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PubMed1995

Effects of passive immunization against parathyroid hormone-related protein: PTHrP is the responsible factor in mediating hypercalcemia in the Walker carcinosarcoma 256 rat model.

The Walker carcinosarcoma (WCS) 256 is a well-characterized rat model of humoral hypercalcemia of malignancy (HHM). We addressed the question of whether parathyroid hormone-related protein (PTHrP) is the factor responsible for mediating HHM in this model. WCS 256 cells were subcutaneously implanted in female rats. We examined the plasma at days 0, 2, 4, 6, and 8. The midregional PTHrP measured by radioimmunoassay (RIA) and the plasma calcium increased significantly. Measuring PTHrP by a two-site immunoradiometric assay (IRMA) showed comparable results. There was a strong positive correlation between plasma calcium and midregional PTHrP (r = 0.85, p < 0.0001). A strong positive correlation between tumor weight and both midregional PTHrP (r = 0.83, p < 0.0001) and plasma calcium (r = 0.87, p < 0.0001) was also found. After surgical removal of the tumor at day 5, both plasma calcium and plasma PTHrP levels fell to within the normal range. Ip administration of native polyclonal antiserum against PTHrP(53-84) led to a significant decrease of plasma calcium. Extracted WCS 256 tumor showed 5-fold increased levels of midregional PTHrP compared with liver. Immunohistochemistry and Western blot were positive for PTHrP. RNA from the WCS 256 tumor was positive for PTHrP whereas liver tissue RNA was negative. WCS 256 cells grown in vitro also secreted PTHrP into the medium. We conclude that PTHrP is synthesized and secreted by WCS 256 and that PTHrP is the factor responsible for mediating hypercalcemia in the WCS 256 rat model.

Analysis of Variance↗

PubMed1994

Influence of interleukin-2 infusion on cell cycle kinetics in the Walker-256 carcinosarcoma.

The effect of recombinant human interleukin-2 (IL-2) on tumor cell cycle kinetics was evaluated in rats bearing the Walker-256 carcinosarcoma. Seven days after implantation, tumor-bearing rats were infused intravenously with IL-2 at a dose of 500 mg/kg body weight or 5% dextrose for 6 h. Tumor cell mean DNA synthesis time (TDNA), labeling index, potential doubling time (Tpot), and growth fraction (GF) were determined in vivo by use of bromodeoxyuridine (BrdUrd) pulse labeling and bivariate BrdUrd/DNA analysis using flow cytometry. IL-2 treatment significantly reduced the relative number of S-phase cells by 11.9% and increased the number of cells in the G0/G1 phase by 9.4%. The labeling index was reduced from 41.3 +/- 2.5% to 32.7 +/- 1.2% (P < .01). Estimates of TDNA derived from the change in BrdUrd movement relative to DNA content were not affected by IL-2 treatment. Based on these cytokinetic changes, IL-2 infusion significantly increased tumor Tpot from 15.3 +/- 0.3 h to 21.5 +/- 0.2 h (P < .001) and reduced GF from 1.01 +/- 0.07 to 0.83 +/- 0.01 (P < 0.001). The inhibitory effect of IL-2 infusion on tumor cell growth, which may be either direct or secondarily mediated by other factors, contrasts with other stimulatory effects of this cytokine on lymphoid cell proliferation.

Animals↗

PubMed1996

Tissue polypeptide antigen production in a uterine carcinosarcoma cell line in a serum-free culture.

Carcinosarcomas (malignant mixed Mullerian tumors, MMMT) of the female genital tract are uncommon neoplasms, most of which show a highly aggressive behavior. However, the biological characteristics of MMMT, especially the producibility of tumor-related substances in vitro, have yet to be clarified. Using a serum-free culture model system which was newly established from an FU-MMT-2 cell line originating from an MMMT of the human uterus, the biological and immunocytochemical characteristics of MMMT cells were examined in vitro. As a control model, the uterine fibroblasts were also cultured in the same conditions. Moreover, several tumor markers were also measured by a radioimmunoassay in the serum of five patients with MMMT. FU-MMT-2 produced and secreted tissue polypeptide antigen (TPA), a tumor marker closely related to the keratin family, under serum-free culture conditions. Moreover, TPA was also immunocytochemically demonstrated in carcinoma cells as well as sarcoma cells in FU-MMT-2. On the other hand, the uterine fibroblasts showed no detectable producibility of the substances examined in vitro. An elevation of the serum TPA levels was also detected in four of five (80%) patients with MMMT. This is the first serum-free culture study of MMMT, which appears to provide a useful model for further studies of the tumor biology in MMMT of the female genital tract. An evaluation of the serum TPA level thus appears to be useful in determining the optimum management of patients with MMMT. In addition, the demonstration of TPA in sarcoma cells of FU-MMT-2 in vitro supports both the theory of a single cell origin and the current concept of MMMT as a "metaplastic carcinoma," as substantiated in our previous study.

Aged↗

PubMed1982

Effects of hyperthermia and hyperglycemia on the metastases formation and on survival of rat bearing W256 carcinosarcoma.

Hyperthermia (temperatures less than 42 degrees C) is widely used in the treatment of cancer. Current thrust in this field is directed towards using agents which can potentiate the effects of hyperthermia. Combined local hyperthermia (43 degrees C/2 hours) and hyperglycemia (6g glucose/kg body weight; mean blood glucose levels of 500 mg%) was investigated for treating a metastasizing form of a rat W256 carcinosarcoma. Glucose loading of the tumor-bearing rats rendered the foot tumors physically more easy to heat (due to inhibition of tumor blood flow), but combined hyperthermia and hyperglycemia lead to a decrease in survival rate (13% compared to 41% with heat alone), most animals died with widespread metastases in lymph nodes, lungs and kidneys. The data does not support the postulate that hyperglycemia leads to sensitization of tumor destruction by hyperthermia. We suggest that Corynebacterium parvum, a non-specific immunostimulant, should be thoroughly investigated as a potentiator of hyperthermia.

Animals↗

PubMedDate not supplied

In vitro effects of bone- and platelet-derived transforming growth factor-beta on the growth of Walker 256 carcinosarcoma cells.

Conditioned media from fetal rat calvarial cultures has previously been shown to stimulate the growth of the bone-metastasizing Walker 256 carcinosarcoma cell line. In the current investigation we looked at the possibility that transforming growth factor-beta (TGF-beta), present in conditioned media, and positively correlated with resorption in vitro, may be responsible for the enhanced proliferation of Walker cells cultured in these conditioned media. Purified platelet-derived TGF-beta produced a dose-dependent growth response in Walker cells with an ED50 equal to 0.05 ng/ml. Bone-derived TGF-beta activity in conditioned media, measured by NRK fibroblast colony formation, correlated well with percentage resorption in bone cultures, and growth activity in Walker cell culture. In addition to this, the growth response normally seen with conditioned media cultures of Walker cells was significantly inhibited by the addition of anti-TGF-beta 1 neutralizing antibody. We conclude that TGF-beta is an important growth stimulatory component from fetal rat calvaria.

Animals↗

PubMed1982

Anticoagulant treatment of rats with Walker 256 carcinosarcoma.

Various anticoagulant, antiplatelet, and fibrinolytic agents have been found to be effective in reducing metastatic growth of experimental animal tumors. This effectiveness is attributed to the requirement for hemostatic factors in the implantation and growth of metastases. However, clotting and platelet factors are also present at the site of a primary tumor, the Walker 256 carcinosarcoma. Yet maximally tolerated doses of heparin or warfarin did not affect the primary growth of this rat tumor.

Animals↗

PubMed1987

The Walker 256/B carcinosarcoma in thyroparathyroidectomized rats: a model to evaluate inhibitors of bone resorption.

The Walker 256/B mammary carcinosarcoma implanted in male Fischer rats was used to evaluate bone resorption inhibitors. The model was improved by thyroparathyroidectomizing the animals to avoid counter-regulation by parathyroid hormone or calcitonin, by pair-feeding them, and by using 2 hour fasting calciuria as a resorption index to minimize the influence of differences in growth or in intestinal calcium absorption. Over a 10 day period, the control animals displayed a progressive increase of plasma calcium (Ca) and fasting urinary Ca excretion, a decrease of plasma phosphate, and an increase of urinary phosphate excretion. Osteocalcin did not change. The daily administration of dichloromethylene bisphosphonate (Cl2MBP) totally prevented the increase of fasting urinary Ca excretion, whereas plasma Ca remained at a higher level than thyroparathyroidectomized (TPTX) control rats. Osteocalcin decreased. Two new aminobisphosphonates, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP), and 6-amino-1-hydroxyhexylidene-1,1-bisphosphonate (AHHexBP) had a similar effect. The order of potency shown by the three bisphosphonates was similar to that reported using the metaphyseal bone density evaluation method in growing rats: AHBuBP greater than AHHexBP greater than Cl2MBP, the difference each time being one order of magnitude. The analysis of the relationship between urinary and plasma values in tumor-bearing animals suggested an increased renal tubular reabsorption of Ca and a decreased reabsorption of phosphate (Pi). Therefore, in this model of malignant osteolysis, urinary Ca excretion is the best marker for bone resorption.

Animals↗

PubMedDate not supplied

Effect of methionine replacement by homocystine in cultures containing both malignant rat breast carcinosarcoma (Walker-256) cells and normal adult rat liver fibroblasts.

When malignant W-256 rat breast carcinosarcoma cells are mixed with an equal number of normal adult rat liver fibroblasts and allowed to grow in a medium containing sufficient L-methionine and an excess of vitamin B12 and of folic acid, the malignant cells outgrow the normal cells, and within 2 weeks the tissue culture flasks contain only neoplastic cells. However, when ample DL-homocystine or homocysteine replaces methionine in the medium containing the same amount of vitamin B12 and folic acid, and seeded with the same type and number of malignant and normal cells, the malignant cells die and the normal cells thrive. Substantiating this conclusion are the results of injections into rats of comparable numbers of cells from each group after 3 weeks of growth in tissue culture. Fatal malignancies are produced by the homocystein-cultivated cells.

Animals↗

PubMed1985

Syntheses of carbon-11 labelled ornithine and lysine. Preliminary accumulation studies in rats with Walker 256 carcinosarcoma.

DL-[1-11C]ornithine and lysine have been synthesized by carboxylation of the corresponding alpha-lithioisocyanide with a radiochemical yield of up to 14% without correction for decay. The total preparation time is 50 min. Accumulation of both DL-[1-11C]ornithine and lysine in Walker 256 carcinosarcoma is observed, with a tumor/non-tumor ratio of 4.9 and 4.5 respectively, at 45 min after intravenous injection.

Animals↗

PubMed1985

The preparation of carbon-11 labelled proline for positron emission tomography. Preliminary distribution studies in rats with Walker 256 carcinosarcoma.

DL-[1-11C]Proline has been synthesized by carboxylation of alpha-lithiopyrrolidyl-N-tert-butyl-formamidine with a radiochemical yield of up to 18% without correction for decay. The total synthesis time is 45 min. Accumulation of DL-[1-11C]proline has been shown in Walker 256 carcinosarcoma transplanted in rats. A tumor/non-tumor ratio of 5.9 was found at 45 min after i.v. injection.

Animals↗

PubMed1995

Insulin-like growth factor-1 is not mitogenic for the Walker-256 carcinosarcoma.

This study was designed to determine whether intravenous infusion of recombinant human insulin-like growth factor 1 (IGF-1) stimulates tumor growth. In order to determine the potential interaction between nutrition and IGF-1 administration the study was conducted in fasting rats and during continuous feeding by total parenteral nutrition. Tumor cell cycle kinetics including labeling index, DNA synthesis time, cell cycle time in Go/G1, and G2/M in the total cell cycle, and potential doubling time were determined by flow cytometry after in vivo pulse labeling the rats bearing the Walker-256 Carcinosarcoma with 5'-bromo-2'-deoxyuridine (BrdUrd). The results show that IGF-1 treatment has no significant effects on the proliferative characteristics of the tumor model regardless of the feeding status of the animal. This study provides preliminary cell-cycle kinetics data on the short-term effect of IGF-1 on tumor growth. Failure to show a significant effect of IGF-1 on the proliferative characteristics of the tumor suggests that IGF-1 may be given to cancer patients in amounts sufficient to promote weight gain without deleterious stimulation of tumor proliferation.

Animals↗

PubMed1989

The hypercalcemic Walker carcinosarcoma 256 of the rat causes an increase in serum 1,25-dihydroxyvitamin D3.

We have studied vitamin D metabolism in rats with the transplantable hypercalcemic Walker carcinosarcoma 256, which is a well characterized animal model for humoral hypercalcemia of malignancy. 25-Hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) concentrations were determined in blood samples obtained from parathyroidectomized (PTX) female rats at different time intervals after intramuscular tumor cell inoculation. We observed a dramatic increase in serum 1,25(OH)2D3 (280 +/- 184 vs. 98 +/- 31 pmol/l) 6 days after tumor cell injection and 4 days after the initial rise of serum calcium, whereas 25(OH)D3 tended to decrease. In a separate control experiment we compared this to the effect of exogenous parathyroid hormone in PTX rats and found similar results. In contrast, rats exhibited no change in vitamin D metabolite blood concentration after inoculation of the normocalcemic Yoshida sarcoma, which obviously does not interfere with vitamin D metabolism. We conclude that the humoral bone-resorbing agent produced by the Walker tumor cells causes elevation of serum 1,25(OH)2D3 concentration by this fulfilling an additional criterion of PTH-like activity.

Animals↗

PubMed1991

Relative role of bone and kidney in the hypercalcaemia associated with the rat Walker carcinosarcoma 256.

The rat Walker carcinosarcoma 256 is an animal model for humoral hypercalcaemia of malignancy (HHM). In this model, the relative contribution of bone and kidney in the hypercalcaemia of tumour-bearing rats was investigated. Daily administration of pamidronate, a bone resorption inhibitor, for 2 days prevented the increased fasting Ca2+ excretion observed in the hypercalcaemic rats, although serum Ca2+ remained high. However, the high serum Ca2+ normalised after the acute injection of ethiofos, an inhibitor of renal Ca2+ reabsorption, which was associated with a marked increase of Ca2+ excretion. Changes in Ca2+ were accompanied by similar changes in Mg2+. The results indicate that altered renal Ca2+ handling has a key role in the hypercalcaemia associated with this HHM model.

Amifostine↗

PubMed1983

Enhanced metastasis formation by combined hyperthermia and hyperglycemia in rats bearing Walker 256 carcinosarcoma.

Hyperglycemia has been shown to decrease tumor pH and blood flow rates, consequently this could increase the sensitivity of tumor to hyperthermia. Combined waterbath hyperthermia (43 degrees C/2 h) and hyperglycemia (6 g/kg, i.p.) was investigated on survival of rats bearing a metastasizing form of Walker 256 carcinosarcoma. Hyperthermia alone increased the survival rate of animals from 19% to 42%. Hyperglycemia promoted more uniform tumor heating in the foot. However, combined hyperthermia and hyperglycemia led to a significant decrease in the survival rate of animals (10%; P less than 0.001), and most rats died with widespread metastasis in lymph nodes, lungs and kidneys. These findings do not support the postulate that hyperglycemia leads to sensitization of tumor destruction by hyperthermia.

Animals↗

PubMed1986

Degradation of insulin and glucagon by a factor associated with Walker 256 carcinosarcoma cells.

Earlier studies from this laboratory reported that, in rats bearing the Walker 256 carcinosarcoma, circulating insulin levels were significantly reduced relative to non-tumor-bearing rats. The present study extends this observation to include a significantly (P less than 0.01) reduced plasma level of glucagon in rats bearing the tumor for both 7 and 10 days. In order to determine if the tumor itself somehow plays a role in the degradation of these protein hormones, either cultured Walker 256 tumor cells (in the case of the insulin studies) or cells from freshly excised tumor (for the glucagon studies) were incubated with 125I-labeled insulin or glucagon. Following the incubation period, the amount of TCA-precipitable radio-label remaining in the incubation medium was markedly reduced after exposure to cells. This suggests that the tumor cells have the capability of degrading both insulin and glucagon. In a separate series of experiments, it was found that medium, in which freshly excised tumor cells had been incubated previously and then discarded, retained a substance which degraded 125I-labeled glucagon and that this degradation of glucagon could be blocked by co-incubation with aprotinin, a protease inhibitor.

Animals↗

PubMed1990

Evidence of 1,25-dihydroxyvitamin D synthesis by the rat Walker carcinosarcoma 256.

We tested the existence of 25-hydroxyvitamin D-1 alpha-hydroxylase activity in the Walker carcinosarcoma 256 implanted in rats. This tumour has been shown to induce hypercalcaemia in the host animal. We found this enzyme activity in tumour homogenates, which was in the same range as that in the kidney of tumour-bearing rats. Our results suggest that 1,25-dihydroxyvitamin D synthesized by the Walker tumour might be involved in the mechanism responsible for the hypercalcaemia in the host rat.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed1992

Isolation of a 18,000-Da molecular weight form of parathyroid hormone-related protein from the rat Walker carcinosarcoma 256.

The hypercalcaemic Walker carcinosarcoma 256 is a rat model for humoral hypercalcaemia of malignancy (HHM). Tumour products such as parathyroid hormone-related proteins (PTHRP) and various growth factors appear to be responsible for this syndrome. Recently, PTHRP immunoreactivity has been detected in the conditioned medium of Walker tumour cells. The present report describes the isolation of a 18,000-Da molecular weight form of PTHRP from Walker tumour homogenates, by using a relatively simple immunoaffinity purification method. Our results suggest that this PTHRP form is similar to that purified from other HHM-related tumours.

Animals↗

PubMed1991

A comparative PET study using different 11C-labelled amino acids in Walker 256 carcinosarcoma-bearing rats.

In Walker 256 carcinosarcoma-bearing rats, the dynamic distribution of L-[1-11C]tyrosine, L-[methyl-11C]methionine, L-[1-11C]methionine and D-[1-11C]methionine has been measured by PET. An equivalent tumor-imaging potential was observed for each of the three L-amino acids. Thirty minutes after injection, the tumors accumulated 57% (P less than 0.01) more 11C-activity from L-[1-11C]methionine than from L-[methyl-11C]methionine. At the same point of time, the livers showed a 33% (P less than 0.001) higher 11C-uptake with L-[methyl-11C]methionine than with L-[1-11C]methionine. The dynamic tissue data are in agreement with the findings in experiments with 14C-analogs.

Amino Acids↗