Nagarajan 25/3/09 11:32 am Page 59
Modulating Factors in Cervical Carcinogenesis
respectively. Global downregulation of type 1 and type 2 cytokines was 2 subgroups correlated with the levels of infiltrating inflammatory cells,
observed in a subgroup of patients who more frequently presented which are known to release free radicals. These observations may suggest a
advanced-stage tumours.
10
Biopsies of patients with no IFNγgene expression commonality in terms of oxidative DNA damage among infection,
did not appear to be less infiltrated by T cells than control biopsies with inflammation and the end-point malignancy in the uterine cervix. The level
measurable IFNγ gene expression.
11
of 8-oxodG, which is implicated in several cancers, was high in chronically
inflamed cervix. It is possible that this modification is an early event in
We have demonstrated the possible involvement of a newly described carcinogenesis. The levels of bulky aromatic adducts of the PAH type were
cytokine, IL-17, in the modulation of the growth of cervical carcinomas. This significantly higher in the invasive cancer group compared with normal and
study further confirms the prognostic value of yet another two cytokines, IL- dysplastic cervix.
14
This suggests their possible role in cervical carcinogenesis.
6 and IL-8, as prognostic markers in invasive cervical carcinomas. It was also
clearly demonstrated that in some clinical situations the decrease in In another study, we observed that there was a many-fold increase in these
intratumoral type 1 cytokines is not associated with a type 2 polarisation, but adduct levels during and post-radiotherapy in cancer cervix patients. This
rather reflected global deactivation of T cells at the tumour site. These data reflects the DNA damage caused due to radiation and a compromised state
provide support for immunotherapeutic approaches designed to reverse the of the cell to fix the lesion. Identification of biomarkers that predict tumour
anergic state of T cells in cancer. formation and progression would drastically improve the current clinical
scenario. Although these novel adducts are indicative of an association
Analysis of DNA Adducts in Invasive Cervical Carcinomas between inflammation and cancer, it has to be noted that this is a cross-
DNA adducts represent an early, detectable and critical step in sectional study. Only further evaluation in a longitudinal study of these novel
carcinogenesis, and thus may serve as an internal dosimeter of carcinogen adducts, which show a significant quantitative change in disease
exposure. Although relatively few studies have reported on endogenous progression, may prove their suitability for identification of high-risk
DNA adducts compared with adducts from exogenous carcinogens, it is subjects. The interplay between radiation exposure, oxidative stress and the
becoming clear that reactive intermediates (e.g. hydroxyl radicals) produced biological consequences of exposure such as lethality and mutagenesis is
during normal physiological or pathophysiological processes continuously intriguing. Measurement of DNA adducts holds promise not only in
damage cellular macromolecules. These intermediates can also convert assessing the state of oxidative damage of DNA in cancer-sufferers, but also
cellular constituents (e.g. lipids) to second-generation DNA-damaging reflect the outcome post-radiotherapy. One principal application of DNA
species.
12
A standard method used for measuring adducts from adduct detection to molecular epidemiology studies in humans may be
endogenous carcinogens in humans is the
32
P post-labelling assay that has assessment of carcinogenic risk.
the advantage of high sensitivity, which allows the detection of 1/10
8–10
nucleotides and requires as little as 10µg of DNA. However, it does not The aim of modern radiotherapy is to optimise the probability of tumour
allow adduct identification without authentic standards.
13
To determine control while minimising the unwanted acute or late radiation-induced
changes in oxidative and other DNA adducts during cervical cancer damage on normal tissues. Detection and monitoring of DNA adduct levels
development, we analysed DNA from specimens collected from in patients undergoing radiation therapy would reveal the patient response
cervicitis/inflammation, biopsy-proven dysplasia and invasive cancer cases. to radiation so that suitable interventions in terms of radiation dose is made
Over 60 adducts were detected in cancer-free and cancerous tissues. Based for patients with radio-resistant tumours, but at the same time regulating
on chromatography solvents and elution profiles, all adducts were classified the dose of exposure in radiosensitive patients. Furthermore, studies with
into six groups. With the exception of the highly lipophilic L-2 adducts, larger populations would allow the majority of the cancer patients to receive
which have been reported previously in the human cervix, all other groups optimised radiation and hopefully better tumour control. Our findings
of adducts are novel. support the hypothesis that infections of the cervix lead to inflammation,
and the release of ROS by endogenous factors leads to high oxidative
Similar DNA adduct profiles were detected in the normal specimens, damage to the DNA. Some of the modifications thus accumulated may lead
dysplasia and cancer biopsies, each exhibiting at least six subgroups of to irreversible changes in the genome and initiate cancer.
adducts, P-1, P-2, PL-1, PL-2, L-1 and L-2, based on their descending polarity
(or ascending lipophilicity). A known oxidative lesion 8-oxodeoxyguanosine One approach is to intervene in this process that involves interfacing
(8-oxodG), formed predominantly, decreased progressively from the infection, inflammation and oxidative damage. The bottom line is to
inflammation to dysplasia to invasive cancer. The progressive decrease was prognosticate and stratify a response based on the marker profile for use on
also evident for several adducts in both the P-1 and P-2 subgroups. a routine basis in conjunction with other clinical parameters. In the
Individual adducts in the PL-1 and PL-2 subgroups were either unaffected or management scenario, it may take several patient studies to develop a
exhibited progressive decline, but the clusters of adducts in the L-1 subgroup database. Nonetheless, the approach would potentially benefit the patient
were practically unchanged. The most lipophilic adducts, the L-2 type, and make this technology viable point-of-care diagnostics. ■
showed a progressive increase. The newly detected subgroups of adducts
were up to 500 times higher than the previously known highly lipophilic This is an ongoing study. Parts of the data are taken from our earlier work
endogenous I-compounds. In addition, some adducts in the P-1, P-2 and L- with Indo-French and Indo-US research collaborations.
1. Munagala R, et al., Int J Oncol, 2008; in press. 6. Kumari P, et al., Curr Science, 2003; 84:434–8. 11. Tartour E, et al., J Natl Cancer Inst, 1998;90: 287–94.
2. Walboomers JM, et al., J Pathol, 1999;189:12–19. 7. Nagarajan B, Ann Natl Acad Med Sci, 2003;39: 61–4. 12. Loft S, Poulsen HE, J Mol Med, 1996;74:297–312.
3. Tartour E, et al., Cancer Res, 1999;59:3698–3704. 8. Tartour E, et al., Cancer Res, 1994;54:6243–8. 13. Gupta R. In: Pfeifer GP (ed), Technologies for Detection of DNA
4. Benchetrit F, et al., Blood, 2002;99:2114–21. 9. Munagala R, Nagarajan B, Curr Sci, 2008;94:1292–6. damage and Mutations, New York: Plenum Press, 1996; 45–61.
5. Srivani R, Nagarajan B, Int J Gynecol Cancer, 2003;13:331–9. 10. Gey A, et al., Eur J Cancer, 2003;39:595–603. 14. Ravoori S, et al., Int J Oncol, 2006;29:1437–43.
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