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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infections with high-risk strains of human papillomaviruses (HPVs) and with herpes simplex virus type 2 (HSV 2), as well as inactivation of the p53 tumor suppressor gene, are important cofactors in cervical carcinogenesis. We analyzed 41 paraffin-embedded cervical intraepithelial lesions, including 25 cases of low-grade cervical intraepithelia neoplasia (CIN), and 16 cases of high-grade CIN for the presence of HPV 16/18 and HSV 2 genomic sequences and for the nuclear accumulation of the p53 protein. HPV 16 DNA was detected in 24.% of low-grade CINs and in 43.7% of high-grade CINs. HPV 18 was found only in 8.% of low-grade CINs. None of the cases tested scored positive for HSV 2 DNA. Nuclear accumulation of p53 was found in 4% of low-grade CINs, and in 31.2% of high-grade CINs, including 57.1% of the lesions that were positive for HPV 16. These results indicate that HPV 16 infection was over sixfold more common than HPV 18 infection and that p53 overexpression was significantly associated with high-grade lesions.
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PMID:p53 expression and genetic evidence for viral infection in intraepithelial neoplasia of the uterine cervix. 783 72

We have shown previously that overexpression of c-Ha-ras, v-mos or c-fos increases the spontaneous level of chromosomal aberrations and gene mutations in NIH 3T3 cells, and that reduction of the Fos protein level inhibits aberration induction by c-Ha-ras and v-mos and also by irradiation with ultraviolet light (van den Berg et al., Mol. Carcinogenesis, 4, 460-466). In order to examine whether fos is also involved in DNA recombination, thymidine kinase (tk) deficient human osteosarcoma cells containing two versions of the herpes simplex virus tk gene inactivated by base insertion were either transiently or stably transfected with various fos expression plasmids. The frequency of tk+ revertants was significantly enhanced both upon transient transfection with RSV-promoter-fos gene constructs and by stimulation of Fos synthesis in stably transfected cells harbouring an inducible metallothionein promoter-fos construct. No such increases were observed in cells transfected with plasmids containing a truncated version of c-fos. The data indicate that c-fos is involved in generating various types of genetic changes including homologous recombination; a role of c-fos in genetic instability may contribute to its action in tumor promotion and progression.
Carcinogenesis 1993 May
PMID:Overexpression of c-fos increases recombination frequency in human osteosarcoma cells. 809 16

Cancer of the head and neck has been associated with herpes simplex virus type-1 by serologic studies that have used virus particles or complex mixtures of viral proteins as antigens. Recently a peptide was found to be encoded by the transforming region of the virus that is mutagenic and is postulated to be involved in cell transformation. Sera from young adult patients with head and neck cancer and from control subjects were examined for the presence of antibody to this peptide with the use of an enzyme-linked immunosorbent assay. Antibody to the peptide was detected in many sera and showed a significant correlation with antibody to the virus in sera from control subjects. Antipeptide antibodies were largely of the IgM isotype, and patients had significantly higher levels of antibody than control subjects. This study is consistent with an association between HSV-1 and head and neck cancer and suggests that this viral peptide should be investigated further for its role in carcinogenesis.
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PMID:Antibody to a mutagenic peptide of herpes simplex virus in young adult patients with cancer of the head and neck. 838 64

Human papillomaviruses (HPVs) contribute to the development of benign and malignant cervical cancer; however, the exact role of papillomaviruses in the multistage carcinogenesis process is unclear. The development of HPV-immortalized cervical and foreskin cell lines represents a useful model for studying the role of HPVs in cervical cancer. Studies with these cells show that HPV genes regulate epithelial cell growth and differentiation. Transfection of HPV types associated with invasive cervical cancer results in immortalization of human epithelial cells, whereas HPVs not associated with cancer are ineffective. The combination of E6 and E7 genes, which are normally retained and expressed in cervical carcinomas, is sufficient for immortalization; however, the E7 gene alone induces immortality less efficiently. Although the immortalized cells actively express HPV oncoproteins observed in cervical cancer, after injection of immortal cells into nude mice, tumors are rare, having been reported only for HPV-18. Immortalized cells are resistant to terminal differentiation; in fact, HPVs may contribute to the carcinogenic process by uncoupling the processes of cell growth and differentiation. Host regulation of viral genes also is important in the malignant process. Endogenous cytokines modify HPV gene expression and influence the pathogenesis of HPV infection in the cervix. HPV gene expression is regulated by cellular transcriptional activators and repressors. This normal regulation is altered by viral integration. HPVs become integrated preferentially at chromosomal regions near fragile sites and protooncogenes. In fact, immortality is associated with induction of structural rearrangements frequently affecting HPV integration sites. Structural and numerical alterations nonrandomly involve chromosomes 1, 11, 19, and 20, with chromosome 1 alteration being the most predominant. Wild-type functions of Rb and p53 are necessary to control normal cell growth, and mutation or loss of these suppressor genes often contributes to cancer development. In HPV-containing carcinomas, pRb and p53 were wild type. However, in carcinomas lacking HPV, both suppressor genes were mutated. Functional inactivation of these tumor suppressor genes by HPV oncoproteins E6 and E7 may explain this difference. Treatment of HPV-immortalized cells with ras or a subfragment of herpes simplex virus (HSV) of HPV-immortalized cells resulted in locally invasive carcinomas when the cells were implanted subcutaneously in nude mice. These experiments indicate that HPV integration and expression are insufficient for malignancy but that HPVs do participate in the multistep development of cancer.
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PMID:Cellular and molecular alterations in human epithelial cells transformed by recombinant human papillomavirus DNA. 839 44

Gene therapy has now become a standard experimental approach for treating cancers that have failed conventional therapies. As the understanding of the molecular nature of carcinogenesis develops, new approaches are being taken to directly target tumor cells, thus bypassing the difficulties of killing cells that are resistant to chemotherapy and radiation. One emerging gene therapy approach has been through the genetic modification of tumor cells with a suicide gene such as the herpes simplex virus thymidine kinase gene (HSV-TK) and ganciclovir (GCV) therapy. Death of tumor cells modified with the HSV-TK gene leads to killing of unmodified in situ tumor cells in a phenomenon termed the "bystander effect." The basis both for this effect and other gene therapy trials underway for the treatment of cancer will be discussed.
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PMID:In situ use of suicide genes for cancer therapy. 860 30

High prevalence of both tobacco use and latent herpes simplex virus type 1 suggests the opportunity for synergism between these agents as cocarcinogens. In this study, postprimary human oral epithelial cell cultures were infected with herpes simplex virus type 1 pretreated with 2% extracts of either loose leaf, moist, or dry snuffs. Cultures were subsequently periodically exposed to the tobacco. Parameters measured included percentage of cultures undergoing active virus production, onset and time course of cytopathic effects, and concentration of virus released into the media over time. Results showed inhibition of both herpes simplex virus-mediated cell lysis and viral replication by tobacco extracts. This is the first time that these phenomena have been demonstrated in normal human oral epithelial cells. The work described here provides evidence to support a hypothesis that herpes simplex virus type 1 and smokeless tobacco may act synergistically in oral carcinogenesis.
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PMID:Attenuation of the natural course of herpes simplex virus infection in human oral epithelial cell cultures by smokeless tobacco extracts suggests the possibility of a synergistic mechanism for carcinogenesis. 885 Apr 86

Angiogenesis is an essential component of multifactorial carcinogenesis and thus a potential target of therapeutic intervention. To develop a novel cancer gene therapy strategy based on suppression of tumor angiogenesis, we examined the feasibility of targeting and preferential killing of proliferating endothelial cells by use of the von Willebrand factor (vWf) promoter and herpes simplex virus thymidine kinase gene (HSV-TK). Based on previous reports on the vWf promoter, we tested two putative vWf promoter regions. The luciferase assay showed that the shorter region, which encompasses most of the first noncoding exon, had stronger activity in endothelial cells. Although the promoter activity was low when employed as an internal promoter for retroviral and adenoviral vectors, endothelial cell specificity was suggested; the promoter, when used to drive the HSV-TK gene, could preferentially suppress endothelial cell growth in the presence of prodrug ganciclovir, suggesting the feasibility of designing an anti-angiogenesis gene therapy using the vWf promoter and the suicide gene/prodrug strategy.
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PMID:Use of von Willebrand factor promoter to transduce suicidal gene to human endothelial cells, HUVEC. 886 49

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which alkylates many positions in DNA including the 06 position of guanine, efficiently induces intrachromosomal homologous recombination in mouse L-cells. To investigate the role of 06-methylguanine in the induction of homologous recombination in human cells, three cell strains containing duplicated copies of the Herpes simplex virus I thymidine kinase (Htk) gene and three cell strains containing duplicated copies of the gene coding for hygromycin phosphotransferase (hyg) were treated with MNNG. Neither the Htk genes nor the hyg genes code for a functional enzyme because each contains an insertion mutation at a unique site, i.e. 8-bp XhoI linker insertions in the Htk genes and 10-bp HindIII linker insertions in the hyg genes. These cell strains differ in their level of 06-alkylguanine-DNA alkyltransferase (AGT), which specifically removes the methyl group from the 06 position of guanine. Generation of a functional Htk or hyg gene has been shown to require intrachromosomal homologous recombination between the two mutant Htk genes or the two mutant hyg genes. In all six cell strains, MNNG induced a dose-dependent increase in the frequency of homologous recombination. In each set, there was an inverse correlation between the frequency of MNNG-induced recombination and the level of AGT activity. To further study the role of 06-methylguanine in the induction of homologous recombination, we used 06-benzylguanine to inactivate AGT in two additional human cell strains containing the hyg recombination substrate. After depletion of AGT activity by 06-benzylguanine, both cell strains showed a significantly elevated level of MNNG-induced homologous recombination. These results indicate that 06-methylguanine is the principal lesion responsible for the induction of homologous recombination in these human cells by this methylating agent.
Carcinogenesis 1996 Oct
PMID:O6-methylguanine induces intrachromosomal homologous recombination in human cells. 889 93

Mutagenic metabolites produced due to chronic infection of cervical epithelium are suspected to be a plausible risk factor in cervical carcinogenesis. One hundred twenty-four symptomatic women attending a maternal and child health (MCH) clinic were studied clinically, cytologically, microbiologically, and biochemically for genital tract infections and for the presence of mutagens in the endocervical secretions using Ames' test. Human papillomavirus (HPV) was the leading infection (53.3%), followed by chlamydial infection (25.8%) and seropositivity for herpes simplex virus (25.1%). Mutagenic products in the endocervical secretions was detected in 23 women (18.5%). The univariate and multivariate (adjusted for other genital infections, age, and parity) analysis showed that the mutagenic mucus was associated with only chlamydial infection of endocervical region (OR = 3.7; 95% CI = 1.7,7.3). This shows that chlamydia is associated with mutagenicity of endocervical mucus.
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PMID:Mutagenicity of endocervical mucus associated with genital tract infections. 893 45

To investigate a possible cause-and-effect relationship between sexually transmitted diseases and cervical cancer, we performed a sero-epidemiological study on the presence of antibodies against a number of sexually transmitted agents (STAs) in patients with cervical cancer and their matched controls. In this study, we used serological techniques to investigate the presence of antibodies to cytomegalovirus, herpes simplex virus type 2, human immunodeficiency virus, Chlamydia trachomatis, Treponema pallidum and human papillomavirus (HPV) early protein E7 in sera from patients with cervical cancer, cervical intra-epithelial neoplasia and individually matched, healthy controls. The presence of antibodies to infectious agents other than HPV appeared not to be associated with risk of cervical neoplasia in either univariate or multivariate analysis. After adjustment for cytology, schooling and presence of HPV DNA in cervical scrapes, there was a significantly higher prevalence of antibodies to HPV-16 E7 protein in sera from patients with cervical cancer (OR = 3.6, 95% CI 1.0-12.9) than in healthy controls. The highest antibody prevalence was found among HPV-16 DNA-positive cervical cancer patients (33%). Our results indicate that in these study groups past infections with the STA considered seems to be of no apparent relevance for cervical carcinogenesis and that the HPV-16 anti-E7 response appears to be associated with cervical cancer.
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PMID:A sero-epidemiological study of the relationship between sexually transmitted agents and cervical cancer in Honduras. 939 51


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