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INHIBITION OF SV40* TRANSFORMATION OF 3T3 CELLS BY INTERFERON 

INHIBITION OF SV40* TRANSFORMATION OF 3T3 CELLS BY INTERFERON 

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Objectives: To better understand how immune responses may be harnessed against breast cancer, we investigated which immune cell types and signalling pathways are required for spontaneous control of a mouse model of mammary adenocarcinoma. Methods: The NOP23 mammary adenocarcinoma cell line expressing epitopes derived from the ovalbumin model ant...

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... Indeed, inhibitory activity of interferons a, b and g against polyoma viruses, specifically against BK, JC and SV40 virus has been demonstrated. [60][61][62][63][64][65] The sequence of events is schematically outlined in Figure 3. ...
Article
A large number of epidemiological observations suggest an infectious origin of hematopoietic malignancies, including various forms of leukemia, nonHodgkin's lymphomas, Hodgkin's lymphomas and multiple myelomas. Incidence of nonHodgkin's lymphomas and Hodgkin's lymphomas, although not of leukemias, is substantially increased under immunosuppression. Specific chromosomal modifications (translocations) resulting in fusion genes frequently emerge as early, but not sufficient, events for malignant progression in most of these conditions. Presently less than 10% of the global incidence of leukemias and lymphomas can be linked to infections (Epstein-Barr virus, human T-lymphotropic retrovirus, human herpesvirus type 8 and Helicobacter pylori). For individual tumor types of the remaining more than 90%, several risk factors have been identified. They include occupational hazards, such as engagement in community services and agriculture, as well as time-space clustering. In childhood leukemias, a protective effect was noted for multiple infections during the first year of life and for at least 6 months of breastfeeding. A high socioeconomic state and absence of multiple contacts during the early phase of life have been described as risk factors. A hypothesis is presented here which combines these observations. It postulates a wide-spread viral infection, nontumorigenic when replication competent, but potentially leukemiogenic or carcinogenic when replication-incompetent viral genomes infect cells with specific chromosomal modifications. Existing data on polyoma-like virus types seem to render members of this or structurally related virus families as putative candidates for these malignancies.
... 3) Polyoma virus [3,179]. 4) SV 40 [177,179,230]. 5) Adenovirus [178]. ...
Interferon, a product of mammalian tissues, was originally described as an antiviral agent over twenty years ago. Only in the past few years has evidence started to accumulate that interferon actually played a role in vivo in natural virus infections.Initially, evidence was accumulated showing that interferon could inhibit the replication of many viruses in vitro. The interferon, through induction of a second antiviral protein, could inhibit in vitro viral transcription or translation. Later, indirect evidence for an effect of interferon on in vivo viral infections was obtained by showing that (a) a temporal relationship existed between the appearance of interferon in viral infections and the progress of the infection and (b) treatment of virally infected animals with exogenous interferon or interferon inducer often resulted in less severe infections.The most recent and direct evidence for a role for interferon in natural viral infections involves the use of an anti-interferon globulin. In several cases, injection of the anti-interferon globulin into animals infected with a wide variety of viruses resulted in a severely altered course of infection. These studies suggest that interferon is directly involved in the progress of viral infections. The involvement of the interferon in the viral infections could be a direct effect of the interferon on viral replication, or an interaction of the interferon with other host defenses, such as the immune system.
... Studies with simian virus 40 (SV40) seemed, however, to contradict the findings with infectious RNA (140). In agreement with the findings of Oxman et al. (96,102,103), the production of SV40 early mRNA and T antigen was markedly inhibited in interferon-treated monkey cells, when these cells were infected with intact SV40. If, however, infectious SV40 deoxyribonucleic acid (DNA) was employed, the results were directly opposite those obtained with infectious RNA. ...
... SV40 differs from the other DNA viruses discussed in that it lacks a structural RNA polymerase and so at least early in infection must depend on a cellular polymerase. Interferon treatment inhibited SV40 T antigen production in acutely infected, but not in transformed, cells (101,102). Transformation of mouse 3T3 cells by SV40 was also inhibited by interferon treatment (131). These results were consistent with a primary effect on either virus uncoating (140) or virus-directed transcription (103) or translation (52). ...
... SV40 is the only other DNA virus in which virus-directed protein synthesis in interferontreated cells has been studied at all. In interferon-treated cells there is marked inhibition of the synthesis of viral T antigen in lytic infections (102). This could have been due, however, either to the previously discussed inhibition of virus uncoating (140) or to inhibition of virusdirected transcription (103). ...
... In the case of the MOLON~Y strain of murine sarcoma virus (MSV-M), a defective virus genome has been 'rescued' by addition of an appropriate helper virus (Huebner et al. 1966). Interferon is known to inhibit virus protein synthesis and consequently the synthesis of the enzymes necessary for the replication of the virus genome, unless the latter is integrated in the cellular genome (Oxman & Black, 1966). It was postulated that in some cell populations transformed by oncogenic RNA viruses, interferon might affect the synthesis of virus antigens and the cells might recover some of the characteristics they possessed before transformation. ...
Article
Balb/c mouse embryonic fibroblasts were transformed in vitro by the murine sarcoma virus (MSV) (moloney strain). These cells have a disorderly growth pattern. When grown in soft agar 61% of them formed colonies. They contained ‘C’ type MSV particles and the transplantation antigen of the murine leukosis group of viruses. After 200 passages with interferon in the tissue culture medium, a cell line (MSV-IF+) emerged. This cell line recovered orderly growth and only 0.5% of the cells gave rise to colonies in soft agar. It contained about ten times more ‘C’ type particles than the original MSV cells. These particles harboured the MSV and leukaemia genome. The cells also retained the group and transplantation antigens. MSV-IF+ cells were completely resistant to exogenous interferon. When challenged with Newcastle disease virus they produced about ten times more interferon than the original MSV cells. Newcastle disease virus did not induce a refractory state to further interferon induction. When challenged five times every 48 hr the cells always produced a significant amount of interferon. It was postulated that this MSV-interferon cell line, unlike the original cell population, was not able to produce or use a repressor of interferon synthesis. In addition, the transformed cells recovered, to some degree, properties of the original normal cells.
Article
Treatment of Rous sarcoma virus-transformed rat cells with rat interferon-alpha (specific activity, 10(6) U/mg of protein) for 24 h caused a 50% reduction in intracellular pp60src-associated protein kinase activity. Staphylococcus aureus V8 protease digestion of pp60src, derived from 32P-labeled monolayer cultures incubated with or without interferon, revealed no differences either in the phosphopeptide pattern or in the phosphoserine-phosphotyrosine ratio. However, [3H]leucine pulse-labeling experiments showed that the synthesis of pp60src was reduced by 42 to 48%, relative to the level of bulk protein synthesis, in the interferon-treated cultures. Rat interferon-alpha also reduced the growth rate of Rous sarcoma virus-transformed rat cells in a dose-dependent manner over a 72-h period. The decrease in growth rate was accompanied by increases in the thickness and number of actin fibers per cell and by a decline in intracellular tyrosine phosphorylation by pp60src. The results suggest that interferon can inhibit the expression of the transformation-related phenotype by selectively reducing the synthesis of the Rous sarcoma virus transforming gene product. However, the interferon effects on the cytoskeletal organization and proliferation of Rous sarcoma virus-transformed cells may be due at least in part to the predominance of interferon-induced phenotypic changes over those caused by pp60src.
Chapter
Infection of 3T3 cells by SV40 virus was studied. SV40 produced in permissive cells a carrier state that progressed to the transformed state. Carrageenan was shown to block the immune response partially. A measure of the relative inhibition of normal and transformed 3T3 cells could be a test of the effectiveness of potential anticancer drugs in selectively inhibiting cancer cells and thus offers a possible screening procedure for potential anticancer drugs.
Article
T-antigens of transplanted hamster tumors induced by human adenovirus type 12 were studied by fluorescent antibody technique within 24 hours after differential hypothermia (DH) treatment, in which one side cheek pouch tumor was warmed at 37±1°C under generalized hypothermia of the body and the other side tumor at 20±1°C for 10 hours. A high proportion of the tumor cells in the viable portions of the control tumors demonstrated specific fluorescent staining in three type. The most striking and consistent pattern was the presence of numerous fluorescent particles in the cytoplasm, which were granular and fleck-like shapes. A second type of fluorescence was fluorescent particles in the nucleus in addition to the cytoplasmic staining, and a third type was homogenous staining of nucleus. Immediately after DH treatment, the treated warmed tumor cells presented diminution of fluorescent staining, especially large numbers of granular fluorescences in the cytoplasms. Fleck-like and homogenous nuclear staining of the treated tumor cells scattered even at 10 and 15 hours after DH treatment, when treated tumor cells revealed necrobiotic findings in sections of HE and nucleic acid stain. But no fluorescence was observed at 20 and 24 hours after DH treatment, while not-treated hypothermic tumor cells demonstrated about same fluorescent staining as control tumor cells. It was suggested that cytoplasmic granular fluorescence diminished because DH treatment had an effect on thermo-sensitivity of T-antigen because DH treatment had an effect on thermo-sensitivity of T-antigen and/or inhibited T-antigen production, as well as loss of fleck-like and hemogenous nuclear fluorescence was due to tumor cell necrosis by DH treatment.
Chapter
The word ‘interferon’ (Isaacs and Lindenmann 1957), or more correctly ‘interferons’, refers to a family of proteins defined by their capacity to induce antiviral activity in cells through cellular metabolic events that involve both RNA and protein synthesis (Levine 1964, Taylor-Papadimitriou 1964). Three main classes of interferons have been discovered, initially classified according to their antigenic properties: (1) α interferon (leukocyte interferon) produced by null lymphocytes, B-lymphocytes and macrophages; (2) β interferon (fibroblast interferon) produced by fibroblasts, epithelial cells, myoblasts and lymphoblasts; (3) γ interferon (immune interferon) produced by T-lymphocytes (for recent comprehensive information, see Stewart (1979) and Pestka (1981)).
Chapter
Die kanzerogene Wirkung von Viren läßt sich an den zahlreichen onkogenen Virusarten erkennen, die in verschiedenen Säugetier- und Vogelarten Tumoren oder Leukämien hervorrufen. Für eine Virusätiologie bestimmter Tumor- und Leukämieformen auch des Menschen bestehen sehr starke Hinweise. Der Beweis steht allerdings noch aus. Klinische Beobachtungen und epidemiologische Studien konnten bisher eine endgültige Beweisführung deshalb nicht erbringen, weil die onkogenen Funktionen dieser Viren nicht nach den Bedingungen der klassischen Infektionslehre ablaufen. Das betrifft vor allem die Tatsache, daß aus Tumoren oder dem tumortragenden Organismus das onkogene Virus nicht direkt, sondern nur durch indirekte, wenn auch spezifische Funktionszeichen und -merkmal nachgewiesen werden kann. Um sie exakter zu erkennen und damit möglicherweise die Aufklärung und Diagnose virusinduzierter Tumoren verbessern zu können, müssen zur Zeit vorwiegend experimentelle Arbeiten mit onkogenen Virusarten vorgenommen werden. Der Virusforschung stehen hier günstige experimentelle Modellsysteme zur Verfügung, mit denen die Mechanismen der Krebszellentstehung und Tumorbildung durch Viren bis in molekularbiologische Dimensionen hinein verfolgt werden können.
Chapter
The present chapter will focus on the action of compounds that affect translation and have a certain specificity in their action against cells infected with animal viruses.