v. injection of tumour cells. Histological examination of intramuscular and pulmonary tumours revealed little evidence of host cellular immune response in either saline- or aprotinin-treated rats.

Animals↗
PubMed1989

Prediction of 5-fluorouracil cytotoxicity towards the Walker carcinosarcoma using peak integrals of fluoronucleotides measured by MRS in vivo.

19F-magnetic resonance spectroscopy (MRS) can be used to non-invasively monitor metabolism of 5-fluorouracil (5FU) to cytotoxic fluoronucleotides (FNuct). We investigated whether the levels of FNuct formed from 5FU and observed in vivo by MRS in the Walker carcinosarcoma predicted cytotoxicity. Fifty mg kg-1 5FU caused tumour FNuct formation and, when repeated daily for 1 week, significant tumour growth inhibition (P less than 5%). Twenty-five mg kg-1 5FU produced less tumour FNuct (P less than 5%) and did not cause significant tumour regression. Tumour regression and tumour FNuct formation were also suppressed by 50 mg kg-1 5FU combined with a molar equivalent dose of allopurinol (P less than 2%). Tumour extracts were analysed by hplc and MRS confirming the observations in vivo and demonstrating that peak integrals in vivo were directly proportional to 5FU and FNuct concentrations. Hplc analysis of extracts showed that 50% of FNuct in tumours treated with 5FU was the cytotoxic nucleotide FUTP; this was lowered to 5% by a molar equivalent dose of allopurinol (P less than 2%). Twenty-five mg kg-1 5FU also produced significantly less FUTP (36%) than the 50 mg kg-1 dose (P less than 5%). These results suggest that MRS-detectable changes in tumour FNuct (mostly in FUTP) can be used to predict 5FU cytotoxicity.

Animals↗
PubMed1992

Enhanced 5-fluorouracil cytotoxicity and elevated 5-fluoronucleotides in the rat Walker carcinosarcoma following methotrexate pre-treatment: a 19F-MRS study in vivo.

5-fluorouracil (5FU) is activated intracellularly to cytotoxic 5-fluoronucleotides (FNuct). These were detected non-invasively in rats bearing the Walker carcinosarcoma by 19F-magnetic resonance spectroscopy (MRS) following an i.v. bolus dose of 5FU (50 mg kg-1). Pre-treatment of the rats (3 to 24 h earlier) by methotrexate (MTX) (20 or 50 mg kg-1) did not affect the rate of 5FU disappearance but did significantly increase the rate of FNuct formation (P less than 0.002) and the final amount formed (P less than 0.02) as assessed by MRS in vivo. MTX (20 mg kg-1) caused substantially the same effects on FNuct formation (P less than 0.002 for rate and P less than 0.05 for the amount) when 5FU was administered i.p. although higher doses of 5FU (120 mg kg-1) were necessary to observe the 19F-signals. Quantitative analysis by MRS in vitro of extracts from the freeze-clamped tumours treated by 5FU i.v. confirmed that MTX pre-treatment increased FNuct formation 3-fold (P less than 0.05). Hplc quantitative analysis demonstrated that 50% of the FNuct was the cytotoxic nucleotide FUTP which was also increased 3-fold in MTX treated animals (P less than 0.05). Since the Walker tumour is probably sensitive to 5FU action via FUTP incorporation into RNA, these results suggested that drug regimes in which MTX preceded 5FU (MTX-5FU schedule) would be more cytotoxic that 5FU alone. At an MTX dose of 20 mg kg-1 24 h prior to 5FU there was significant inhibition of growth (P less than 0.05) compared to no treatment, MTX alone or the reverse schedule of 5FU-MTX. These results suggest MRS may be of clinical value in optimising chemotherapy using schedules where MTX precedes 5FU.

Animals↗
PubMed1975

Electrophoretic and centrifugation behaviour of mitochondrial ribonucleic acid from Walker 256 carcinosarcoma.

To investigate the possibility that mitochondrial transcription could be altered in tumours we started by characterizing the RNA obtained from mitochondria, isolated from Walker carcinosarcoma and purified by a procedure devised to compensate for the lower size and density of these organelles in 10-day tumours. The RNA was extracted by the 'hot phenol' technique and analysed by electrophoresis in 2.7 and 2.5% polyacrylamide gels at different running times, identifying the usual cytoplasmic contaminants 28 and 18S peaks plus the other five major peaks at 40, 20.5, 16.3, 15.4, and 4Se. The 28 and 18Se peaks were not eliminated by digitonin treatment of the mitochondria, indicating that they arise from cytoplasmic ribosomes tightly associated with the mitochondria. From its sensitivity to DNAase (deoxyribonuclease), resistance to RNAase (ribonuclease) and coincidence with external marker DNA, the 40Se peak was identified as containing mainly DNA. Sucrosegradient centrifugation for different periods showed a major component at 16.2S, the 28 and 18S cytoplasmic RNA species, peaks at 13.8, 6.4 and 4S and a small 19.5S peak. By polyacrylamide-gel electrophoresis of the purified RNA classes separated by one or two cycles of centrifugation, the following correlation were established: 20.5Se19.5S; 16.3Se16.2S; 15.4Se13.8S. The 6.4S RNA ran as a mixture of 4 and 4.7Se species. When the 20.5Se and 15.4Se RNA species were centrifuged, they behaved as 16.2S and 13.8S respectively, thus suggesting that the 16.2S (16.3Se) arises by cleavage from the 19.5S(20.5Se), the 13.8S (15.4Se) being the other RNA from mitochondrial ribosomes.

Animals↗
PubMed1985

Nucleoside transport in Walker 256 rat carcinosarcoma and S49 mouse lymphoma cells. Differences in sensitivity to nitrobenzylthioinosine and thiol reagents.

The characteristics of nucleoside transport were examined in Walker 256 rat carcinosarcoma and S49 mouse lymphoma cells. In Walker 256 cells the initial rates of uridine, thymidine and adenosine uptake were insensitive to the nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR) (1 microM), but were partially inhibited by dipyridamole (10 microM), another inhibitor of nucleoside transport. In contrast, the transport of these nucleosides in S49 cells was completely blocked by both inhibitors. Nucleoside transport in Walker 256 and S49 cells also differed in its sensitivity to the thiol reagent p-chloromercuribenzenesulphonate (pCMBS). Uridine transport in Walker 256 cells was inhibited by pCMBS with an IC50 (concentration producing 50% inhibition) of less than 25 microM, and inhibition was readily reversed by beta-mercaptoethanol. In S49 cells uridine transport was only inhibited at much higher concentrations of pCMBS (IC50 approximately equal to 300 microM). In other respects nucleoside transport in Walker 256 and S49 cells were quite similar. The Km and Vmax. values for uridine transport were nearly identical, and the transporters of both cell lines appeared to accept a broad range of nucleosides as substrates. Uridine transport in Walker 256 cells was non-concentrative and did not require an energy source. These studies demonstrate that nucleoside uptake in Walker 256 cells is mediated by a facilitated-diffusion mechanism which differs markedly from that of S49 cells in its sensitivity to the transport inhibitor NBMPR and the thiol reagent pCMBS.

4-Chloromercuribenzenesulfonate↗
PubMed1991

Osteolytic activity of Walker carcinosarcoma 256 is due to parathyroid hormone-related protein (PTHrP).

The hypercalcemic Walker carcinosarcoma 256 of the rat is an animal model for humoral hypercalcemia of malignancy. Previous in vivo studies suggested the production of a parathyroid hormone-related protein (PTHrP) by the Walker tumor. Therefore, we have measured immunoreactive PTHrP in serum-free conditioned medium from cells derived from this tumor using an antibody raised against human PTHrP(1-34). Walker tumor cell conditioned medium (WCM) displaced 125I-hPTHrP(1-34) from the antibody in a dose dependent manner, whereas control medium contained no immunoreactive PTHrP. In contrast, we detected no secretion of immunoreactive rat parathyroid hormone (rat PTH) by the Walker tumor cells using a midregional radioimmunoassay for rat PTH. WCM stimulated adenylate cyclase in osteoblast like cells, the dose-response curve paralleling that of hPTHrP(1-34). This effect could be inhibited by the PTH antagonist (8Nle, 18Nle, 34Tyr)bPTH(3-34) and by the addition of anti-hPTHrP(1-34) antibody. Bone resorbing activity of WCM in organ culture (calvaria of fetal rats) was not inhibited by indomethacin and glucocorticoids, suggesting a prostaglandin independent mechanism of osteoclast activation in this model.

Adenylyl Cyclases↗
PubMed1976

A fetal protein in chromatin of Novikoff hepatoma and Walker 256 carcinosarcoma tumors that is absent from normal and regenerating rat liver.

Antibodies to chromatin proteins of Novikoff hepatoma cells formed precipitin bands in the double-diffusion immunoprecipitation assay with chromatin proteins of Novikoff hepatoma, Walker 256 carcinosarcoma, and 18-day fetal rat liver. The antigen used for preparation of antiserum was the chromatin proteins initially extracted with 3 M NaCl-7 M urea and soluble after dialysis to 0.14 M NaCl-0.35 M urea. The chromatin proteins used for analytical studies were extracted with 0.6 M NaCl containing 0.01 M Tris-HCl (pH 8) and 100 muM phenylmethylsulfonyl fluoride. Corresponding chromatin proteins of normal and 18-hr regenerating rat liver, heart, and kidney did not form precipitin bands. The antigen was purified from the chrmatin of Novikoff hepatoma cells by exclusion chromatography on Sephadex G-150 and preparative nondenaturing polyacrylamide gel electrophoresis. Its migration on denaturing sodium dodecyl sulfate-polyacrylamide gels corresponded to a molecular weight of 26,000. Amino acid analysis showed that the ratio of acidic to basic amino acids was 1.4 to 1.0. Evidence for its homogeneity included its migration as a single protein spot on two-dimensional polyacrylamide gel electrophoresis and its single lysine amino-terminal amino acid. This protein is a glycoprotein, as shown by the presence of 15 moles of galactosamine per mole of antigen. These studies demonstrate the presence of a fetal glycoprotein in the chromatin of two tumors that may have an important role in determining their gene products.

Animals↗
PubMed1994

Dietary level of maize oil affects growth and lipid composition of Walker 256 carcinosarcoma.

Walker 256 carcinosarcoma cells (1 x 10(4)) were injected into the right thigh muscle of Sprague-Dawley rats (125 g) consuming isoenergetic (200 g fat/kg) diets containing 20, 100 and 200 g maize oil/kg and 180, 100 or 0 g hydrogenated lard/kg respectively. Ten rats from each dietary regimen were killed every 4th day. Tumours grew rapidly from day 0 to day 8 post-transplant regardless of dietary regimen. However, after 8 d more tumours regressed and there were fewer deaths in animals fed on 200 g maize oil/kg compared with animals fed on 20 or 100 g maize oil/kg. Linoleic acid (LA) levels were higher in phospholipids (PL) of growing tumours than in regressing tumours whereas arachidonic acid levels in PL were lower in growing tumours indicating a possible alteration in the desaturation and elongation of LA. Serum prostaglandin E2 levels were slightly lower in rats with regressing tumours than in rats with growing tumours.

Animals↗
PubMed1998

Carnitine palmitoyltransferase II activity is decreased in liver mitochondria of cachectic rats bearing the Walker 256 carcinosarcoma: effect of indomethacin treatment.

The syndrome of cancer cachexia is accompanied by several alterations of lipid metabolism, especially that in the liver. In this study we have investigated a possible mechanism whereby the presence of the Walker 256 carcinosarcoma affects hepatic fatty acid oxidative capacity in tumour-bearing rats. Hepatic mitochondrial outer membrane carnitine palmitoyltransferase I (CPT I), generally accepted as the main site of regulation of fatty acid oxidation, was unaffected by the presence of the extra-hepatic tumour. However, mitochondrial inner-membrane carnitine palmitoyltransferase II (CPT II) activity was markedly decreased in mitochondria isolated from the liver of tumour-bearing rats. Immuno-detection by Western blotting using a CPT II-specific antibody identified two bands (corresponding to M(r) 69,000 and 54,000) in tumour-bearing rats whereas only the normal-sized CPT II was present (at the expected M(r) 69,000) in mitochondria from control rats. It is suggested that the emergence of the second, smaller protein may represent a catalytically less active protein that arises in vivo, since its appearance was not affected by the inclusion of proteolysis inhibitors in the mitochondrial preparation buffers. Treatment of the tumour-bearing rats with indomethacin, a prostaglandin (including PGE2) synthesis inhibitor, increased CPT II activity to levels even higher than those found in the control animals. It is suggested that PGE2 may play a role in the control of CPT II expression in the liver of tumour-bearing rats. Indomethacin treatment did not affect either of the two CPT activities of the mitochondria isolated from tumour tissue.

Animals↗
PubMed1980

Protein quality, food intake and growth in normal and Walker 256 carcinosarcoma-bearing rats.

The effect of supplementation of dietary gluten with its first and second limiting amino acids (lysine and threonine) on food intake and growth was examined in normal and Walker 256 carcinosarcoma-bearing male, Sprague-Dawley rats. Two diets were used. Diet G had 16.4% gluten and diet GLT had (%): gluten 15, L-lysine.HCl 1, and L-threonine, 0.4 Normal and tumor-bearing animals (7) were fed each diet from day 7 until day 20 post-transplant of the tumor bearers. Food intake in the tumor-bearers was lower than that of controls (P < 0.01) from day 10 post-transplant. Normal animals fed diet GLT ate more than those fed diet G throughout the experiment. A similar effect of protein quality on the food intake of tumor-bearers was seen until day 15 post-transplant; thereafter, food intake of tumor-bearers was similar on both diets. Tumor-bearing animals had lower (P < 0.01) protein and lipid contents than controls on both diets. Diet had no effect on tumor weight or content of protein, lipid, DNA or RNA. Protein and lipid contents of hosts and controls on diet GLT were higher (P < 0.5) than for their counterparts on diet G.

Animals↗
PubMed1984

Effects of diets deficient in glucose and glucose precursors on the growth of the Walker carcinosarcoma 256 in rats.

The effects of carbohydrate-deficient diets on the growth of the Walker carcinosarcoma 256 in rats and on the carcinostatic action of the glucose analogue 2-deoxyglucose were studied. All diets contained 13.0% casein with glucose levels as indicated and the balance of calories present as corn oil free fatty acids. The growth of the tumor was directly related to the glucose level in such diets; after 16 days rats fed 0.0, 1.5 and 4.5% glucose had tumors weighing 7.0, 11.1 and 13.3 g, respectively. The decrease in tumor weight was related to dietary glucose level rather than the anorexia produced by the diets low in glucose, as shown by the fact that tumors in rats fed 4.5% glucose were larger than rats fed 1.5% glucose even when the rats fed 4.5% glucose were pair-fed to the levels consumed by those fed 1.5% glucose. 2-Deoxyglucose (0.2%) also caused a reduction in tumor growth in a manner independent from the anorexia produced by its presence in the diet. This carcinostatic effect was potentiated by low glucose levels in the diets in the rats fed 4.5% glucose plus 0.2% 2-deoxyglucose had proportionally greater reductions in tumor weights due to the glucose analogue than did rats fed 20% glucose plus 0.2% 2-deoxyglucose.

Animals↗
PubMed1984

The influence of diet on the regression of the Walker carcinosarcoma 256 in rats.

Regression of the Walker carcinosarcoma 256 has been observed in rats inoculated with 10(4) viable tumor cells. The regression was found to be affected by dietary composition. Tumors in rats fed a commercial laboratory diet (CLD) regressed after a 9-day initial growth period while tumors in rats fed a purified diet high in free fatty acids continued to grow. Diets with 20% corn oil promoted tumor regression, but rats fed diets containing 20% free fatty acids from corn oil had tumors that continued to grow. The nonsaponifiable fraction (NSF) of corn oil appeared to promote tumor regression when this fraction was added to diets containing corn oil fatty acids. At the end of the experiment (14 days), the tumors of rats fed a free fatty acid diet weighed 13-17 g. The tumors of rats fed CLD, corn oil diet and the corn oil free fatty acid diet plus the NSF of corn oil weighed 1-5 g. These results indicate that something in the NSF of corn oil was associated with the regression of the tumor. However, the nature of the dietary components promoting tumor regression, and the host response to those components, have not been determined.

Animals↗