Reduced poly(ADP‐ribosyl)ation in lymphocytes of laryngeal cancer patients: Results of a case‐control study

Abstract

Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme that is catalytically activated by DNA strand breaks, plays a complex role in DNA repair. Using NAD ؉ as a precursor, it catalyzes the formation of ADP-ribose polymers, which are attached to various proteins. Defects in DNA repair pathways have been associated with increased risks for cancer in humans. We investigated whether differences in the activity of PARP are associated with the risk for laryngeal cancer. In a case-control study on genetic, lifestyle and occupational risk factors for laryngeal cancer, PARP activity was assessed as DNA damage-induced poly(ADP-ribose) formation in human peripheral blood lymphocytes by quantitative immunofluorescence analysis. Polymer formation was determined as the cellular response to bleomycin, a well-known inducer of DNA strand breaks, in lymphocytes from 69 laryngeal cancer patients and 125 healthy controls. The frequency of bleomycin-induced polymer formation, measured as mean pixel intensity, was significantly lower in cases (74.6, SE ‫؍‬ 3.7) than in controls (94.5, SE ‫؍‬ 3.5) and not influenced by smoking, age or sex. There was no significant difference between cases (59.1, SE ‫؍‬ 5.2) and controls (50.5, SE ‫؍‬ 3.7) in basal polymer formation (in cells not treated with bleomycin). When the highest tertile of polymer formation was used as the reference, the odds ratio for the lowest tertile of bleomycininduced polymer formation was 3.79 (95% confidence interval 1.37-10.47, p ‫؍‬ 0.01). Peripheral blood lymphocytes from laryngeal cancer patients thus showed significantly less bleomycin-induced poly(ADP-ribose) formation. Our results suggest that a reduced capacity of somatic cells to synthesize poly(ADP-ribose) might be associated with an increased risk for laryngeal cancer. The underlying mechanism remains to be investigated. © 2002 Wiley-Liss, Inc. Key words: biomarker; bleomycin; molecular epidemiology; laryngeal cancer; poly(ADP-ribose) polymeraseLaryngeal carcinoma is the commonest tumor of the head and neck and the second commonest respiratory tract cancer after lung cancer in white persons. Respiratory cancers are paradigms of environmentally induced diseases and epidemiologic studies have identified smoking and alcohol intake as the most important risk factors. Other risk factors (poor nutrition, exposure to asbestos and other occupational exposures) have also been associated in some studies with the risk for laryngeal cancer. 1-3 These risk factors alone cannot, however, completely explain all cases of this cancer. Many studies have been conducted to identify biomarkers that reflect host susceptibility more closely. Those that have been found include variations in carcinogen metabolism, DNA adduct formation and DNA repair activity. 4,5 The pathogenic implications of these markers have been established for environmentally induced cancers such as lung tumors and head-and-neck squamous cell carcinoma. 6,7 An important reaction in DNA repair pathways is poly(ADP-ribosyl)ation, which is induced by the presence ...

Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice

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The ADPRT V762A Genetic Variant Contributes to Prostate Cancer Susceptibility and Deficient Enzyme Function

“…The results from these studies suggest that base excision repair (BER) is involved in CaP susceptibility (3,4,6,7). Because adenosine diphosphate ribosyl transferase/ poly(ADP-ribose) polymerase-1 (ADPRT/PARP-1) plays a critical role in both BER and maintaining the genomic stability of cells exposed to genotoxic stress and because previous studies associated higher ADPRT/PARP-1 enzyme activation with lower human cancer risk (8,9), we hypothesize that genetic polymorphisms of ADPRT may contribute to lower enzyme activity and CaP risk.…”

Apoptosis in Lymphocytes of Pancreatic Cancer Patients: Influence of Preoperative Enteral Immunonutrition and Extensive Surgery

“…The activation of PARP-1 by genotoxic stimuli facilitates cell survival. The lymphocytes of cancer patients show a lower expression of PARP-1, which may indicate a higher level of DNA damaged (Rajaee-Behbahani et al 2002). This molecule has been found a potential target for the development of pharmacological strategies to increase the antitumor efficacy of chemotherapeutic agents that induce DNA damage in cancer cells (Peralta-Leal et al 2008).…”