This Article Abstract Full Text (PDF) Erratum (v25,p5678) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Govindarajan, R. Articles by Lang, N. P. Search for Related Content PubMed PubMed Citation Articles by Govindarajan, R. Articles by Lang, N. P. Social Bookmarking                            What's this?

Thiazolidinediones and the Risk of Lung, Prostate, and Colon Cancer in Patients With Diabetes

Rangaswamy Govindarajan, Luke Ratnasinghe, Debra L. Simmons, Eric R. Siegel, Madhu V. Midathada, Lawrence Kim, Peter J. Kim, Randall J. Owens, Nicholas P. Lang

From the Central Arkansas Veterans Health Care System; and the University of Arkansas for Medical Sciences, Little Rock, AR

Address reprint requests to Rangaswamy Govindarajan, MD, MRCP (United Kingdom) University of Arkansas for Medical Sciences, 4301 West Markham, Slot 508, Little Rock, AR 72205; e-mail: govindarajanrang{at}uams.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Purpose Peroxisome proliferator-activated receptor gamma (PPAR) mediates cell cycle arrest and adipocyte differentiation; has tumor suppressor activity in liposarcoma, lung, and prostate cancers; and suppresses colonic polyp formation in adenomatous polyposis coli (APC)^min/+ mice. To assess the influence of thiazolidinediones (TZDs), which are PPAR ligands used to treat diabetes mellitus, a retrospective analysis of a database from 10 Veteran Affairs medical centers was conducted.

Patients and Methods Data on male patients 40 years and older diagnosed to have diabetes mellitus between 1997 and 2003 were obtained from the Veterans Integrated Services Network 16 (VISN 16) data warehouse. Subsequent diagnoses of colorectal, lung, and prostate cancer and use of TZD, other antidiabetic agents, and insulin were identified. Cox regression with time-dependent covariates was used to estimate the association between TZD use and cancer risk. Relative risks were adjusted for confounders (age, race/ethnicity, body mass index, use of insulin, and other oral antidiabetic agents).

Results Of 87,678 individuals, 1,137 had colorectal cancer, 3,246 had prostate cancer, and 1,371 had lung cancer. We observed a 33% reduction in lung cancer risk among TZD users compared with nonusers after adjusting for confounder interactions (relative risk, 0.67; 95% CI, 0.51 to 0.87). The risk reduction for colorectal and prostate cancers did not reach statistical significance.

Conclusion TZD use was associated with reduced risk of lung cancer. Further studies are warranted to confirm our findings.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Peroxisome proliferator-activated receptors (PPARs) are members of a super family of nuclear receptors. The PPAR subfamily has three isotypes: alpha (), beta/delta (β/), and gamma (), which are ligand-activated transcription regulators important in cellular homeostasis.^1-3 Stimulation of PPAR induces cell cycle arrest and has a role in the terminal differentiation of adipocytes. PPAR agonists bind to the DNA only in the PPAR:RXR (retinoid X receptor) heterodimer form. PPAR agonists induce cell cycle arrest and apoptosis of lung cancer cell lines in vitro.^4,5 The metabolites of arachidonic acid, 15-HETE [15(s)-hydroxyeicosatetraenoic acid] and linoleic acid, 13 HODE [13(s)-hydroxoctadecadienoic acid], are ligands for either PPAR or mitogen-activated protein (MAP) kinase and may mediate the pathogenesis of prostate cancer.⁶ In the normal prostate gland, activation of MAP kinase induces phosphorylation of PPAR, which in turn suppresses differentiation and de-represses growth. Thiazolidinediones (TZDs) suppress MAP kinase activation and, hence, the phosphorylation of PPAR, and in turn induce differentiation and growth repression. TZDs increase the number of intestinal polyps in adenomatous polyposis coli (APC)^min/+ mice in small doses, but have the opposite effect at higher doses and are not tumorigenic in wild-type mice.^7-10 Some of the antineoplastic actions of TZDs may be mediated by antiangiogenic effects.^11,12

TZDs (glitazones) are synthetic ligands for PPAR that are used to treat diabetes mellitus. There are insufficient clinical data regarding the protective effects of glitazones on cancer.^1,9,13 To assess whether the glitazones have a cancer preventive effect, we conducted a retrospective study of male veteran diabetics aged 40 years and older. The objective of the study was to assess whether there was a difference in the risk of development of three malignancies—lung, prostate, and colorectal cancer—that are common in the veteran population and for whom published preclinical data provided a possible rationale for a role for TZD action.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Study Population
The population for this retrospective study was derived from an electronic database covering 10 Veterans’ Affairs (VA) hospitals (Alexandria, LA; Biloxi, MS; Fayetteville, AR; Houston, TX; Jackson, MS; Little Rock, AR; Muskogee, OK; New Orleans, LA; Oklahoma City, OK; and Shreveport, LA) that comprise the Veterans Integrated Services Network 16 (VISN 16). All of the data in the database, such as diagnosis, laboratory values, and treatment, were entered into the electronic patient charts, which in turn were exported to the VISN 16 and the VA national database.¹⁴ The protocol was approved by the institutional review board of the University of Arkansas for Medical Sciences and the VA administration. Male patients aged 40 years or older who were newly diagnosed with diabetes mellitus between October 1997 and September 2003 were eligible. Cancer diagnosis dates were collected through September 20, 2003, and patient contact dates (visits, laboratory test dates) were collected through December 2, 2004. The diabetic subjects were identified using the International Classification of Diseases (ICD) code 250.XX (XX: all patients with diabetes mellitus type 1, type 2, with and without complications, were identified). Those who had a diagnosis of cancer at the time of diagnosis of diabetes mellitus were excluded. ICD-9 codes were used to identify the diagnosis of lung cancer (162.9), colorectal cancer (153.9 and 153.10), and prostate cancer (185.00).

Covariate Data
Dates of first use of TZD, other oral antidiabetic agents, and insulin; age; race/ethnicity; sex; height; weight; and hemoglobin (Hgb) A₁C measures were extracted from the database. The information extracted was current as of the date of data extraction in March 2005. Body mass index (BMI) was calculated as weight divided by height squared (kg/m²). The duration of TZD prescription for each patient was obtained from the database from the dates of first and last prescription. The duration of TZD exposure for each patient was estimated from the database from the dates of first and last prescription and from the amounts dispensed at each prescription. Under the assumption that dispensed amounts were to be taken at one tablet per day, some prescriptions were for 90 or 180 days, but a large majority were for 30 days. Accordingly, 30 days plus the number of days between first and last prescription dates was taken as a crude estimate of TZD exposure duration.

Statistical Analyses
Cox proportional hazards regression with time-dependent covariates for drug exposures was used to estimate the association between TZD use and cancer risk. The relative risk (RR) of development of cancer was defined as the hazard ratio for time to cancer development in patients who became exposed to TZD, other oral agents, insulin, or combinations of the three, compared with that for patients not yet exposed to these drugs. Risk increases and reductions with TZD exposure were computed as the absolute value of [RR – 1] and expressed as percentages. RRs were estimated unadjusted, adjusted for only age and race/ethnicity, and adjusted for all available confounders. In the analyses, the response variables were times to cancer, defined as the times from date of diabetes diagnosis to date of diagnosis of colorectal, lung, or prostate cancer. Study participants who reached their last follow-up without a diagnosis for a particular cancer were censored for that cancer at the last follow-up date. The Cox regressions modeled TZD, insulin, and other oral antidiabetic agents as time-dependent covariates using first drug-use dates to mark the onset of exposure, with time-dependent drug-drug interactions for patients who began a second drug, with stratification to control for age and race/ethnicity, and with covariate adjustment to control for BMI and HgbA₁C. SAS version 9.1 (SAS Institute, Cary, NC) was the statistical software package used to perform the computations presented. P values less than .05 were considered to be statistically significant despite the multiple comparisons so as not to inflate type II error in this hypothesis-generating observational study.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Eighty-seven thousand six hundred seventy-eight patients met the study inclusion criteria, of whom 72,323 had nonmissing data for height, weight, and HgbA₁C. Eleven thousand two hundred eighty-nine patients were treated with TZD, and 76,389 were never prescribed a TZD. The median duration of TZD exposure was 364 days. Table 1 presents characteristics of the study population. Age was equally distributed between TZD users and nonusers, with equal medians, equal lower quartiles, and nearly equal upper quartiles. The race/ethnicity breakdown for TZD users was 62% white, 12% African American, and 26% unknown, compared with 57% white, 17% African American, and 26% unknown for TZD nonusers. The imbalance was considered modest for a study population of this magnitude. The higher median BMI, higher use of insulin and other oral antidiabetic agent use among those who uses a TZD compared with those who did not use a TZD are in accordance with the prescribing tendency of TZD for more advanced and refractory diabetes. A median HgbA₁C level, a measure of control of diabetes, was also higher among TZD users than among nonusers.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

TZD may also influence tumor growth and development through an antiangiogenic mechanism. PPAR ligand 15d-PGJ2 inhibits the angiogenic effect of vascular endothelial growth factor in the rat cornea model.¹² PPAR is highly expressed in vascular endothelial cells and is lost on exposure to TZD, suggesting that the antiangiogenic properties of PPAR ligands may play a role in inducing an antineoplastic effect.¹¹ The effective concentration of the glitazones in in vitro studies ranged from 20 to 50 µmol/L, in keeping with the clinical concentration of glitazone one might expect from therapeutic dosing.^5,21 Although the laboratory data indicate that TZDs act as ligands for PPAR and, in turn, have an effect on the growth and differentiation of prostate cancer cells, success has been limited to serum prostate-specific antigen (PSA) stabilization and downregulation of PSA expression.^6,22 Likewise, a phase II trial treating patients with metastatic colorectal cancer with troglitazone did not produce any measurable effect.²³ Nonetheless, this data set provided an excellent opportunity to perform a hypothesis-generating study to better refine the clinical area and conditions appropriate for further exploration regarding the impact of TZD use on malignant diseases.

The veteran population is a select group of subjects who utilize a single system for their medical needs. We chose diabetics because this the only group of patients treated with TZD. The incidence of certain types of cancer has been reported to be higher in diabetics as opposed to nondiabetics.^24-26 This should not influence the results of our study because we are comparing the incidence of cancers among diabetics who are receiving glitazones to those who are not, and not to nondiabetics.

We observed a reduction for the incidence of lung cancer of 29% both unadjusted and when adjusted for race/ethnicity and age, and a reduction of 33% when adjusted for race/ethnicity, age, BMI, HgbA₁C, insulin use, other oral antidiabetics, and drug-drug interactions. The decrease in the incidence of lung cancer among TZD users is probably mediated by RXR- receptor–mediated pathways. The incidence of colorectal and prostate cancers was not influenced by TZD usage when the population was analyzed as a whole, but there was an increase in the incidence of prostate cancer among white and African American patients. There was a decrease in the incidence of colon cancer among African American patients (Table 3). The difference in the racial incidence of prostate and colorectal cancers is difficult to explain, and may have to do with the statistical power of detection as well as a hypothetical difference in the metabolism of the glitazones in white and African American populations. Other explanations could include a known racial/ethnic variation in the single nucleotide polymorphism frequency in metabolic pathways important to xenobiotic metabolism, as well as the general observation of racial/ethnic differences in the incidence of cancers reported in the literature.^27,28 Survival bias is one possible explanation for why risk with TZD use is elevated for prostate cancer and not for colorectal cancer. The increase in the incidence of prostate cancer is a surprising finding in this population, and needs to be studied in detail. We restricted the patient population to those with lung, prostate, and colorectal cancers because these cancers occurred frequently enough in the participant population to provide adequate statistical power to detect a statistically significant level of risk reduction.

This study evaluates the role of TZD in reducing the incidence of lung cancer in a clinical setting. This study includes a large number of patients supporting preclinical data on the protective effect of PPAR ligands on carcinogenesis. VISN 16 has a large database that is a reliable source of patient data because patients in this database are all treated within a single system. This database is extracted from the electronic medical record used by all the clinicians to enter the patient information in an ongoing basis and is an excellent source of clinical data that can be used to ask questions and generate hypothesis for future clinical trials. However, this study, being retrospective in nature, has several limitations. Smoking history was not collected for the vast majority of patients. Racial information was not available for 24% of patients. The information was obtained from a database that is not a research tool, that has the data entered by various clinical services, and that is not designed as a research tool to collect prospective data. The duration of therapy with TZD is not taken into the analysis because the study was not designed to analyze the association between the duration of exposure to TZD and the impact on the incidence of cancer. All patients who had a diagnosis of cancer after the date of exposure to TZD have been taken into account, irrespective of the fact that the duration of therapy with TZD might not be sufficient to have a meaningful impact on cancer development. This could have a negative impact on our study resulting from under-reporting of the impact of TZD on the risk of cancer development. It is possible that some patients treated with TZD might have developed cancer that was not diagnosed and entered into the database at the time of the study, which could lead to over-reporting of the impact of TZD on the risk of cancer development.

Nonetheless, we believe that this study has several strengths that tend to offset these limitations. All inclusion and exclusion criteria were implemented using computer programming statements (either Structured Query Language queries or SAS data steps), thus eliminating the patient inclusion/exclusion errors that commonly occur with manually collected retrospective data. The study was limited to males over the age of 40 years with diabetes, thus removing possible confounding with sex and with presence and type of diabetes. Only newly diagnosed diabetics without prior cancers entered onto the study, thus removing the influence of unknown treatment histories that occurred before the study period. The association between TZD use and cancer incidence was modeled as a time-to-event process via Cox regression, with diabetes diagnosis date marking a subject's entry date into the set at risk for developing cancer, and with date of cancer diagnosis marking the date the subject experienced the event of interest. By this means, the TZD effect on cancer incidence could be detected as delay of occurrence as well as nonoccurrence; and to this end, the inclusion/exclusion criteria were set up to guarantee a minimum of 15 months’ follow-up time after risk-set entry, to give the cancer time to occur. Because a patient's exposure to TDZ, other oral antidiabetics, and insulin often commenced well after his entry into the risk set, the drug exposures were modeled in the Cox regressions as time-dependent covariates that, for each subject, changed status from "unexposed" to "exposed" on the date of the subject's first prescription. In this manner, a cancer that occurred in a TZD-using subject before his first use of TZD would properly be associated with when he did not use them. These features, we believe, are enough to give our study credibility despite the limitations noted herein.

This is a single large database that can be a potential source to get preliminary data to support the conduct of further clinical trials. This is a hypothesis-generating, rather than a hypothesis-testing study. To better understand the role of TZD use on lung cancer development, two studies designs have the potential to provide useful information. One study could answer the question of protective effect of TZD on lung cancer would be a randomized study to look at the incidence of bronchial dysplasia in high-risk individuals (smokers). Another option is to study the effect of TZD in prevention of second cancers among patients with stage IB and IIA lung cancers postresection in a randomized, placebo-controlled study.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Rangaswamy Govindarajan, Madhu V. Midathada, Peter J. Kim, Nicholas P. Lang

Provision of study materials or patients: Nicholas P. Lang

Collection and assembly of data: Luke Ratnasinghe, Eric R. Siegel, Nicholas P. Lang

Data analysis and interpretation: Rangaswamy Govindarajan, Luke Ratnasinghe, Eric R. Siegel, Madhu V. Midathada, Lawrence Kim, Randall J. Owens, Nicholas P. Lang

Manuscript writing: Rangaswamy Govindarajan, Luke Ratnasinghe, Debra L. Simmons, Eric R. Siegel, Madhu V. Midathada, Lawrence Kim, Randall J. Owens, Nicholas P. Lang

Final approval of manuscript: Rangaswamy Govindarajan, Luke Ratnasinghe, Debra L. Simmons, Eric R. Siegel, Nicholas P. Lang

	ACKNOWLEDGMENTS

 
We thank Melody Darbe and Sam Barnhart for data extraction from the VISN database.

	NOTES

 
Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-15, 2005, Orlando, FL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
1. Fajas L, Debril M-B, Auwerx J: Peroxisome proliferator activated receptor-gamma: From adipogenesis to carcinogenesis. J Mol Endocrinol 27:1-9, 2001[Abstract]

2. Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr Rev 20:649-688, 1999[Abstract/Free Full Text]

3. Desvergne B, Wahli W, Feilchenfeldt J: Peroxisome proliferator-activated receptors (PPARs) and associated transcription factors in colon cancer: Reduced expression of PPARgamma-coactivator 1 (PGC-1). Nat Rev Cancer 4:61-70, 2004[CrossRef][Medline]

4. Keshamouni VG, Reddy RC, Arenberg DA, et al: Peroxisome proliferator activated receptor gamma activation inhibits tumor progression in non small cell lung cancer. Oncogene 23:100-108, 2004[CrossRef][Medline]

5. Tsubouchi Y, Sano H, Kawahito Y, et al: Inhibition of human lung cancer cell growth by the peroxisome proliferator-activated receptor-gamma agonists through induction of apoptosis. Biochem Biophys Res Commun 270:400-405, 2000[CrossRef][Medline]

6. Jiang M, Shappell S, Hayward S: Approaches to the understanding the importance and clinical implications of peroxisome proliferator activated receptor gamma signaling in prostate cancer. J Cell Biochem 91:513-527, 2004[CrossRef][Medline]

7. Niho N, Takahashi M, Shoji Y, et al: Dose dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPAR gamma ligands. Cancer Res 63:6090-6095, 2003[Abstract/Free Full Text]

8. Kitamura S, Miyazaki Y, Shinomura Y, et al: Peroxisome proliferator-activated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells. Jpn J Cancer Res 90:75-80, 1999[CrossRef]

9. Kopelovich L, Fay JR, Glazer RI, et al: Peroxisome proliferator-activated receptor modulators as potential chemopreventive agents. Mol Cancer Ther 1:357-363, 2002 [erratum appears in Mol Cancer Ther 1:564, 2002][Free Full Text]

10. Saez E, Tontonoz P, Nelson MC, et al: Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 4:1058-1061, 1998[CrossRef][Medline]

11. Panigrahy D, Singer S, Shen L, et al: PPAR gamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest 110:923-932, 2002[CrossRef][Medline]

12. Xin X, Yang S, Kowalski J, et al: Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 274:9116-9121, 1999[Abstract/Free Full Text]

13. Desvergne B, Michalik L, Wahli W: Be fit or sick: Peroxisome proliferator-activated receptors are down the road. Mol Endocrinol 18:1321-1332, 2005[CrossRef]

14. Maynard C, Chapko M: Data resources in the department of Veterans Affairs. Diabetes Care 27:B22-B26, 2004[Abstract/Free Full Text]

15. Bren-Mattison Y, Putten VV, Chan D, et al: Peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC). Oncogene 24:1412-1422, 2005[CrossRef][Medline]

16. Baek SJ, Wilson LC, Hsi LC, et al: Troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand, selectively induces the early growth response-1 gene independently of PPAR gamma: A novel mechanism for its anti-tumorigenic activity. J Biol Chem 278:5845-5853, 2003[Abstract/Free Full Text]

17. James SY, Lin F, Kolluri SK, et al: Regulation of retinoic acid receptor beta expression by peroxisome proliferator-activated receptor gamma ligands in cancer cells. Cancer Res 63:3531-3538, 2003[Abstract/Free Full Text]

18. Satoh T, Toyoda M, Hoshino H, et al: Activation of peroxisome proliferator-activated receptor-gamma stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells. Oncogene 21:2171-2180, 2002[CrossRef][Medline]

19. Hisatake JI, Ikezoe T, Carey M, et al: Downregulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor gamma in human prostate cancer. Cancer Res 60:5494-5498, 2000[Abstract/Free Full Text]

20. Shappell SB, Gupta RA, Manning S, et al: 15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells. Cancer Res 61:497-503, 2001[Abstract/Free Full Text]

21. Kitamura S, Miyazaki Y, Hiraoka S, et al: PPARgamma inhibits the expression of c-MET in human gastric cancer cells through the suppression of Ets. Biochem Biophys Res Commun 265:453-456, 1999[CrossRef][Medline]

22. Smith MR, Manola J, Kaufman D, et al:Roziglitazone versus placebo for men with prostate carcinoma and rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy. Cancer 101:1569-1574, 2004[CrossRef][Medline]

23. Kulke MH, Demetri GD, Sharpless NE, et al: A phase II study of troglitazone, an activator of the PPARgamma receptor, in patients with chemotherapy-resistant metastatic colorectal cancer. Cancer J 8:395-399, 2002[Medline]

24. Larsson SC, Orsini N, Wolk A: Diabetes mellitus and risk of colorectal cancer: A meta analysis. J Natl Cancer Inst 97:1679-1687, 2005[Abstract/Free Full Text]

25. Silverman DT, Hoover RN, Brown LM, et al: Why do black Americans have a higher incidence of pancreatic cancer than white Americans? Epidemiology 14:45-54, 2003[CrossRef][Medline]

26. Zendehdel K, Nyren O, Ostenson CG, et al: Cancer incidence in patients with type I diabetes mellitus: A population-based cohort study in Sweden. J Natl Cancer Inst 95:1797-1800, 2003[Abstract/Free Full Text]

27. Burchard EG, Ziv E, Coyle N, et al: The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med 348:1170-1175, 2003[Free Full Text]

28. Evans WE, Relling MV: Moving towards individualized medicine with pharmacogenomics. Nature 429:464-468, 2004[CrossRef][Medline]

Submitted May 2, 2006; accepted December 6, 2006.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				D. Gras, P. Chanez, V. Urbach, I. Vachier, P. Godard, and C. Bonnans Thiazolidinediones induce proliferation of human bronchial epithelial cells through the GPR40 receptor Am J Physiol Lung Cell Mol Physiol, June 1, 2009; 296(6): L970 - L978. [Abstract] [Full Text] [PDF]

				R. L. Keith Chemoprevention of Lung Cancer Proceedings of the ATS, April 15, 2009; 6(2): 187 - 193. [Abstract] [Full Text] [PDF]

				L. C. Vinikoor, M. D. Long, T. O. Keku, C. F. Martin, J. A. Galanko, and R. S. Sandler The Association between Diabetes, Insulin Use, and Colorectal Cancer among Whites and African Americans Cancer Epidemiol. Biomarkers Prev., April 1, 2009; 18(4): 1239 - 1242. [Abstract] [Full Text] [PDF]

				F. Ondrey Peroxisome Proliferator-Activated Receptor {gamma} Pathway Targeting in Carcinogenesis: Implications for Chemoprevention Clin. Cancer Res., January 1, 2009; 15(1): 2 - 8. [Abstract] [Full Text] [PDF]

				O. Gealekman, A. Burkart, M. Chouinard, S. M. Nicoloro, J. Straubhaar, and S. Corvera Enhanced angiogenesis in obesity and in response to PPAR{gamma} activators through adipocyte VEGF and ANGPTL4 production Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1056 - E1064. [Abstract] [Full Text] [PDF]

				G. D. Girnun, L. Chen, J. Silvaggi, R. Drapkin, L. R. Chirieac, R. F. Padera, R. Upadhyay, S. B. Vafai, R. Weissleder, U. Mahmood, et al. Regression of Drug-Resistant Lung Cancer by the Combination of Rosiglitazone and Carboplatin Clin. Cancer Res., October 15, 2008; 14(20): 6478 - 6486. [Abstract] [Full Text] [PDF]

				R. Nemenoff, A. M. Meyer, T. M. Hudish, A. B. Mozer, A. Snee, S. Narumiya, R. S. Stearman, R. A. Winn, M. Weiser-Evans, M. W. Geraci, et al. Prostacyclin Prevents Murine Lung Cancer Independent of the Membrane Receptor by Activation of Peroxisomal Proliferator-Activated Receptor {gamma} Cancer Prevention Research, October 1, 2008; 1(5): 349 - 356. [Abstract] [Full Text] [PDF]

				M. Monami, C. Lamanna, N. Marchionni, and E. Mannucci Rosiglitazone and Risk of Cancer: A meta-analysis of randomized clinical trials Diabetes Care, July 1, 2008; 31(7): 1455 - 1460. [Abstract] [Full Text] [PDF]

				V Costa, D Foti, F Paonessa, E Chiefari, L Palaia, G Brunetti, E Gulletta, A Fusco, and A Brunetti The insulin receptor: a new anticancer target for peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) and thiazolidinedione-PPAR{gamma} agonists Endocr. Relat. Cancer, March 1, 2008; 15(1): 325 - 335. [Abstract] [Full Text] [PDF]

				M. G. Backlund, J. M. Amann, and D. H. Johnson Novel Strategies for the Treatment of Lung Cancer: Modulation of Eicosanoids J. Clin. Oncol., February 20, 2008; 26(6): 825 - 827. [Full Text] [PDF]

				A. I. Neugut, B. Lebwohl, and D. L. Hershman Cancer Chemoprevention: How Do We Know What Works? J. Clin. Oncol., April 20, 2007; 25(12): 1461 - 1462. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Erratum (v25,p5678) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Govindarajan, R. Articles by Lang, N. P. Search for Related Content PubMed PubMed Citation Articles by Govindarajan, R. Articles by Lang, N. P. Social Bookmarking                            What's this?