UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central theme of this communication is the recognition of an immunodiagnostic potential in a herpes virus antigen, the molecular interrelationship of which with cervical tumor cells is described. In addition to the productive infection caused by herpes simplex virus type 2 (HSV-2) we are confronted by latency and, as suggested by recent studies, by cancer. These different types of virus-host cell interactions are discussed at the host, as well as at the cellular level. A defined level of molecular interaction between host and viral gene products must exist if the virus is to co-exist with the host, as is the case in latency and carcinogenesis. The molecular interpretations posit the presence, in the squamous cervical tumor cells, of a product of the expression of the viral genome that has immunodiagnostic potential. The antigen designated AG-4 fulfills these predictions and appears to have immunodiagnostic potential. AG-4 is present in cervical tumor biopsies, but not in normal cervical tissue. It is a structural component of the HSV-2 virion that, in tissue cultures infected with HSV-2, is synthesized preferentially under conditions that prevent the normal replication of the virus. In view of its structural nature it is most probably virus-coded. AG-4 antibody identified in complement fixation assays with antigen prepared in tissue culture, disappears following successful tumor removal and reappears during cancer recurrence. This antibody also potentially identifies those patients with cervical atypia that are at high risk of neoplastic progression. The clinical benefits of the assay are evident.
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PMID:Immunodiagnostic potential of a virus-coded, tumor-associated antigen (AG-4) in cervical cancer. 19 36

Herpes simplex virus (HSV) infections can enhance the progression of neoplastic diseases. Since macrophages can be activated to become tumorilytic and may figure prominently in host defense against cancer, the ability of HSV to modify macrophage-mediated tumoricidal functions was evaluated. Murine peritoneal macrophages treated with HSV could not be activated to a tumoricidal state by mouse recombinant gamma-interferon (IFN-gamma). Addition of HSV 4 h after treatment with IFN-gamma, at a time when the macrophages are fully committed to developing the cytotoxic phenotype, blocked macrophage-mediated lysis of syngeneic melanoma target cells. This inhibition of activation and cytotoxicity was not due simply to uptake of virus particles, because treatment with heat-inactivated HSV at 4-h posttreatment with IFN-gamma had no effect. In addition, HSV did not undergo a productive infection within macrophages, suggesting that the observed inhibitory activity might be due to a virus-induced product. In this regard, treatment of macrophages with recombinant alpha-interferon suppressed the activation of these cells by IFN-gamma, suggesting that virus-induced alpha-interferon may be mediating all or part of the suppressive activity. These studies suggest that enhancement of tumor progression following HSV infection may be related to the virus-induced suppression of macrophage-mediated tumoricidal activity.
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PMID:Herpes simplex virus-induced suppression of macrophage-mediated tumoricidal activity in murine macrophages. 243 19

The alpha-fetoprotein (AFP) gene is normally expressed in fetal liver and transcriptionally silent in adult tissues, but can be abnormally reactivated in hepatocellular carcinoma (HCC). We linked 7.6 kb of 5'-flanking DNA from the mouse AFP gene to the herpes simplex virus (HSV) thymidine kinase gene (tk), and a line of transgenic mice was produced that expressed TK in a pattern similar to endogenous AFP. When these AFP/tk transgenic mice were crossed to another transgenic line that develops multifocal HCC due to expression of a SV40 large T-antigen transgene under regulation of the albumin promoter/enhancer complex, a significant delay of tumor progression could be achieved by administration of ganciclovir (GCV), a cytotoxic compound that is a substrate for phosphorylation by viral, but not mammalian, TK. Control animals carrying only the tk gene were unaffected by GCV treatment. These results illustrate the feasibility of prophylactic gene therapy for ablation of cancer, utilizing a strategy in which the tk gene is regulated by a promoter expected to be active only in tumor cells.
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PMID:Delayed morbidity and mortality of albumin/SV40 T-antigen transgenic mice after insertion of an alpha-fetoprotein/herpes virus thymidine kinase transgene and treatment with ganciclovir. 751 48

The replacement of functional genes into cells that lack genes or have mutant genes is the basis of gene therapy. In cancer, where cells often have multiple genetic defects, the replacement of critical genes may suffice to suppress cell growth or induce cell death. The high frequency of mutations of the p53 tumor-suppressor gene in human cancers, including primary brain tumors, suggests that p53 plays a critical role in carcinogenesis and tumor progression. We report the successful transfer of the wild-type p53 gene using a defective herpes simplex viral vector into a human medulloblastoma cell line containing a mutant copy of p53. Upon gene transfer, we detected novel expression of wild-type p53 protein in the cells. In addition, the p53 protein was functionally active, since gene transfer resulted in increased levels of mdm2 proteins and induced cell cycle arrest of the majority of transduced cells. To our knowledge, this is the first report of the use of this vector system to carry wild-type p53. We conclude that defective herpes simplex viral vectors can transfer and express p53 in human primary brain tumor cells in vitro, restoring wild-type p53 tumor-suppressor functions.
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PMID:Gene transfer of wild-type p53 results in restoration of tumor-suppressor function in a medulloblastoma cell line. 764 54

Retinoids (vitamin A and its natural and synthetic derivatives) have shown potential as chemopreventive agents, and diets poor in vitamin A and/or its precursor beta-carotene have been linked to an increased risk of cancer at several sites including the cervix. Human papillomavirus (HPV) plays an important role in the etiology of cervical cancer. We have developed an in vitro model of cancer progression using human keratinocytes (HKc) immortalized by HPV16 DNA (HKc/HPV16). Although immortal, early passage HKc/HPV16, like normal HKc, require epidermal growth factor (EGF) and bovine pituitary extract (BPE) for proliferation and undergo terminal differentiation in response to serum and calcium. However, following prolonged culture, growth factor independent HKc/HPV16 lines that no longer require EGF and BPE can be selected (HKc/GFI). Further selection of HKc/GFI produces lines that are resistant to serum- and calcium- induced terminal differentiation (HKc/DR). HKc/DR, but not early passage HKc/HPV16, are susceptible to malignant conversion following transfection with viral Harvey ras or Herpes simplex virus type II DNA. We have investigated the sensitivity of low to high passage HKc/HPV16 and HKc/GFI to growth control by all-trans-retinoic acid (RA, an active metabolite of vitamin A). Early passage HKc/HPV16 are very sensitive to growth inhibition by RA, and in these cells RA decreases the expression of the HPV16 oncogenes E6 and E7. However, as the cells progress in culture they lose their sensitivity to RA. Growth inhibition by RA may be mediated through the cytokine transforming growth factor-beta (TGF-beta), a potent inhibitor of epithelial cell proliferation. RA treatment of HKc/HPV16 and HKc/GFI results in a dose-and time-dependent induction (maximal of 3-fold) in secreted levels of TGF-beta. Also, Northern blot analysis of mRNA isolated from HKc/HPV16 demonstrated that RA treatment induced TGF-beta 1 and TGF-beta 2 expression about 3- and 50-fold, respectively. We next studied the effect of TGF-beta 1 and TGF-beta 2 on the proliferation of early to late passage HKc/HPVa6, HKc/GFI and HKc/DR. While early passage HKc/HPV16 were as sensitive as normal HKc to growth inhibition by TGF-beta 1 and TGF-beta 2, the cells became increasingly resistant to TGF-beta during in vitro progression, with the proliferation of HKc/DR being virtually unaffected by TGF-beta 1 or TGF-beta 2 treatment. Overall, loss of growth inhibition by RA parallels loss of TGF-beta sensitivity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Progressive loss of sensitivity to growth control by retinoic acid and transforming growth factor-beta at late stages of human papillomavirus type 16-initiated transformation of human keratinocytes. 764 23

Basic studies on transduction of the interleukin-2 (IL-2) gene into tumor cells were carried out in order to develop a new immunotherapy for head and neck carcinomas. We transduced the IL-2 gene into KB cells using defective herpes simplex viral (HSV) amplicon vector as the gene transfer vehicle. A high level of IL-2 was produced by IL-2 gene transduced KB cells (KB/IL-2). Human peripheral blood mononuclear cells (PBMC) cultured in medium containing the culture supernatant of KB/IL-2 cells showed stronger cytotoxic activity against KB cells than the control. In in vivo studies, high levels of IL-2 and interferon-gamma (IFN-gamma) were detected in the serum of nude mice transplanted with KB/IL-2 cells. The spleen cells of KB/IL-2 cell-transplanted nude mice exhibited high cytotoxic activity. Three of 5 nude mice transplanted with KB/IL-2 cells were completely cured of their tumor, and all 3 mice survived for over 120 days. All 5 nude mice transplanted with KB/lacZ cells, and all 5 nude mice transplanted with KB cells died within 120 days as a result of tumor progression. In conclusion, transduction of IL-2 gene tumor cells was corroborated by the high level of IL-2 produced by KB/IL-2 cells. The mechanisms of tumor rejection on KB/IL-2 transplanted nude mice were thought to be that effector cells stimulated by IL-2 derived from transplanted KB/IL-2 cells killed tumor cells, and IFN-gamma produced by activated NK cells showed a synergistic effect on tumor cells-killing.
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PMID:[Basic studies on IL-2 gene therapy for head and neck carcinoma]. 971 Oct 80

The introduction of therapeutic genes into proliferating tumor cells in vivo by direct intralesional injection of retroviral vectors can provide an effective and valuable approach for the treatment of a variety of solid tumor types. Efficient transduction of tumor cells in situ by direct injection was demonstrated using a retroviral vector containing the beta-galactosidase (beta-gal) gene. Ablation therapy in vivo was demonstrated using a retroviral vector containing the Herpes simplex virus thymidine kinase gene (HSV-TK) to deliver the TK gene into the murine colorectal tumor cell line CT26. Ablation of CT26 tumor cells in situ was achieved by directly injecting high-titer HSV-TK retroviral vector preparations into the site of tumor cell inoculation followed by intraperitoneal (i.p.) delivery of ganciclovir (GCV). This gene therapy strategy demonstrated a markedly lower rate of tumor progression, with several complete regressions, compared to animals in control groups. We also demonstrated that resistance to subsequent challenges with unmodified CT26 cells and an enhanced cellular immune response is associated with tumor regression in immunocompetent animals. Our results demonstrate the feasibility of direct in situ administration of HSV-TK retroviral vectors for the treatment of cancer and suggest that a cellular immune response may be elicited by this therapy.
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PMID:Ablation of tumor cells in vivo by direct injection of HSV-thymidine kinase retroviral vector and ganciclovir therapy. 1041 79

Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses <==2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.
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PMID:Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. 1093 31

Previous uncontrolled clinical trials have shown the in vivo retrovirus (RV)-mediated transduction of glioblastoma cells with the herpes simplex virus thymidine kinase (HSV-tk) gene and subsequent systemic treatment with ganciclovir to be feasible and well tolerated. However, because of continued tumor progression in most patients, the antitumor effect could not be determined using historical controls. Here, we describe a phase III, multicenter, randomized, open-label, parallel-group, controlled trial of the technique in the treatment of 248 patients with newly diagnosed, previously untreated glioblastoma multiforme (GBM). Patients received, in equal numbers, either standard therapy (surgical resection and radiotherapy) or standard therapy plus adjuvant gene therapy during surgery. Progression-free median survival in the gene therapy group was 180 days compared with 183 days in control subjects. Median survival was 365 versus 354 days, and 12-month survival rates were 50 versus 55% in the gene therapy and control groups, respectively. These differences were not significant. Therefore, the adjuvant treatment improved neither time to tumor progression nor overall survival time, although the feasibility and good biosafety profile of this gene therapy strategy were further supported. The failure of this specific protocol may be due mainly to the presumably poor rate of delivery of the HSV-tk gene to tumor cells. In addition, the current mode of manual injection of vector-producing cells with a nonmigratory fibroblast phenotype limits the distribution of these cells and the released replication-deficient RV vectors to the immediate vicinity of the needle track. Further evaluation of the RV-mediated gene therapy strategy must incorporate refinements such as improved delivery of vectors and transgenes to the tumor cells, noninvasive in vivo assessment of transduction rates, and improved delivery of the prodrug across the blood-brain and blood-tumor barrier to the transduced tumor cells.
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PMID:A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. 1109 43

Herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) therapy was performed in five cases of recurrent glioblastoma multiforme. In the last study, the authors demonstrated response of the HSV-TK/GCV therapy against tumor progression (Adachi N, et al.: No Shinkei Geka). The aim of this study is to estimate the biosafety of in vivo HSV-TK gene transfer and GCV administration in five cases. Six parameters were analyzed sequentially up to the 6th month after the vector producer cells (VPCs) inoculation as follows; i) clinical symptom, ii) vital sign, iii) peripheral blood cell count, iv) blood biochemical analysis, v) serological test, vi) molecular biological test in peripheral leukocytes. In addition, ten systemic organs extracted from the two subjects in whom death occurred were also analyzed biologically. One case suffered from transient deterioration of left hemiparesis on the 34th day, which could be considered a probably-related but not adverse event. Serological tests detected anti-VPC antibody at the 1st month in one case and anti-vector antibody at the 1st and 4th month in another. The other examinations revealed no abnormal findings at all. These data indicate that the HSV-TK/GCV therapy might be a satisfactorily safe approach against glioblastoma multiforme.
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PMID:[The biosafety of the HSV-TK/GCV gene therapy in five cases of recurrent glioblastoma multiforme]. 1112 92

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