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J G Sinkovics

Publications and source records attributed to J G Sinkovics.

At least 19 recordsLinked to original sources
PubMed1992

Viral expressions in Reed-Sternberg cells.

In the murine system natural hybridoma formation was observed first in 1968-9. In the #620 to 818 system a mouse leukemia virus-(MLV-) producer diploid lymphoma cell fused with an immune plasma cell. The tetraploid fusion product cells grew in suspension cultures and as ascites tumors in mice and continued the production of MLV particles and MLV-neutralizing antibodies. Analogy between the #620 to 818 system and the origin of RS cells is proposed. Indirect evidence suggests retroviral infection of the mononuclear HD cell which presumably is an interdigitating reticulum (IR) cell. Reactive B and T cells interact in an abnormal manner and fuse with the retrovirally infected IR cell. The fusion product cells display hyperdiploidy and a disarray of markers as IR markers are lost due to dedifferentiation (and regained upon differentiation induction) and B and/or T cell markers are gained. Conventional theories for the origin of RS cells fail to explain the great heterogeneity of their markers. Derivation of RS cells from IR cells and B and/or T lymphocytes as natural hybridomas offers plausible explanation for all the features of RS cells.

Animals↗
PubMed1991

Kaposi's sarcoma: its 'oncogenes' and growth factors.

Viral genes capable of inducing vascular tumors in the skin of transgenic mice are the tat gene of HIV-1 and polyoma virus' middle T antigen gene. Instead of vascular tumors, the tat gene of HTLV-I causes thymic atrophy and mesenchymal tumors in transgenic mice. No proof exists that any of these genes contribute to the induction of KS but HIV-1 tat is a strong suspect. The gene product K-FGF of the oncogene K-fgf/hst (int) uses bFGF receptors, is homologous with bFGF and acts as a mitogen for fibroblasts, endothelial cells and melanocytes. The overexpression of the K-fgf gene in KS is not proven unequivocally; some doubts exist suggesting the activation of this gene during the laboratory procedure of transfection with KS cell heavy DNA. Growth factor(s) not well identified (IL-6?) are released from HTLV-I- or II, or HIV-1- or 2-infected T4 lymphocytes and in particular from HIV-1-infected macrophages. This growth factor(s) promote(s) the continuous proliferation of endothelial cells and KS cells. AIDS-KS cells release other growth factors identical with or closely related to basic FGF, a major inducer of angioneogenesis. In addition, acidic FGF, IL-1 alpha and -beta, GM-CSF, PDGF-B and TGF-beta are released from AIDS-KS cells. The release of GM-CSF is induced by IL-1. GM-CSF promotes granulocytic, monocytic and endothelial cell proliferation. TGF-beta is known to suppress lymphocyte-mediated cytotoxicity and may act as a local immunosuppressive factor together with interferon inactivators. We theorize that when TGF-beta production ceases, TNF-beta (lymphotoxin) production switches on leading to programmed cell death (apoptosis) of KS cells resulting in regression of these lesions. The newly discovered angiogenesis factors VEGF/VPF may emerge as protooncogene-oncogene products analogous to PDGF and c-sis activation. AIDS-KS heavy DNA transfects NIH3T3 cells. NIH3T3 cells carrying this gene induced angiosarcomas when implanted in mice. An as yet unidentified large virus (mycoplasma?) was derived from these cells during passages in culture. No causative relationship between this agent and Kaposi sarcoma has as yet been established. Even though IFN-alpha exerts antiretroviral effects in AIDS, we propose that the therapeutic effect of IFN-alpha in AIDS-KS is based on antiangiogenesis activity by suppressing protooncogenes-oncogenes of the FGF family.(ABSTRACT TRUNCATED AT 400 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1991

Viral oncolysates as human tumor vaccines.

Postoncolytic immunity entails immune reactions acquired through an oncolytic virus infection or through repeated immunizations with viral oncolysates (or virally modified tumor cell membranes) that are valid and operational also against virally not modified tumor cells of the same type. NK cells react to budding virions, induce target cell lysis primarily but not exclusively by the production of granzymes and pore-forming proteins and operate without direction from memory cells. In contrast, immune T cells (including some TIL) are MHC-restricted, act under the direction of memory cells and lyse target cells primarily but not exclusively by the release of lymphotoxin (TNF beta) causing programmed cell death (apoptosis) through endonuclease activation and target cell DNA fragmentation. This author proposes that it is not NK, but the immune T cells that mediate postoncolytic immunity. Oncogene amplification may protect immortalized tumor cells even when expressing peptide antigens through MHC molecules against lymphotoxin-mediated apoptosis; but virally-infected tumor cells releasing budding virions remain susceptible to NK cells. Highly immunogenic viral oncolysates should present both budding virions for NK cells and processed viral and tumoral peptide antigens co-jointly for immune T cells.

Cell Death↗
PubMed1991

Hodgkin's disease revisited: Reed-Sternberg cells as natural hybridomas.

The formation of natural hybridomas during the course of malignant lymphoproliferative diseases was first observed in 1969, and many times thereafter. This natural phenomenon remains experimentally unexplored even though it exerts fundamental influence on the natural history and outcome of neoplastic cell proliferations. Instead, hybridomas artificially constructed in the laboratory from 1975 on are being extensively studied and utilized for the production of highly specific monoclonal antibodies in the diagnosis and treatment of infectious and malignant diseases. This review lists examples of natural hybridomas formed in murine and human neoplasms. Indirect evidence supports the notion that hybridomas are generated in African Burkitt's lymphoma (BL) in the form of large, immunoresistant tetraploid BL cells emerging in immunoreactive relapsed patients; and in Hodgkin's disease (HD) in the form of Reed-Sternberg (RS) cells. RS cells may be formed when retroviral antigens expressed by the mononuclear HD cell attract reactive B and T cells, and instead of an immune attack by reactive cells, fusion with reactive cells takes place. The resulting RS cells may further fuse with other reactive cells (e.g., with two B cells, one expressing kappa, the other lambda light chains) or with each other, forming quadromas. RS cells appear multinucleated and hyperploid; they express the products of activated genes of the interdigitating dendritic cell (the retrovirally infected mononuclear HD cell) and those of reactive B and/or T cells. Thus, RS cells present themselves with a great variety of marker expression. Molecular mediators and immunoglobulins released from RS cells are responsible for the activities of proliferating polyclonal reactive cells and/or for the depletion of these cells in HD lesions. Multinucleated giant RS cells in anaplastic lymphomas and the syncytial subtype of RS cells of nodular sclerosing HD should be studied first for retro- or herpes viral antigen expressions and for fusion with reactive cells or with other RS cells.

Animals↗
PubMed1991

Programmed cell death (apoptosis): its virological and immunological connections (a review).

Programmed cell death is a physiological, energy-consuming mechanism leading to suicide of the cell. Cell death is accomplished by the activation of endonucleases that fragment the cell's nuclear DNA. Some tumour cells remain susceptible to programmed death. These are hormone- and growth factor-dependent tumour cells. Hormone or growth factor deprivation induces signals leading to apoptosis. Other tumours gain strong resistance to apoptosis. One of the normal functions of the bcl-2 gene is to provide longevity to memory B cells. When this gene becomes translocated in follicular B cell lymphomas, it renders lymphoma cells resistant to apoptosis. Latent membrane protein encoded by an EBV gene, either by itself or by amplifying bcl-2, enables tumour cells (nasopharyngeal carcinoma; Reed-Sternberg cell of Hodgkin's disease) to resist apoptotic death. Loss of antioncogene p53 provides for resistance against programmed cell death. Breakdown of resistance to apoptosis in tumour cells can be achieved by oncolytic viruses; generation of lymphotoxin and tumour necrosis factor; monoclonal antibodies; transfection with plasmid vectors carrying p53; gamma irradiation; and certain chemotherapeutic agents.

Autoantibodies↗
PubMed1988

Infiltration of interleukin-2-inducible killer cells in ascitic fluid and pleural effusions of advanced cancer patients.

Using ascitic fluid or pleural effusion obtained from 13 ovarian or metastatic breast cancer patients, we separated tumor cells from effusion-associated lymphocytes (EAL) with Percoll density centrifugation. Lymphocytes were incubated with recombinant interleukin 2 (IL-2) for 3-4 days and then assessed for tumoricidal activity in a 51chromium-release assay. The IL-2-activated EAL were found to lyse autologous fresh tumor cells, as well as allogeneic fresh tumor cells and FMEX tumor cells, a melanoma cell line which is resistant to natural killer cell activity but is sensitive to lysis by lymphokine-activated killer cells. There was little or no tumoricidal activity seen in freshly isolated EAL or in EAL which were cultured in medium without IL-2. Phenotypically, the IL-2-activated EAL were largely CD3-, although some cytolytic activity was found in CD3+ populations. Also, most activity was found in cells positive for CD2 (OKT11) and CD16 (Leu 11b), and negative for the monocyte marker Leu M3. These results indicate that the activated cell types found in EAL were predominantly natural killer/lymphokine-activated killer-like with a small contribution from T-cells. Finally, EAL were readily activated by IL-2 in medium containing autologous effusion fluid, indicating that in situ activation of tumoricidal activity by IL-2 can occur in the face of potentially inhibitory substances or cells that may exist in the effusions. Direct introduction of IL-2 may therefore be a potential therapeutic modality of effusion-forming cancers.

Adult↗
PubMed1988

Oncogenes and growth factors.

Certain polypeptide gene products regulate mitosis, differentiation, and other basic biologic functions of cells. These genes and their products are well preserved throughout evolution. Other sets of genes encode receptors for these polypeptides. Polypeptide growth factors can stimulate the cells that express receptors for them. Autocrine growth occurs when a cell produces a growth factor and also expresses receptors for it. When certain genes remain in a permanently switched-on position or are amplified, excessive amounts of growth factors are produced and receptor-positive cells continuously respond, thus achieving illegitimate growth advantage over other cells. Permanently switched-on and/or point-mutated receptor-encoding genes direct the synthesis of truncated receptors that do not need to capture their ligand for signaling receptor activation, thus their cells remain in a permanently activated state. When immortalization and/or malignant transformation results from these activities, the gene is recognized as a protooncogene-oncogene. Acutely transforming retroviruses contain close derivatives of these cellular genes (c-onc----v-onc) obtained through transduction. Genes encoding the synthesis of nontransforming growth factors (angiogenesis factors, colony-stimulating factors, interleukins, etc.) imitate protooncogenes in stimulating the growth and differentiation-dedifferentiation on nonimmortalized cells. Immortalized and malignantly transformed cells may retain receptors to regulatory growth factors that may induced differentiation and/or cessation of mitosis. Growth factors or receptors produced in excess by transformed cells may be neutralized by monoclonal antibodies (McAb) breaking the chain of autocrine or paracrine growth. Protooncogenes-oncogenes may be deactivated by biological response modifiers (dexamethasone, interferons, bacterial toxins, etc.). These interventions may lead to a new treatment modality for the malignant process.

Clinical Trials as Topic↗
PubMed1978

Transfer factor and possible applications in gynecology.

Dialyzable transfer factor (TFd) is reviewed against its historical background, preparation methods, physiochemical properties, possible mechanisms of action, pharmacology, and clinical studies, including several areas relating to gynecology. The possible role of TFd as an adjunct in the treatment of cancer is discussed. The discussion centers on gynecologic cancer in several patients who have received TFd. The difficulties and future possibilities for this modality of treatment are considered.

Animals↗
PubMed1978

Chemoimmunotherapy of small cell bronchogenic carcinoma.

Thirty-one patients with small cell bronchogenic carcinoma were treated with a regimen of cyclophosphamide, Adriamycin and vincristine. Radiotherapy was given to patients with limited disease. Nonspecific immunotherapy consisting of BCG scarification was administered after each chemotherapy course. The results of treatment for this group were compared with those for a group of 45 patients treated similarly but with no immunotherapy. Therapeutic results, expressed in length of survival and rate of response, were similar. Myelosuppression was not modified by the addition of BCG scarification. This study showed no benefit from the use of such nonspecific immunotherapy.

Adult↗
PubMed1978

Chemoimmunotherapy of sarcomatoid renal cell carcinoma.

Sarcomatoid renal adenocarcinomas are rare, invariably fatal tumors. There is only one report of treatment of this tumor with chemotherapy. We report a case of an advanced sarcomatoid renal adenocarcinoma treated with chemoimmunotherapy consisting of cyclophosphamide, vincristine, Adriamycin (doxorubicin), DTIC, BCG, and sarcoma viral oncolysate. The patient had an objective response with a marked reduction in the size of the tumor mass. The residual tumor was removed surgically, and the patient remains in complete remission two years after the diagnosis was made.

Abdominal Neoplasms↗