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DNA methylation: gene expression regulation

Abstract

Epigenetic modifications are responsible for the modulation of gene expression without affecting the nucleotide sequence. The observed changes in transcriptional activity of genes in tumor tissue compared to normal tissue, are often the result of DNA methylation within the promoter sequences of these genes. This modification by attaching methyl groups to cytosines within CpG islands results in silencing of transcriptional activity of the gene, which in the case of tumor suppressor genes is manifested by abnormal cell cycle, proliferation and excessive destabilization of the repair processes. Further studies of epigenetic modifications will allow a better understanding of mechanisms of their action, including the interdependence between DNA methylation and activity of proteins crucial to the structure of chromatin and gene activity. Wider knowledge of epigenetic mechanisms involved in the process of malignant transformation and pharmacological regulation of the degree of DNA methylation provides an opportunity to improve the therapeutic actions in the fight against cancer.

Open access
Presence and role of Simian Virus 40 (SV40) in malignant pleural mesothelioma

Presence and role of Simian Virus 40 (SV40) in malignant pleural mesothelioma

Background. Evidence of a possible role of viruses in cancer first emerged in the early 1900s and was confirmed after the discovery of Epstein-Barr virus (EBV) in Burkitt's lymphoma cells. Thereafter, several oncogenic viruses and retroviruses were characterised. It is estimated that 15% of human malignancies are of viral aetiology. Oncogenic viruses use different proteins to interfere dramatically with the cellular cell cycle and affect many signalling pathways and checkpoints, causing genomic instability, immunoresistance and immortality.

Conclusions. Simian virus 40 (SV40) is a small DNA virus from the genus polyomavirus, closely related to human polyomaviruses John Cunningham virus (JCV) and BK virus (BKV) and is highly oncogenic for rodents. The virus accidentally entered the human population through contaminated early batches of polio vaccine in the 1960s. After the discovery of SV40-like DNA sequences in mesothelioma samples in 1994, a new wave of research started, focusing on the role of SV40 in malignant pleural mesothelioma and human cancer in general. Although the virus is not considered a cancer causing agent for humans, it is thought to have a (not yet defined) role in the development of the malignancy. Further research to better understand the interactions between the virus and the mesothelial cell is still ongoing.

Open access
Detection of Mutations in Selected Proto-Oncogenes of Canine Lymphoma

Abstract

Lymphomas belong among the most frequently diagnosed tumours of the haematopoietic system in dogs. The clinical manifestations and genetic and molecular basis of canine lymphoma resembles those of human non-Hodgkin lymphoma and therefore it can serve as a suitable model for the study of this disease. Neoplastic diseases are the consequence of a number of genetic and epigenetic changes in somatic cells. One of such changes are gene mutations that can subsequently cause changes in the activity of proto-oncogenes and tumour suppressor genes. The aim of our study was to detect potential mutations in selected exons of proto-oncogenes in DNA isolated from samples of lymphoma obtained from two donors - a Bernese Mountain Dog and a female mongrel. On the basis of literary data descriptions of human and canine haematopoietic neoplastic diseases, our investigations of potential changes in DNA focused on proto- oncogenes C-KIT - exons 8, 17; NRAS - exons 1, 2;FLT3 - exons 14, 15 and 20. The investigated samples were amplified by polymerase chain reaction (PCR) and subjected to sequencing. The DNA sequences were compared with reference sequences in the database Ensembl. The comparison of sequences of the C-KIT gene revealed an A/G transition at the 35th nucleotide of exon 8 in the mongrel. It involved a synonymous exchange of the nucleotide in the codon that did not cause a change in the amino acid. In the same sample we recorded several point mutations in the intron regions surrounding the exons 14 and 20 of the FLT3 gene. Changes in the intron regions can affect the expression of genes and thus can play an important role in the origin and development of tumours. No genetic mutations were detected in any gene regions of the Bernese Mountain Dog. In the case of the NRAS gene, no changes were observed in any sample collected from the donors.

Open access
Carcinogenesis induced by low-dose radiation

Abstract

Background

Although the effects of high dose radiation on human cells and tissues are relatively well defined, there is no consensus regarding the effects of low and very low radiation doses on the organism. Ionizing radiation has been shown to induce gene mutations and chromosome aberrations which are known to be involved in the process of carcinogenesis. The induction of secondary cancers is a challenging long-term side effect in oncologic patients treated with radiation. Medical sources of radiation like intensity modulated radiotherapy used in cancer treatment and computed tomography used in diagnostics, deliver very low doses of radiation to large volumes of healthy tissue, which might contribute to increased cancer rates in long surviving patients and in the general population. Research shows that because of the phenomena characteristic for low dose radiation the risk of cancer induction from exposure of healthy tissues to low dose radiation can be greater than the risk calculated from linear no-threshold model. Epidemiological data collected from radiation workers and atomic bomb survivors confirms that exposure to low dose radiation can contribute to increased cancer risk and also that the risk might correlate with the age at exposure.

Conclusions

Understanding the molecular mechanisms of response to low dose radiation is crucial for the proper evaluation of risks and benefits that stem from these exposures and should be considered in the radiotherapy treatment planning and in determining the allowed occupational exposures.

Open access
Polyamines and carcinogenesis

SUMMARY

The naturally occurring polyamines, spermine, spermidine and the diamine putrescine are widespread in nature. They have been implicated in growth and differentiation processes. In 1967, we reported that cancer cells are rich in polyamines. Subsequently, it has been shown that polyamines are released from cancer cells and may be detected in body fluids such as urine, blood and cerebrospinal fluids. It has also been demonstrated that the increase in cellular polyamine levels is an early and an obligatory event in the process of malignant transformation. This increase in cellular polyamine concentration is due to the activation of ornithine decarboxylase (ODC), which catalyses the rate limiting step in polyamine synthesis by converting ornithine to putrescine. Assays of urinary and blood polyamines have been used to detect cancer and to determine the success of therapy. A sensitive, rapid, chemiluminescence-based method for the determination of diamines and polyamines was developed and 2.000 urine samples were tested. An interesting "gene therapy" system for injecting amine oxidases into normal and transformed cells was developed as follows: serum amine oxidase and porcine kidney damine oxidase were trapped within reconstituted Sendai virus envelopes. Chick or rat fibroblasts, transformed by Rous sarcoma virus, were more susceptible to the injected enzymes, compared to the normal culture, when macromolecular synthesis was tested. An in vitro chemosensitivity assay for the testing of the sensitivity of cancer cells from individual patients ("tailored treatment") was also developed. All these studies stress the importance of polyamines in carcinogenesis.

Open access
Impact of Panax ginseng and Ginkgo biloba extracts on expression level of transcriptional factors and xenobiotic-metabolizing cytochrome P450 enzymes

Summary

Introduction: Despite widespread use of Panax ginseng and Ginkgo biloba, the data on the safety as well as herb-drug interactions are very limited. Therefore, we postulate that P. ginseng and G. biloba may modulate the activity and content of cytochrome P450 isozymes involved in the biotransformation of diverse xenobiotic substances. Objective: The aim of our study was to determine the influence of herbal remedies on the expression level of CYP enzymes and transcriptional factors. Methods: Male Wistar rats were given standardized Panax ginseng (30 mg/kg p.o.) or standardized Ginkgo biloba (200 mg/kg p.o.) for 3 and 10 days. The expression in liver tissue was analyzed by realtime PCR method. Results: Our results showed a decrease of CYP3A1 (homologue to human CYP3A4) mRNA level after P. ginseng extract treatment. The CYP2C6 (homologue to human CYP2C9) expression was also reduced. Additionally, after 10 days of the treatment with P. ginseng an increase of CYP1A1 (homologue to human CYP1A1) and CYP1A2 (homologue to human CYP1A2) expression was observed. Moreover, G. biloba extract also caused an increase of expression level for CYP1A1, CYP2C6, CYP3A1 and CYP3A2. Conclusion: Our findings suggest that herbal extracts can modulate the expression of transcriptional factors and CYP enzymes involved in xenobiotic metabolism and chemical carcinogenesis.

Open access