The role of genetic factors in predisposition to squamous cell cancer of the head and neck

© 1999 Cancer Research Campaig

Genome Instability and Bleomicin Sensitivity Test

Procjena individualne osjetljivosti na mutagene često je dio istraživanja u epidemiološkim studijama koje prate pojavnost zloćudnih bolesti u populacijama. Posljedica djelovanja mutagena u genomu izloženih osoba jest nastanak određene, manje ili veće, količine oštećenja, uvjetovane individualnim razlikama u osjetljivosti. Viša razina takve genomske nestabilnosti znači opasnost (rizik) od razvoja zloćudnih bolesti. Interindividualne razlike u odgovoru na mutagene obično se povezuju i s promijenjenom (većinom smanjenom) sposobnosti (kapacitetom) za popravak DNA. Citogenetičke studije su pokazale da je genom tumorskih stanica nestabilniji od normalnih, a time i skloniji akumuliranju oštećenja, bilo da je nestabilnost uzrokovana nasljeđem, izloženošću ili kombinacijom tih dvaju učinaka. U oboljelih ispitanika utvrđena je povećana učestalost kromatidnih i kromosomskih aberacija naspram normalne populacije te sklonost razvoju određenih vrsta neoplazija. U praćenju povezanosti promijenjenog odgovora i pojavnosti tumora služe nam različiti biomarkeri. Kao indirektni pokazatelji uspješnosti popravka DNA često se rabe testovi osjetljivosti na mutagene u kulturama limfocita periferne krvi. Jedan od takvih testova je i bleomicinski test. Radiomimetik i citostatik, a po strukturi glikopeptid, bleomicin se u stanici prevodi u aktivni oblik sposoban cijepati molekulu DNA što uzrokuje brojne jednolančane i dvolančane lomove. Kao jednostavna i jeftina metoda, zasniva se na utvrđivanju ukupnog broja jednolančanih lomova u kromosomima limfocita uzgajanih u staničnoj kulturi koji su u uvjetima in vitro tijekom kasne G2-faze staničnog ciklusa bili izloženi bleomicinu. Ovaj revijalni rad daje pregled utjecaja raznih faktora na rezultate samog testa i pokazuje njegovu široku primjenu u proučavanju genomske nestabilnosti koju najčešće uzrokuje kombinacija raznih faktora.Estimation of individual susceptibility to mutagens is often a part of epidemiological studies monitoring the appearance of malignant disease in different populations. Genome exposure to mutagens can lead to DNA damage. The rate of damage depends on individual differences in response, which are usually associated with differences in DNA repair capacity. Cytogenetic studies have shown that the genome of tumour cells is less stable than normal cells and therefore accumulates more damage. Tumour patients show a higher frequency of chromatid and chromosomal aberrations and a predisposition to certain types of tumours. One of the common biomarkers used in monitoring tumour appearance and changed response to DNA damage is the bleomycin test. In its active form, bleomycin (glycopeptid) is a radiomimetic cytostatic that can damage the DNA molecule and cause multiple single and double strands. The bleomycin test is simple and inexpensive, and is based on scoring chromatid breaks in lymphocytes in vitro exposed to bleomycin during the late G2 phase of the cell cycle. This review looks into different factors that may affect test results and discusses its wide implementation in studies of genome instability usually caused by a combination of factors

Cytogenetic studies on the in-vitro genotoxicity of 4-nitroquinoline-1-oxide on human-lymphocytes

Using the UV-mimetic mutagen 4-nitroquinoline-1-oxide (4NQO) to induce genetic damage in human cells (lymphoblastoid lines and primary cultures of peripheral blood samples), chromosome aberrations were induced by treating the cells with 4NQO at 1 X 10(-5) M for 24 h. The overwhelming majority of chromosome aberrations was of the chromatid (S + G2) type instead of the chromosome (G1) type. The most common chromatid aberrations were simple breaks, isochromatid breaks, and chromatid exchanges. When the number of chromatid breaks per cell value was used as a measurement for 4NQO sensitivity, lymphoblastoid cells from a xeroderma pigmentosum patient showed the highest sensitivity, followed by the cells of two melanoma patients and normal persons. These preliminary results suggest that 4NQO may be employed to develop an assay system as a biomarker for determining UV sensitivity in the human population

Correction of the acid-base balance in the presence of the hypoxic-ischemic brain damage in newborns

One of the current problems of perinatal neurology is the hypoxic-ischemic brain damage in newborns associated with the influence of the hypoxia upon the fetus, intranatal and postnatal asphyxia on one hand and a lack of the efficient therapy schemes on the other hand. Due to this, the purpose of this pilotstudy isto identify the effects of drug Cytoflavin, included into the complex therapy scheme for the newborns with the cerebral ischemia of II-III stages, on the blood acid-base balance. A retrospective analysis of the results of the complex therapy for 16 newborns with the moderate (14 children) and severe (2 children) brain ischemia was performed. Cytoflavin was included in the standard therapy schemes for all children at a dose of 2 ml/kg per day at a dilution of 5% glucose solution at the ratio of 1:5, intravenously, microfluidically for 20 hours for 3 days. In addition to the standard examination, the blood acid-base balance assessment using the follow-up microgasometric method was included (after 60 min and then every 6 hours until 72 hours of observation). All children had positive tendency to the arresting of the metabolic acidosis (in the form of the decrease of the base deficiency after 24 hours and increase of pH level (the level of 7.30 was reached by 12 hours of age in full-term newborns and 24 hour of age in the preterm newborns). The revealed positive changes in the time of the metabolic acidosis arresting along with the small volumes of the infusion and good tolerability are the cause for the planning of the subsequent, more large-scale studies

Differential sensitivity among 3 human subpopulations in response to 4-nitroquinoline-1-oxide and to bleomycin

An assay employing the UV-mimetic mutagen 4-nitroquinoline-1-oxide (4NQO) to estimate a person's UV-sensitivity was developed. This sensitivity may be translated into an individual's susceptibility to acquire cutaneous malignancies. We used cytogenetic recordings on cultured lymphocytes from 103 normal individuals, 62 melanoma patients, and 71 patients with head and neck cancer. The frequency of chromosome damage (chromatid breaks) caused by exposure to 4NQO was used to measure sensitivity. Preliminary results showed that a significantly higher proportion of melanoma patients was 4NQO sensitive compared to the other two groups, whose 4NQO sensitivity was statistically not different. Although a number of theoretical and technical problems remain to be resolved and a great deal of additional information (especially clinical and epidemiological) is needed, it appears that 4NQO sensitivity may be effectively employed as a biological marker for identification of individuals at risk for melanoma (and possibly other cutaneous neoplasms as well)