D Ratnasinghe

National Cancer Institute (USA), Maryland, United States

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Publications (15)54.1 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Associations between lung cancer risk and common polymorphisms in the DNA repair genes xeroderma pigmentosum complementation group D (XPD), X-ray repair cross-complementing group 1 (XRCC1), XRCC3 and apurinic/apyrimidinic endonuclease/redox factor 1 were examined within a randomized clinical trial designed to determine whether alpha-tocopherol, beta-carotene, or both would reduce cancer incidence among male smokers in Finland. We found no direct association between lung cancer risk and any of the DNA repair genotypes studied, however, the association between XPD codon 751 genotype and lung cancer was modified by alpha-tocopherol supplementation, and the association between XRCC1 codon 399 genotype and lung cancer was modified by the amount of smoking. Our results suggest that common alterations in single DNA repair genes are not major determinants of lung cancer susceptibility among smokers.
    Cancer Letters 04/2003; 191(2):171-8. DOI:10.1016/S0304-3835(02)00638-9 · 5.62 Impact Factor
  • P S Albert · D Ratnasinghe · J Tangrea · S Wacholder
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    ABSTRACT: The case-only design, which requires only diseased subjects, allows for estimation of multiplicative interactions between factors known to be independent in the study population. The design is being used as an alternative to the case-control design to study gene-environment interactions. Estimates of gene-environment interactions have been shown to be very efficient relative to estimates obtained with a case-control study under the assumption of independence between the genetic and environmental factors. In this paper, the authors explore the robustness of this procedure to uncertainty about the independence assumption. By using simulations, they demonstrate that inferences about the multiplicative interaction with the case-only design can be highly distorted when there is departure from the independence assumption. They illustrate their results with a recent study of gene-environment interactions and risk of lung cancer incidence in a cohort of miners from the Yunnan Tin Corporation in southern China. Investigators should be aware that the increased efficiency of the case-only design is a consequence of a strong assumption and that this design can perform poorly if the assumption is violated.
    American Journal of Epidemiology 11/2001; 154(8):687-93. · 4.98 Impact Factor
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    ABSTRACT: In order to examine whether a polymorphism in the promoter region of the myeloperoxidase (MPO) gene is associated with lung cancer among male smokers, we conducted a case-control study nested within a Finnish clinical trial cohort. Although we found no evidence of an overall association between lung cancer risk and MPO genotype, the variant MPO genotype was associated with an increased risk of lung cancer among a subset of older men. These findings contrast with those from previous studies that report decreased lung cancer risk among MPO variant individuals.
    Cancer Letters 04/2001; 164(2):161-7. DOI:10.1016/S0304-3835(01)00384-6 · 5.62 Impact Factor
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    ABSTRACT: We explored the association between polymorphisms of the DNA repair gene XRCC1 (codons 194, 280, and 399) and lung cancer risk in a case-control study nested within a cohort of tin miners. Cases were those diagnosed with lung cancer over 6 years of follow-up (n = 108). Two controls, matched on age and sex, were selected for each case by incidence density sampling. Of the three polymorphisms, only the XRCC1 Arg280His allele was associated with increased lung cancer risk (odds ratio, 1.8; 95% confidence interval, 1.0-3.4) after adjustment for radon and tobacco exposure. In addition, individuals with the variant Arg280His allele who were alcohol drinkers seemed to be at higher risk for lung cancer compared with those with the homozygous wild-type genotype. Conversely, individuals with the variant Arg194Trp allele who were alcohol drinkers seemed to be at lower risk for lung cancer compared with those with the homozygous wild-type genotype. Polymorphisms of XRCC1 appear to influence risk of lung cancer and may modify risk attributable to environmental exposures.
    Cancer Epidemiology Biomarkers & Prevention 03/2001; 10(2):119-23. · 4.32 Impact Factor
  • D Ratnasinghe · J A Tangrea · C Stewart · N K Bhat · J Virtamo · D Albanes · P R Taylor
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    ABSTRACT: To evaluate the association between CYP1A1 genotype and lung cancer risk and to assess the effect of CYP1A1 genotype and antioxidant supplementation on the smoking--lung cancer relationship we conducted a case-control study nested within a large cancer prevention trial cohort. Controls (n = 324) were matched to cases (n = 282) on age (+/- 5 years), intervention group and study clinic in a 1:1 ratio, using incidence density sampling. Genotype was determined by a PCR-based method and logistic regression was used to calculate relative risk estimates. Overall, we found no association between CYP1A1 genotype and lung cancer risk. CYP1A1 genotype did not modify the effect of smoking on lung cancer risk. However, in an examination of subgroups defined by randomized intervention assignment our findings suggest that alpha-tocopherol supplementation may reduce the risk of lung cancer associated with cumulative smoking exposure regardless of CYP1A1 genotype with the greatest effect seen among those with the variant CYP1A1 allele.
    Anticancer research 01/2001; 21(2B):1295-9. · 1.87 Impact Factor
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    ABSTRACT: It is generally accepted that P-glycoprotein 170 (MDR1/Pgp170) expression in breast tumors results in poor response to chemotherapy due to its ability to export chemotherapeutic agents. Studies indicate that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may enhance the anti-tumor activity of cancer chemotherapeutic agents and reduce the risk of many cancers. The best known function of NSAIDs is to block the enzyme cyclooxygenase (Cox), the rate limiting enzyme in the conversion of arachidonic acid to prostaglandins. In this study we investigated whether expression of the inducible isoform of Cox (Cox-2) is linked with the multidrug resistance phenotype in breast cancer. Expression of Cox-2 and MDR1/Pgp170 was investigated in tumor specimens along with normal epithelium in breast cancer patients using immunohistochemisrty. Expression of Cox-2, MDR1/Pgp170, Protein Kinase C (PKC), and Activator Protein 1 (AP1) were investigated in a series of increasingly resistant human MCF-7 breast cancer cells compared to wild type using immunohistochemistry, Western blots, Northern blots, RT-PCR, and Southern blots. Immunohistochemical analyses of human breast tumor specimens revealed a strong correlation between expression of Cox-2 and MDR1/Pgp170. In drug resistant cell lines that over-express MDR1/Pgp170 there was also significant up-regulation of Cox-2 expression. In addition, PKC and AP1 subunits c-Jun and c-Fos were also upregulated. We hypothesized that increased prostaglandin production by Cox-2 induces PKC and the expression of transcriptional factor c-Jun, which in turn, induces the expression of MDR1/Pgp170. We propose that pretreatment with selective Cox-2 inhibitors may be useful in the prevention of multidrug resistance in response to cancer chemotherapy and should be further evaluated.
    Anticancer research 01/2001; 21(3C):2141-7. · 1.87 Impact Factor
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    ABSTRACT: Human cellular glutathione peroxidase 1 (hGPX1) is a selenium-depen- dent enzyme that participates in the detoxification of hydrogen peroxide and a wide range of organic peroxides. We conducted a case-control study nested within the a-Tocopherol, b-Carotene Cancer Prevention Study cohort to evaluate the association between the proline to leucine polymor- phism at codon 198 of hGPX1 and lung cancer risk. Cases (n 5 315) were matched to controls on age (65 years), intervention group, and study clinic using incidence density sampling in a 1:1 ratio. The prevalence of the hGPX1 Pro198leu variant allele was 58% for controls and 71% for cases (P < 0.001). Using conditional logistic regression, we found a sig- nificant association between hGPX1 genotype and lung cancer risk. The odds ratio for heterozygotes was 1.8 (95% confidence interval, 1.2-2.8) and 2.3 (95% confidence interval, 1.3-3.8) for homozygous variants com- pared to wild-type individuals. Due to its high prevalence, the hGPX1 variant may contribute significantly to lung cancer risk among Cauca- sians but not among ethnic Chinese who do not exhibit this polymorphism.
    Cancer Research 12/2000; 60(22). · 9.28 Impact Factor
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    ABSTRACT: Individuals with specific phase I and phase II enzyme polymorphisms may be at increased risk for squamous cell carcinoma of the esophagus. However, to our knowledge there has been only one previous report that evaluates a potential role for these polymorphisms in increasing risk for preneoplastic squamous lesions of the esophagus. To explore this further, we examined polymorphisms in CYP1A1, CYP2E1, GSTM1 and GSTT1, both independently and in combination, for potential associations with the risk of biopsy-proven squamous dysplasia of the esophagus in asymptomatic adults from Linxian, a high risk region in China. Cases consisted of 56 individuals from an esophageal cancer screening study with an endoscopic biopsy diagnosis of mild or moderate squamous dysplasia. Each case was matched on age (+/- 1 year) and gender to a control. Controls were defined as screening study participants with an endoscopic biopsy diagnosis of normal mucosa or esophagitis. DNA was extracted from frozen cell samples obtained by cytologic balloon examination and genotyped using standard methods. Individuals who were GSTM1 null (homozygous for GSTM1*0) were found to have a tendency for an increased risk of esophageal squamous dysplasia (odds ratio=2.6, 95% CI, 0.9-7.4). No excess risks were observed for inheritance of other putative at risk genotypes CYP1A1*2B, CYP2E1*6 or GSTT1*0. The risk associated with the inheritance of combined genotypes was not significantly different than the risk estimates from the univariate analysis. These results are consistent with the notion that exposure to environmental carcinogens that are detoxified by GSTM1, such as polycyclic aromatic hydrocarbons, may contribute to the etiology of esophageal cancer in Linxian.
    Cancer Letters 09/2000; 156(1):73-81. DOI:10.1016/S0304-3835(00)00442-0 · 5.62 Impact Factor
  • D. Ratnasinghe
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    ABSTRACT: To evaluate the association of prediagnostic serum antioxidants and lung cancer risk we conducted a case-control study nested in an occupational cohort of tin miners. Male workers free of cancer enrolled in the cohort. During up to 6 years of follow-up, 339 lung cancer cases were diagnosed and, among these cases, those who donated blood prospectively (n = 108) were eligible for this study. For each case, two controls alive and free of cancer at the time of case diagnosis were matched on age and date of blood collection. Overall, we observed no association between serum alpha-tocopherol, gamma-tocopherol or selenium levels and lung cancer risk. However, a significant gradient of decreasing lung cancer risk with increasing serum alpha-tocopherol was apparent for men less than 60 years old (odds ratio by tertile: 1.0, 0.9, 0.2; trend p = 0.002). Alpha-tocopherol was also protective in men who reported no alcohol drinking (OR by tertile: 1.0, 0.6, 0.3; trend p = 0.008). Although there were no significant overall associations between prospectively collected serum alpha-tocopherol, gamma-tocopherol or selenium and incidence of lung cancer, results from this study suggest that higher alpha-tocopherol levels may be protective in men less than 60 years old and in those who do not drink alcohol.
    Cancer Causes and Control 03/2000; 11(2):129-35. DOI:10.1023/A:1008977320811 · 2.96 Impact Factor
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    ABSTRACT: To examine the association between pre-diagnostic serum carotenoid levels and lung cancer risk and the effects of alcohol intake on the carotenoid-lung cancer relationship, we conducted a case-control study in an occupational cohort from the Yunnan Tin Corporation in China. During 6 years of follow-up, 339 cases of confirmed lung cancer were diagnosed. Among these cases, those who donated pre-diagnostic blood (n = 108) were eligible for this study. For each case, two individuals alive and free of cancer at the time of case diagnosis, matched on age, sex, and date of blood collection, were selected as controls. Serum beta-carotene (odds ratios (ORs) for tertiles: 1, 1.3, 2.0) and beta-cryptoxanthin (ORs for tertiles: 1, 1.8, 2.9) levels were positively associated with lung cancer risk after adjustment for tobacco use and radon exposure. Among alcohol drinkers, higher serum carotenoid levels were significantly associated with increased lung cancer risk (alpha-carotene OR 2.2, 95% confidence interval (CI) 1.1-4.4, beta-carotene OR 7.6, 95% CI 3.1-18.6, lutein/zeaxanthin OR 2.3, 95% CI 1.2-6.6 and beta-cryptoxanthin OR 7.6, 95% CI 2.7-21.5). Conversely, risk estimates among non-drinkers suggest a possible protective association for higher carotenoid levels.
    Alcohol and Alcoholism 01/2000; 35(4):355-60. · 2.09 Impact Factor
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    ABSTRACT: Genetic susceptibility polymorphisms may be of substantial importance in the modulation of cancer risk. The prevalence for an array of polymorphic genes was determined in a cohort of male smokers who participated in a cancer prevention trial in Finland. A random sample of 120 individuals was selected from the trial cohort and the prevalence of variant alleles for nine genes was determined using a polymerase chain reaction-based approach. The prevalence values from this study were also compared with those of other populations derived from previous studies. Our results show that, with the exception of cytochrome P450-1A1 (CYP1A1) and cytochrome P450-2E1 (CYP2E1), all genes tested were sufficiently polymorphic to warrant an investigation of gene-environment studies. Most of the variant alleles, including alcohol dehydrogenase 3 (ADH3), glutathione-S-transferase (GSTM1), methionine synthase (MS), methylene tetrahydofolater reductase (MHTFR), CYP2E1 and CYP1A1, exhibited similar frequencies to other Caucasian populations. Interestingly, the prevalence of androgen receptor-CAG repeat (AR-CAG) and vitamin D receptor (VDR) polymorphisms differed significantly between the alpha-tocopherol, beta-carotene (ATBC) Study and other Caucasian populations. We present herein results from this survey and conclude that the ATBC study population in Finland is sufficiently heterogeneous to facilitate analysis of genetic polymorphisms and disease associations.
    European Journal of Cancer Prevention 11/1999; 8(5):441-7. DOI:10.1097/00008469-199910000-00010 · 2.76 Impact Factor
  • D Ratnasinghe · J A Tangrea · M J Roth · S M Dawsey · M Anver · B A Kasprzak · N Hu · Q H Wang · P R Taylor
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    ABSTRACT: Several studies indicate that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of gastric corpus and possibly gastric cardia cancers. The best known action of NSAIDs is to block the enzyme cyclooxygenase, the rate limiting enzyme in the conversion of arachidonic acid to prostaglandins. We investigated the expression of cyclooxygenase-2 (Cox-2) in adenocarcinomas of the gastric cardia (N=19) and corpus (N=15) and in adjacent normal epithelium from a high risk Chinese population. Immunohistochemical detection of Cox-2 revealed positive staining in 36% of the gastric cardia cancer cases and 60% of the gastric corpus cancer cases, whereas histologically normal tissue from the same patients were negative. Smooth muscle, stroma and inflammatory cells were also positive. Our results suggest that Cox-2 is overexpressed in a large proportion of adenocarcinomas of the gastric corpus and in a smaller number of gastric cardia cancer cases.
    Oncology Reports 09/1999; 6(5):965-8. DOI:10.3892/or.6.5.965 · 2.19 Impact Factor
  • D Ratnasinghe · J Tangrea · M J Roth · S Dawsey · N Hu · M Anver · Q H Wang · P R Taylor
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    ABSTRACT: Several studies indicate that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of esophageal cancer. The best known function of NSAIDs action is to block the enzyme cyclooxygenase, the rate limiting enzyme in the conversion of arachidonic acid to prostaglandins. In this study we investigated the expression of cyclooxygenase-2 (Cox-2) in squamous cell cancers of the esophagus and in normal esophageal squamous epithelium. Immunohistochemical detection of Cox-2 revealed strong positive staining in the well-differentiated regions of esophageal tumors, whereas histologically normal squamous epithelium stained only weakly positive. Smooth muscle cells, some stromal and inflammatory cells were also positive. Poorly differentiated areas of the esophageal tumors were negative. Our results suggest that Cox-2 is over-expressed in well-differentiated regions of squamous cell cancers of the esophagus.
    Anticancer research 01/1999; 19(1A):171-4. · 1.87 Impact Factor
  • D Ratnasinghe · J M Phang · G C Yeh
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    ABSTRACT: Multidrug resistance is one of the major obstacles in cancer chemotherapy. In tumor cells, overexpression of the transmembrane P-glycoprotein 170 (P-gp) is associated with the multidrug resistance phenotype and serves as a drug efflux pump. The activation of P-gp has been suggested to occur at the post-translational level. Protein kinase C mediated phosphorylation may be associated with the drug effux mechanism but the overall phosphorylation pathway has not been completely defined. we report the novel finding of an increase in phosphatase 1B (a tyrosine phosphatase) and a decrease in PP1 and PP2A (serine/threonine phosphatases) expression and activity in our series of early (R65) and late (R500) stage adriamycin resistant MCF-7 cells. In addition, we show a decrease in protein kinase A (PKA) activity and an increase in protein kinase C (PKC) in our drug resistant cells. Analyses of PKC isoforms alpha through epsilon revealed that PKCbeta was not expressed and that all other isoforms increased with increasing resistance, except PKCgamma which was detected only in R65 cells. Our findings suggest that in drug resistant cells, there is a pattern consistant with the maintenance of serine and threonine residues in a phosphorylated state.
    International Journal of Oncology 08/1998; 13(1):79-84. DOI:10.3892/ijo.13.1.79 · 3.03 Impact Factor

Publication Stats

810 Citations
54.10 Total Impact Points

Institutions

  • 1998–2003
    • National Cancer Institute (USA)
      • Center for Cancer Research
      Maryland, United States
  • 2001
    • Northern Inyo Hospital
      BIH, California, United States