Biomedical subjects

Joseph G Sinkovics

Publications and source records attributed to Joseph G Sinkovics.

5 recordsLinked to original sources

PubMed2007

Adult human sarcomas. I. Basic science.

When connective tissue undergoes malignant transformation, glioblastomas and sarcomas arise. However, the ancient biochemical mechanisms, which are now operational in sarcomas distorted by mutations and gene fusions in misaligned chromosomes, were originally acquired by those cells that emerged during the Cambrian explosion. Preserved throughout evolution up to the genus Homo, these mechanisms dictate the apoptosis- and senescence-resistant immortality of malignant cells. A 'retroviral paradox' distinguishes human sarcomas from those of the animal world. In contrast to the retrovirally induced sarcomatous transformation of animal (avian, murine, feline and simian) cells, human sarcomas have so far failed to yield a causative retroviral isolate. However, the proto-oncogenes/oncogenes transduced from their host cells by retroviruses of animals are the same that are active in human sarcomas. Since the encoded oncoproteins arise after birth, they are recognized frequently by the immune system of the host. Immune lymphocytes that kill autologous sarcoma cells in vitro commonly fail to do so in vivo. Sarcoma vaccines generate immune T- and natural killer cell reactions; even when vaccinated patients do not show a clinical response, their tumors become more sensitive to chemotherapy. The aim of this review is to lay a solid molecular biological foundation for the conclusion that targeting the sarcoma oncogenes will result in regression of the disease.

B-Lymphocytes↗

PubMed2006

Evidence accumulating in support of cancer vaccines combined with chemotherapy: a pragmatic review of past and present efforts.

In the early 1970s supervised clinical trials were initiated at The University of Texas M.D. Anderson Hospital in Houston, TX, for the combination of viral oncolysate-based vaccines and contemporary chemotherapy for the treatment of patients with metastatic melanoma and sarcomas. This therapeutic approach was then generally considered to be inappropriate based on a widely held belief that the efficacy of cancer vaccines would be negated by the immunosuppressive effects of the chemotherapy. Not NCI grants, but institutional funds supported these clinical trials. These early clinical trials included in vitro tests for anti-tumor cell antibodies and cytotoxic lymphocytes both in autologous and allogeneic settings and showed that these faculties remained active even after chemotherapy. The contemporary reports of unexpectedly favorable clinical results are recited in this article. Despite these most promising results, support from federal granting agencies (the NIH/NCI) was repeatedly denied; these denials were based on the prevailing dogma that the two treatment modalities are expected to be antagonistic and not synergistic or not even additive. However, thirty years later, now in the new era of molecular medicine, a rapidly increasing number of peer-reviewed publications appear and offer convincing evidence that strongly substantiate the therapeutic value of combined cancer chemoimmunotherapy. The important provision is that the sequencing and dosing of the two major treatment modalities, the vaccination and the chemotherapy, are to be pre-tested and then the methodology is to be adhered to in the new clinical trials. New sophisticated experiments carried out in vitro and in vivo and subsequent clinical trials attest to the potential value of this combinatory approach and explain the underlying molecular mechanisms. This pragmatic review recapitulates the empirically administered earliest clinical trials, and lists and interprets, in view of their molecular immunomodulatory effects, the exemplary new clinical trials.

Antineoplastic Agents↗

PubMed2005

Human natural killer cells: a comprehensive review.

The senior author of this comprehensive review observed and reported in 1969 that his lymphocytes killed allogeneic tumor cells in vitro. Some of his research associates and technicians and other healthy individuals also yielded such killer lymphocytes. The team considered pre-immunization to cancer occurring in individuals after in-family or professional exposure to patients with cancer (in an era when the concept of viral etiology of cancer was receiving major support); or that lymphocytes can acquire through blastic transformation immune reactivity to allogeneic cells anew in vitro. The phenomenon was eventually referred to as 'lymphocytes practicing Burnet's immunosurveillance.' Project site visitors of the USA NCI first viewed these observations as a matter of 'in vitro artifacts' being in opposition to strong tumor- specific cytotoxicity of tumor-bearing patients' lymphocytes recognized in the vast majority of other assays. After NCI funds were released for intramural studies on the phenomenon of non-specific cytotoxicity by lymphocytes, recipients (other than the senior author) of these NCI funds later characterized (1973-1975) the 'indiscriminately' cytotoxic lymphocyte populations as those of 'natural killer (NK) cells.' In this article, the original observations made in 1969-1971 are reviewed based on genuine material preserved by the senior author and are explained in view of recent discoveries that were not available at the time of the original observations. NK cells display a fascinating history arising first in urochordates during the cambrian explosion. At that level, NK cells protected their hosts from incompatible cell colony fusions and against intracellular, especially viral, pathogens. Since then, viruses evolved evasive maneuvers to escape NK cell attack on the infected cells. NK cells persisted after the evolution of adaptive immunity in cartilaginous fish fitting seamlessly into the new system. In mammals, NK cells assumed the role of chief arbitrators between the fetal trophoblast and maternal immune reactions to the semi-allograft fetus. Tumors induce in NK cells the same (inactivating; mediating Th2-type immunity) reactions the fetal trophoblast engenders in utero, but NK cells may overcome the host's tolerance to its tumor and kill tumor cells, especially when converted into lymphokine-activated killer (LAK) cells by molecular mediators of Th1-type immunity. The authors prepare and utilize LAK cells and IL-2 for adoptive immunotherapy of patients with metastatic melanoma and kidney carcinoma. A patient with malignant ascites due to ovarian carcinoma entered remission on LAK cell therapy. Just as dendritic cells, the major antigen presentors, may undergo malignant transformation, NK cells are also subject to transformation into FasL-producer virulent lymphoma-leukemia cells. The senior author reported in 1970 a patient with 'lymphosarcoma cell leukemia' whose circulating lymphoma cells killed indiscriminately human sarcoma and carcinoma cells. The exemplary case history of another patient with NK cell lymphoma-leukemia treated by the authors is presented.

Adult↗

PubMed2004

Chondrosarcoma cell differentiation.

A mixed population of lymphocytes from a healthy donor co-existed with an established culture of allogeneic chondrosarcoma cells, during which time the tumor cells changed from malignantly transformed to benign fibroblast-like morphology; from multilayered to a monolayered growth pattern; lost their potency to grow in colonies in soft agar; and showed signs of senescence. A discussion of possible molecular mechanisms for this event is offered. If there are as yet undiscovered lymphokines that can induce reversal of the malignant geno/phenotype, the cognate gene(s) should be cloned for genetic engineering and for the mass production of the corresponding molecular mediators for clinical trials.

Cell Differentiation↗

PubMed1996

Contradictory Concepts in the Etiology and Regression of Kaposi's Sarcoma. The Ferenc Györkey Memorial Lecture.

The Introduction is an overview of 3 decades of works performed by Professor Ferenc Györkey (in many cases in collaboration with the author) and aimed at the elucidation of viral participation in the etiology of arteriosclerosis, SLE, hairy cell leukemia, HD, AIDS and KS. Controversial issues surrounding the etiology, treatment and regression of KS are discussed in terms of paracrine and autocrine loops of growth factors; protooncogene-oncogene activations, immunosuppression and retro- and/or herpesviral etiology. In regressing KS lesions the roles played by Fas, Bcl-2, Bax, TNFß; apoptotic-antiapoptotic events; and antiangiogenesis agents especially that of Hu-r-IFNa are elaborated on.

Journal Article↗