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Structural patterns and histological behaviour of experimental sarcomas. I. General considerations, histology and histochemistry.

Methylcholanthrene-induced rat sarcomas were used as a model for the examination of morphological and cytological differentiations in tumours of the connective tissue. Particular attention was paid to the question how far these sarcomas are comparable to human connective tissue tumours. The histological examination yields a broad spectrum of mesenchymal differentiations ranging from undifferentiated anaplastic sarcomas over less differentiated fibrosarcomas and malignant fibrous histocytomas to well-differentiated fibrosarcomas, myosarcomas and haemangiopericytomas. It is worth mentioning that different histological structures can be encountered with one and the same tumour.

Animals

Structural patterns and histological behaviour of experimental sarcomas. II. Ultrastructural cytology.

In continuation of our investigations on methylcholanthrene-induced rat sarcomas, in analogy to light microscopical results, various cytological differentiations could be demonstrated by the electron microscope. Some tumour cells are comparable to the cellular counterpart in normal connective tissue, whereas most of the tumour cells show various series of cytological traits of different types of normal connective tissue cells simultaneously. The vast majority of tumour cells exhibited characteristics of fibroblasts and histiocytes coincidently. However, classical fibroblasts and histiocytes were seldom present. One part of the tumour cells showed structural features as known from so-called myofibroblasts and smooth muscles cells. Furthermore, vasoformative potencies of sarcomas with imitation of endothelial and pericytic cells must be emphasized. With respect to the histogenesis of these sarcomas possible origin from the microvasculature is discussed.

Animals

Antibiotic treatment, intestinal aerobic microflora and experimental sarcoma L-1 growth in Balb/c-mice.

The present paper deals with the influence of a 10 days treatment with mezlocillin, piperacillin, cefotaxime, clindamycin or gentamicin on the endogenous intestinal microflora of Balb/c-mice and on the local growth of sarcoma L-1 tumor. Clindamycin and gentamicin demonstrated no influence, whereas cefotaxime and piperacillin caused the eradication of gram-negative resp. gram-positive bacteria but these antibiotics didn't produce a growth inhibition of local L-1 sarcoma tumor. The oral or parenteral application of mezlocillin (a 3 days treatment was sufficient) eradicated the complete aerobic and anaerobic intestinal microflora. This effect was significantly correlated with an increase of the cecum weight and the inhibition of local tumor growth. Possible mechanisms of these effects are discussed.

Animals

Effect of prophylactic and therapeutic administration of BCG vaccine on growth of experimental sarcoma.

The effect of prophylactic and therapeutic administration of BCG vaccine on growth of transplantable sarcomas induced by MSV-Harvey (MSVT1) and 3-methylcholanthrene (MC 11 and MC 12) in C57BL/10Sn mice was studied. Growth of MSVT1 sarcomas was not inhibited by oral or intratumoral BCG therapy. Nor was prophylactic oral administration of BCG followed by therapeutic oral BCG treatment effective. On the other hand, intradermal administration of an adequate dose of BCG vaccine preceding the tumour transplantation inhibited tumour growth. The low (0.05-0.2 mg.) doses of BCG induced resistance comparable to the effect of subcutaneous immunization with tumour cells, whereas the higher (0.5-1.0 mg) doses had no effect. Growth of MC 11 and MC 12 tumours was not affected by prophylactic intradermal BCG administration.

Administration, Oral

[Combined effect of hyperglycemia and chemo- and radiation action on the status of metabolic processes in certain experimental sarcomas in rats].

A number of metabolic parametres were studied in subcellular fractions of rat sarcoma 45, M-1 and carcinosarcoma Worker 256. Administration of high doses of glucose amplified some effects of chemotherapeutic drugs and X-ray therapy, which were manifested as follows: a decrease in glycolysis rate, alteration in the rate of redox reactions, shifts in the ratio between glycolysis and biological oxidation in mitochondria. These alterations were determined by the type of sarcoma, by sequence of operations in the procedure and by cytostatic used. The most effective procedure proved to be simultaneous administration of drugs and X-ray therapy followed by hyperglycemia. Distinct inhibition of glycolysis defected under these conditions may contribute to inhibition of energy metabolism during the sarcoma growth and regression.

Amino Acids

Cancer cachexia is transmissible in plasma.

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.

Animals

Selective depletion of tumor ATP by 2-deoxyglucose and insulin, detected by 31P magnetic resonance spectroscopy.

The purpose of this study was to investigate whether substrate deprivation acutely and selectively decreases ATP concentration in an experimental sarcoma. Two methods of substrate deprivation were examined: glycolysis was inhibited using 2-deoxyglucose (2DG), and plasma substrate levels were reduced using insulin. The effects of treatment on tumor ATP, inorganic phosphate, and pH were studied by 31P nuclear magnetic resonance spectroscopy. 2DG (2 g/kg) was administered i.p. to rats bearing s.c. methylcholanthrene-induced sarcomas. Inhibition of glycolysis by 2DG caused a 52 +/- 13% (SE) decrease in the tumor ATP to inorganic phosphate ratio, associated with a decrease in pH of 0.38 +/- 0.10 unit. The same dose of 2DG caused no significant change in the ratio of phosphocreatine to ATP in brain. Insulin (125 units/kg, i.p.) caused a 68% decline in plasma glucose and a 71% decline in betahydroxybutyrate compared to saline-treated animals. Concomitantly, 31P nuclear magnetic resonance spectroscopy detected a 48 +/- 13% decrease in sarcoma ATP, with a reciprocal elevation of inorganic phosphate in insulin-treated animals. In contrast, the brain phosphocratine/ATP ratio was unaffected by insulin. These results suggest that large tumors are acutely sensitive to inhibition of glycolysis and reductions in plasma levels of substrates for oxidative phosphorylation and glycolysis, while the brain is unaffected. In addition, this work provides support for the use of 31P nuclear magnetic resonance spectroscopy to monitor tumor response to therapy.

Adenosine Triphosphate

Characterization of the pseudocapsule of soft-tissue sarcomas. An experimental study in rats.

The effect of preoperative radiation therapy on the pseudocapsule of experimental rat soft-tissue sarcomas has not been histologically evaluated in a controlled study. The irradiated animal showed marked thickening of the capsular structure surrounding the sarcoma. Everywhere morphologically distinct from the tumor, there was no evidence of tumor invasion into or through this capsular structure. The membrane was consistently thicker and more hyalinized than in the control animals. The nonirradiated animals showed a minimal pseudocapsular structure with a characteristic tumor penetration. Irradiation produced distinct histologic changes in the pseudocapsule. Although assumed on the basis of clinical observations alone, irradiation-induced pseudocapsule has not previously been demonstrated in an experimental model of soft-tissue sarcoma.

Animals

In adequate tumor surgery of chemically induced soft tissue sarcomas--an experimental approach for induction of metastasis formation?

In preceding experiments with nude mice bearing xenotransplanted soft tissue sarcomas after inoculation of cultured sarcoma cells we attained a high percentage of metastatic dissemination by repeated inadequate tumor surgery. In the study presented here we used methylcholanthrene induced sarcomas (rhabdomyosarcomas and undifferentiated sarcomas in part showing the picture of storiform/pleomorphic malignant fibrous histiocytomas) which were produced in NMRI mice and examined (1) whether or not metastasis formation could be triggered or enhanced by repeated inadequate tumor surgery in these animals, and (2) the efficacy of the same surgical procedure following xenotransplantation of the tumors into nude mice. We did not reach an increasing frequency with both experimental arrangements. After discussing several factors which could be in general responsible for inducing metastasis formation and after comparing the results of our several experiments it is suggested that the methylcholanthrene induced soft tissue tumors may not contain cell clones able to metastasize.

Animals

Laboratory investigation, genetics, and experimental models in sarcomas.

The sarcomas, particularly those of soft-tissue origin, pose substantial diagnostic challenges for the clinician and pathologist. Several small round cell sarcomas, including Ewing's sarcoma, peripheral primitive neuroectodermal tumor, and alveolar rhabdomyosarcoma, can be difficult to distinguish from one another. These same sarcomas can be difficult to distinguish from other small round cell tumors, including non-Hodgkin's lymphoma and neuroblastoma. Spindle cell sarcomas, including malignant peripheral nerve sheath tumor, synovial sarcoma, and leiomyosarcoma, present similar diagnostic challenges. This review discusses 1) recent advances in immunohistochemistry, electron microscopy, and cytogenetics that enable a specific diagnosis in virtually all sarcoma cases; 2) cell biology and oncogenetic implications of novel morphologic and genetic findings in sarcomas; and 3) clinical implications of the recent characterization of several family cancer syndrome genes.

Animals