Carcinogenicity of benzo[a]pyrene and thirteen of its derivatives in C3H/fCum mice.
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In combination with chemotherapy [ftorafur (FT)], allogeneic lymphoid cells were transferred to inhibit the growth of a 3-methylcholanthrene-induced transplantable KMT-17 fibrosarcoma in Wistar-King-Aptekman/Hok rats. The transference of allogeneic lymphoid cells 4 days after tumor inoculation did not prove effective in inhibiting the growth of the tumor; administration of FT (300 mg/kg) on Day 3 resulted in a 16.7% survival rate. However, a combination of the transfer of cells and administration of FT resulted in an improved effect of 55.0%. A low dose of FT (100 mg/kg) also increased the therapeutic effect in combination with allogeneic lymphoid cell transfer (28.0%). However, a high dose of FT (500 mg/kg) did not increase the therapeutic effect (30.0%), even if combined with allogeneic lymphoid cell transfer on Day 2, 4, 6, or 9, although a high dose of FT administered alone on Day 4 showed a direct antitumor effect (32.0%). This effect was rather diminished when the transfer was combined on Day 2. (7.1%). The differences in the combination effect of doses of FT seem to depend on the immune status of the host induced by treatment with FT. In order to investigate the mechanism of combination timing of FT and allogeneic lymphoid cell transfer, the specific delayed hypersensitivity reaction to KMT-17 tumor was assayed by the radioisotopic footpad method. The specific delayed hypersensitivity reaction was strengthened by an injection of FT (300 mg/kg).
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[14C]Misonidazole (MISO) becomes bound to macromolecules of mammalian cells upon hypoxic incubation. Intracellular enzyme processes are implicated since the temperature dependence for this process showed an activation energy of 33.5 kcal/mol. The sensitizer bound to both hypoxic and aerobic cells was associated with the macromolecular fraction and the soluble fraction in the proportion, 23 and 77%, respectively. The initial rate of binding of [14C]MISO to the macromolecular (acid-insoluble) fraction of hypoxic EMT-6 mouse tumor and V-79 hamster cells increased proportionally with the square root of extracellular concentration of MISO up to at least 5mM. High concentrations of dimethyl sulfoxide (an effective OH radical scavenger), allopurinol (an effective inhibitor of xanthine oxidase), and diamide (a chemical which can deplete cellular levels of glutathione) had little or no effect on this metabolism-induced binding process. The addition of high concentrations of exogenous cysteamine to hypoxic cell cultures resulted in almost complete inhibition of binding. Extracellular bovine albumin at high concentration in hypoxic cell cultures had little effect on the production of adducts to cell macromolecules and only small amounts of [14C]MISO were found to bind to the extra-cellular bovine albumin. This result suggests that MISO preferentially binds to molecules within the cell in which it is metabolically activated. In experiments where cells labeled under hypoxic conditions with [14C]MISO were subsequently permitted to proliferate in aerobic monolayers, a half-life of the acid-insoluble addition products of approximately 55 hr was measured. A large number of [14C]MISO adducts (approximately 10(9)/cell) can be generated in hypoxic cells without any evidence of cytotoxicity, and they are slowly cleared from cells. These are favorable characteristics as regards the development of this technique as a marker for hypoxic cells in solid tumors.
Murine fibrosarcoma cells can be separated into subpopulations by centrifugation through 10 to 35% Renografin density gradients. Previous work has shown that the heavier cell populations are rich in chronically hypoxic cells. In this study, each subpopulation was characterized for thymidine incorporation, thymidine transport, thymidine triphosphate pool sizes, and thymidine triphosphate specific activities. The heavier cell populations have less accessibility to exogenous thymidine, and they have lower endogenous pools of thymidine triphosphate and synthesize lower levels of DNA than do the lighter cell populations. However, if the cells are removed from the tumors and labeled with [3H]thymidine in vitro, all subpopulations synthesize DNA at similar rates. Two-parameter flow cytometry using acridine orange staining following partial acid denaturation of chromatin identified a small quiescent population in the most dense cell fraction, but the small number of these cells cannot account for the results of the biochemical studies. It appears that the hypoxic cells in the fibrosarcoma tumors are noncycling or slowly cycling, are in all phases of the cell cycle, and recover their ability to synthesize DNA when cultured under in vitro conditions.
Malignancy and antigenicity of fibrosarcoma Meth 1 cells induced in a BALB/c mouse were compared with sarcoma Meth A cells. Furthermore, antitumor effect of levamisole (LMS) against Meth 1 cells and its immunological mechanism were studied. 1) The lifespan of BALB/c mice inoculated i.p. with 10(2) Meth 1 cells was prolonged by the treatment with LMS. 2) Growth of s.c. inoculated secondary tumors was tumor-specifically inhibited in solid Meth 1-bearing mice as compared with that in non-tumor-bearing mice. Administration of LMS (0.625 or 2.5 mg/kg) augmented the growth inhibition of these secondary tumors. 3) Spleen cells of Meth 1-bearing mice showed a growth-inhibitory activity against Meth 1 cells in Winn assay. LMS (0.625 or 2.5 mg/kg) augmented such a growth-inhibitory activity of spleen cells. The activity was attributed to non-adherent, thy 1-positive spleen cells.
We have studied the attachment of mouse fibroblasts, transformed nonmetastatic fibroblasts, and metastatic fibrosarcoma cells to various substrates. The metastatic cells attach preferentially to type IV (basement membrane) collagen in the absence of serum, compared to type I collagen and plastic. In the presence of fibronectin, these cells attach well to both type I and type IV collagens. The normal and transformed fibroblasts attach to all these substrates, although the transformed fibroblasts attach more slowly. The ability to attach to type I collagen and plastic is correlated with the levels of fibronectin and collagen produced by these cells. The data indicate that the transformed and metastatic cells differ from normal cells in their attachment properties and ability to synthesize matrix proteins. The metastatic cells possess a unique system for binding to type IV collagen that could be important in enabling these cells to penetrate tissues bounded by basement membranes.
This paper reports the lack of genetic linkage between spontaneous production of substantial amounts of infectious xenotropic (X-tropic) virus and the susceptibility to chemically induced cancers in two inbred strains of mice, NZB/BLNJ and 129/J, and their genetic crosses. The parental strains and F1, backcross, and F2 progeny between these two strains were partially splenectomized to ascertain X-tropic viral status and were subsequently treated s.c. with 500 microgram of 3-methylcholanthrene in trioctanoin. Progeny from second backcrosses [(F1 X 129) X 129] were also tested for their X-tropic viral status and susceptibility to 3-methylcholanthrene carcinogenesis. Mice were observed for evidence of fibrosarcomas at the site of inoculation over a 10-month period. In this genetic system, spontaneous production of high titers of X-tropic virus segregated as a single autosomal dominant gene. Susceptibility to 3-methylcholanthrene-induced fibrosarcomas did not segregate in these crosses, and susceptibility did not correlate with the degree of X-tropic virus expression.
Patients with malignant bone tumours often come at a very late stage of disease to Medical Colleges. Because of their high mortality rate, accurate & quick diagnosis of these lesions become essential, inspite of clinical, radiological and histopathological assessments. A simple, inexpensive, safe & least traumatic technique-fine needle aspiration cytology (FNAC) in diagnosis of 55 malignant bone tumours was carried out. Specific tumour types metastatic tumour (12), Giant cell tumour (12), Ewing's sarcoma (10), Osteosarcoma (7), Multiple myeloma (7), Chordoma (3), Chondrosarcoma (3) and Fibrosarcoma (1) could be ascertained in 87.2% whereas malignant tumour was suggested in 94.5% (52 cases).
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Macrophage accumulation during the growth of a peritoneal ascites and three s.c. tumors in two animal species was analyzed and correlated with the capacity of the same tumor-bearing host to respond to inflammatory stimuli at sites distant to the tumor. Two of the three s.c. tumors induced systemic defects in macrophage accumulation; the tumor that did not (P-815 mastocytoma) did depress inflammation when transplanted to the peritoneal site. Macrophage accumulation within different tumors varied but, for a given tumor, it occurred in proportion to tumor growth when systemic inflammatory reactions were normal. However, the tumor to macrophage ratio increased dramatically and concurrently with onset of the generalized defect in macrophage inflammatory responsiveness. Accordingly, we concluded that macrophage mobility tested at remote sites is indicative of inflammatory events within the tumor. However, the antiinflammatory effect directed against macrophages is probably not a significant factor in tumor emergence since the required number of tumor cells was large and variable between not only tumors but also sites of transplantation.
In order to study possible connections between Dupuytren's contracture and sarcoma we analysed the records of 18 patients who developed sarcoma 5 years or more after surgery for Dupuytren's contracture. We found an increased frequency of fibrosarcoma and malignant fibrous histiocytoma, but these patients did not differ from the other patients in the study group. Our analysis suggests that neither smoking, diabetes nor cancer syndromes can explain why patients with Dupuytren's contracture have a higher incidence of sarcoma.
The treatment of foot sarcomas is generally a below knee amputation. In selected sarcomas of the forefoot, however, a transtarsal amputation according to Chopart, a calcaneotibial arthrodesis according to Pirogoff, or a supramalleolar amputation according to Syme can be considered the treatment of choice, leading to an optimal functional outcome.
From the records of Memorial Hospital of the past 50 years, 47 cases with an established diagnosis of radiation-induced sarcoma were identified and divided into two groups: the first included 20 cases of soft-tissue sarcoma arising from irradiated tissues, and the second comprised 27 cases of bone sarcoma arising from normal bones in the irradiated field. Medians for the latent periods from irradiation to diagnosis of bone and soft-tissue sarcoma were 11 and 12, years, respectively. In bone sarcomas, the latent period was longer after larger radiation doses and children appeared to be more susceptible to cancer induction than adults. Criteria for establishing the diagnosis of radiation-induced sarcoma and the magnitude of the risk of bone sarcoma are discussed.
Six cases of hepatic sarcoma are reported: leiomyosarcoma in two, malignant fibrous histiocytoma in two malignant hemagiopericytoma in one and fibrosarcoma in one. In addition to the routine paraffin section and HE stain, immuno-histochemical studies with antibodies against vimentin, EMA, CK, S100, ACT, AAT, desmin, AFP, lysozyme and factor VIII and Masson trichrome staining and argyrophilia staining were done. AFP was negative in all 6 patients and the primary sarcoma was characterized by the absence of accompanying liver cirrhosis. The diagnosis, histogenesis and prognosis of primary liver sarcoma are discussed.
The mitogenic responsiveness of peripheral blood lymphocytes obtained from Fischer 344 rats inoculated with avian sarcoma virus was studied. In addition, quantitative alterations in lymphocyte subpopulations were determined in these animals. Only peripheral blood lymphocytes from rats bearing astrocytomas had significantly diminished responses to concanavalin A when compared to control responses. The percentage of lymphocyte subpopulations detected in either the peripheral blood or spleen of tumor-bearing rats did not differ from values obtained with control rats. However, rats bearing astrocytomas had a marked decrease in the absolute number of the various lymphocyte subpopulations as a result of lymphopenia. Neither the sarcoma-bearing rats nor the virus-inoculated rats that did not develop tumors exhibited this lymphopenia. In addition, sera from rats bearing astrocytomas diminished the concanavalin A reactivity of spleen cells obtained from normal rats. The results of this study establish the avian sarcoma virus-induced rat astrocytoma model as a useful immunological parallel for the human disease.
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