Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Assessing intraepithelial neoplasia and drug safety in cancer-preventive drug development

Nature Reviews Cancer volume 7, pages 508–518 (2007)Cite this article

Key Points

  • Focusing development efforts for cancer-preventive drugs on precancerous lesions (that is,intraepithelial neoplasia (IEN)) can reduce costs and accelerate the emergence of new cancer-preventive drugs.

  • IEN addresses both risk and clinical endpoints, as it is part of the process of neoplastic progression and not just a biomarker of it.

  • Examples of IEN conferring high risk for progression are colorectal adenomas, breast ductal carcinoma in situ (DCIS), oral dysplasia, high-grade prostatic intraepithelial neoplasia (PIN), Barrett oesophagus and dysplastic nevi. Risk of progression is best estimated by combining IEN with other risk markers/factors.

  • Examples of cancer-prevention clinical endpoints that involve IEN include treatment and prevention of colorectal adenomas, treatment of oral dysplasia, prevention of DCIS and treatment of Barrett oesophagus. In addition to cancer prevention, clinical benefits include reduced morbidity, reduced cost and increased availability of treatment.

  • Several drugs have shown promising efficacy in preventing cancers and in preventing and treating IEN (for example,tamoxifen, raloxifene, celecoxib, finasteride, toremifene, tea polyphenols and statins), but some have also encountered problems that provide lessons that can be applied in future strategies to bring cancer-preventive drugs to market.

  • Demonstrating long-term drug safety is the toughest challenge. Because target populations for cancer-prevention drugs are asymptomatic, and might take the drugs for many years, little toxicity can be tolerated. Methods must be developed to detect and evaluate significant toxicities that occur rarely, and any toxicity that occurs across multiple trials. This might be improved by rigorous post-marketing surveillance.

Abstract

Despite significant interest from the research community and the population in general, drug approvals for cancer prevention and/or cancer risk reduction are few. This is due, in part, to the requirement that new cancer-preventive drugs must first be shown to be efficacious in reducing cancer incidence or mortality. Moreover, such drugs need to have proven safety for long-term administration. This process can be improved by focusing on precancer (intraepithelial neoplasia) to identify subjects at risk and prove efficacy in shorter, smaller trials as well as on detecting early markers of potential toxicities of chronic exposure to cancer-preventive drug regimens.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: IEN, genetic progression and cancer risk: opportunities for cancer-preventive intervention.

Similar content being viewed by others

References

  1. Bacus, J. W. et al. Image morphometric nuclear grading of intraepithelial neoplastic lesions with applications to cancer chemoprevention trials. Cancer Epidemiol. Biomarkers Prev. 8, 1087–1094 (1999).

    CAS  PubMed  Google Scholar 

  2. Kelloff, G. J. Perspectives on cancer chemoprevention research and drug development. Adv. Cancer Res. 78, 199–334 (2000).

    Article  CAS  Google Scholar 

  3. Kelloff, G. J. et al. Biomarkers, surrogate end points, and the acceleration of drug development for cancer prevention and treatment: an update prologue. Clin. Cancer Res. 10, 3881–3884 (2004).

    Article  CAS  Google Scholar 

  4. Kelloff, G. J. et al. Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer. Cancer Epidemiol. Biomarkers Prev. 9, 127–137 (2000).

    CAS  PubMed  Google Scholar 

  5. O'Shaughnessy, J. A. et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin. Cancer Res. 8, 314–346 (2002). This article defines IEN, its clinical significance, and suggested clinical-trial designs of chemopreventive agents in nine target organs.

    PubMed  Google Scholar 

  6. De Gruttola, V. G. et al. Considerations in the evaluation of surrogate endpoints in clinical trials. Summary of a National Institutes of Health workshop. Control Clin. Trials 22, 485–502 (2001).

    Article  CAS  Google Scholar 

  7. Gail, M. H. The estimation and use of absolute risk for weighing the risks and benefits of selective estrogen receptor modulators for preventing breast cancer. Ann. NY Acad. Sci. 949, 286–291 (2001). A gold-standard statistical-methods paper that calculates absolute risk, as compared to the more commonly used relative risk. The former allows absolute risk assignment to an individual and is valuable for clinical-trial size estimates and counselling of individual patients.

    Article  CAS  Google Scholar 

  8. Gail, M. H. & Greene, M. H. Gail model and breast cancer. Lancet 355, 1017 (2000).

    Article  CAS  Google Scholar 

  9. Fisher, B. et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90, 1371–1388 (1998).

    Article  CAS  Google Scholar 

  10. Freedman, A. N. et al. Cancer risk prediction models: a workshop on development, evaluation, and application. J. Natl Cancer Inst. 97, 715–723 (2005).

    Article  Google Scholar 

  11. Kelloff, G. J. et al. Colorectal adenomas: a prototype for the use of surrogate end points in the development of cancer prevention drugs. Clin. Cancer Res. 10, 3908–3918 (2004).

    Article  CAS  Google Scholar 

  12. Bertagnolli, M. M. et al. Celecoxib for the prevention of sporadic colorectal adenomas. N. Engl J. Med. 355, 873–884 (2006). Comprehensive clinical trial establishing the efficacy of celecoxib for prevention of sporadic colorectal adenomas and the associated toxicity of celecoxib administration.

    Article  CAS  Google Scholar 

  13. Kelloff, G. J. et al. Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer — a plan to move forward. Clin. Cancer Res. 12, 3661–3697 (2006). An update of the comprehensive overview of IEN in reference 5 that defines the concept of molecular IEN and its value in refining the risk of neoplastic progression conferred by histopathological IEN.

    Article  CAS  Google Scholar 

  14. Sporn, M. B. Dichotomies in cancer research: some suggestions for a new synthesis. Nature Clin. Pract. Oncol. 3, 364–373 (2006). This paper establishes neoplastic progression as a continuum from early changes to invasive cancer and, therefore, much can be learned in formulating chemoprevention strategies by evaluating the data generated in cancer-treatment trials of newer molecularly targeted agents.

    Article  Google Scholar 

  15. Kelloff, G. J., O'Shaughnessy, J. A., Gordon, G. B., Hawk, E. T. & Sigman, C. C. Counterpoint. Because some surrogate end point biomarkers measure the neoplastic process they will have high utility in the development of cancer chemopreventive agents against sporadic cancers. Cancer Epidemiol. Biomarkers Prev. 12, 593–596 (2003).

    PubMed  Google Scholar 

  16. Gutman, S. & Kessler, L. G. The US Food and Drug Administration perspective on cancer biomarker development. Nature Rev. Cancer 6, 565–571 (2006). A clear statement of the scientific considerations that underpin regulatory policy for marketing approval of new biomarker tests.

    Article  CAS  Google Scholar 

  17. Frank, R. & Hargreaves, R. Clinical biomarkers in drug discovery and development. Nature Rev. Drug Discov. 2, 566–580 (2003).

    Article  CAS  Google Scholar 

  18. Pepe, M. S. et al. Phases of biomarker development for early detection of cancer. J. Natl Cancer Inst. 93, 1054–1061 (2001). This article defines five distinct, sequential study designs to evaluate the clinical utility of a potential biomarker.

    Article  CAS  Google Scholar 

  19. Rolan, P., Atkinson, A. J. Jr. & Lesko, L. J. Use of biomarkers from drug discovery through clinical practice: report of the Ninth European Federation of Pharmaceutical Sciences Conference on Optimizing Drug Development. Clin. Pharmacol. Ther. 73, 284–291 (2003).

    Article  Google Scholar 

  20. Ransohoff, D. F. Rules of evidence for cancer molecular-marker discovery and validation. Nature Rev. Cancer 4, 309–314 (2004).

    Article  CAS  Google Scholar 

  21. Kelloff, G. J. & Sigman, C. C. New science-based endpoints to accelerate oncology drug development. Eur. J. Cancer 41, 491–501 (2005).

    Article  Google Scholar 

  22. Steinbach, G. et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 342, 1946–1952 (2000).

    Article  CAS  Google Scholar 

  23. Arber, N. et al. Celecoxib for the prevention of colorectal adenomatous polyps. N. Engl. J. Med. 355, 885–895 (2006).

    Article  CAS  Google Scholar 

  24. Fabian, C. J. & Kimler, B. F. Breast cancer chemoprevention: current challenges and a look toward the future. Clin. Breast Cancer 3, 113–124 (2002).

    Article  Google Scholar 

  25. Fabian, C. J. et al. Models for early chemoprevention trials in breast cancer. Hematol. Oncol. Clin. North Am. 12, 993–1017 (1998).

    Article  CAS  Google Scholar 

  26. Chen, Y. et al. Analysis of expression patterns: the scope of the problem, the problem of scope. Dis. Markers 17, 59–65 (2001).

    Article  Google Scholar 

  27. Troester, M. & Perou, C. M. in Cancer Chemoprevention Vol. 2: Strategies for Cancer Chemoprevention (eds. Kelloff, G. J., Hawk, E. T. & Sigman, C. C.), 115–122 (Humana Press, Totowa, New Jersey, 2005).

    Book  Google Scholar 

  28. Reid, B. J. et al. Predictors of progression in Barrett's esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression. Am. J. Gastroenterol. 96, 2839–2848 (2001).

    Article  CAS  Google Scholar 

  29. Galipeau, P. C. et al. A panel of molecular and cytometric markers in Barrett's esophagus predicts progression to esophageal adenocarcinoma. Gastroenterology 126, A114 (2004).

    Article  Google Scholar 

  30. El-Deiry, W. S., Sigman, C. C. & Kelloff, G. J. Imaging and oncologic drug development. J. Clin. Oncol. 24, 3261–3273 (2006).

    Article  CAS  Google Scholar 

  31. Weissleder, R., Tung, C. H., Mahmood, U. & Bogdanov, A. Jr. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nature Biotechnol. 17, 375–378 (1999).

    Article  CAS  Google Scholar 

  32. Fantini, S., Heffer, E. L., Pera, V. E., Sassaroli, A. & Liu, N. Spatial and spectral information in optical mammography. Technol. Cancer Res. Treat. 4, 471–482 (2005).

    Article  Google Scholar 

  33. Roy, H. K. et al. Risk stratification of colon carcinogenesis through enhanced backscattering spectroscopy analysis of the uninvolved colonic mucosa. Clin. Cancer Res. 12, 961–968 (2006).

    Article  Google Scholar 

  34. Muller, M. G. et al. Spectroscopic detection and evaluation of morphologic and biochemical changes in early human oral carcinoma. 97, 1681–1692 (2003).

  35. Kelloff, G. J. et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin. Cancer Res. 11, 2785–2808 (2005).

    Article  CAS  Google Scholar 

  36. Shields, A. F. PET imaging with 18F-FLT and thymidine analogs: promise and pitfalls. J. Nucl. Med. 44, 1432–1434 (2003).

    CAS  PubMed  Google Scholar 

  37. Fisher, B. et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J. Natl Cancer Inst. 97, 1652–1662 (2005). Comprehensive clinical trial establishing the efficacy of tamoxifen for the prevention of breast cancer and the associated toxicity of tamoxifen administration.

    Article  CAS  Google Scholar 

  38. Jensen, E. V. & Jordan, V. C. The estrogen receptor: a model for molecular medicine. Clin. Cancer Res. 9, 1980–1989 (2003).

    CAS  PubMed  Google Scholar 

  39. Armstrong, K., Quistberg, D. A., Micco, E., Domchek, S. & Guerra, C. Prescription of tamoxifen for breast cancer prevention by primary care physicians. Arch. Intern. Med. 166, 2260–2265 (2006).

    Article  Google Scholar 

  40. Port, E. R., Montgomery, L. L., Heerdt, A. S. & Borgen, P. I. Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann. Surg. Oncol. 8, 580–585 (2001).

    Article  CAS  Google Scholar 

  41. Vogel, V. G. et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295, 2727–2741 (2006).

    Article  CAS  Google Scholar 

  42. Freedman, A. N. et al. Estimates of the number of US women who could benefit from tamoxifen for breast cancer chemoprevention. J. Natl Cancer Inst. 95, 526–532 (2003).

    Article  CAS  Google Scholar 

  43. Gatto, N. M. et al. Risk of perforation after colonoscopy and sigmoidoscopy: a population-based study. J. Natl Cancer Inst. 95, 230–236 (2003).

    Article  Google Scholar 

  44. Solomon, S. D. et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation 114, 1028–1035 (2006).

    Article  CAS  Google Scholar 

  45. Bresalier, R. S. et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N. Engl. J. Med. 352, 1092–1102 (2005).

    Article  CAS  Google Scholar 

  46. Ulrich, C. M., Bigler, J. & Potter, J. D. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nature Rev. Cancer 6, 130–140 (2006).

    Article  CAS  Google Scholar 

  47. Solomon, S. D. et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N. Engl. J. Med. 352, 1071–1080 (2005).

    Article  CAS  Google Scholar 

  48. Cauley, J. A. et al. Lipid-lowering drug use and breast cancer in older women: a prospective study. J. Womens Health (Larchmt) 12, 749–756 (2003).

    Google Scholar 

  49. Demierre, M. F., Higgins, P. D., Gruber, S. B., Hawk, E. & Lippman, S. M. Statins and cancer prevention. Nature Rev. Cancer 5, 930–942 (2005).

    Article  CAS  Google Scholar 

  50. Friis, S. et al. Cancer risk among statin users: a population-based cohort study. Int. J. Cancer 114, 643–647 (2005).

    Article  CAS  Google Scholar 

  51. Graaf, M. R., Beiderbeck, A. B., Egberts, A. C., Richel, D. J. & Guchelaar, H. J. The risk of cancer in users of statins. J. Clin. Oncol. 22, 2388–2394 (2004).

    Article  CAS  Google Scholar 

  52. Poynter, J. N. et al. Statins and the risk of colorectal cancer. N. Engl. J. Med. 352, 2184–2192 (2005).

    Article  CAS  Google Scholar 

  53. Reddy, B. S. et al. Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 rats. Cancer Res. 66, 4542–4546 (2006).

    Article  CAS  Google Scholar 

  54. Thompson, I. M. et al. The influence of finasteride on the development of prostate cancer. N. Engl. J. Med. 349, 215–224 (2003).

    Article  CAS  Google Scholar 

  55. Steiner, M. S. & Raghow, S. Antiestrogens and selective estrogen receptor modulators reduce prostate cancer risk. World J. Urol. 21, 31–36 (2003).

    CAS  PubMed  Google Scholar 

  56. Ross, R. K. et al. Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Res. 58, 4497–4504 (1998).

    CAS  PubMed  Google Scholar 

  57. Makridakis, N. & Reichardt, J. K. Pharmacogenetic analysis of human steroid 5α reductase type II: comparison of finasteride and dutasteride. J. Mol. Endocrinol. 34, 617–623 (2005).

    Article  CAS  Google Scholar 

  58. Andriole, G. et al. Chemoprevention of prostate cancer in men at high risk: rationale and design of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. J. Urol. 172, 1314–1317 (2004).

    Article  CAS  Google Scholar 

  59. Steiner, M. S. & Pound, C. R. Phase IIA clinical trial to test the efficacy and safety of toremifene in men with high-grade prostatic intraepithelial neoplasia. Clin. Prostate Cancer 2, 24–31 (2003).

    Article  CAS  Google Scholar 

  60. Price, D. et al. Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial. J. Urol. 176, 965–970 (2006).

    Article  CAS  Google Scholar 

  61. Bettuzzi, S. et al. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res. 66, 1234–1240 (2006).

    Article  CAS  Google Scholar 

  62. Cook, L. S. et al. A population-based study of contralateral breast cancer following a first primary breast cancer (Washington, United States). Cancer Causes Control 7, 382–390 (1996).

    Article  CAS  Google Scholar 

  63. Singletary, S. E., Taylor, S. H., Guinee, V. F. & Whitworth, P. W. Jr. Occurrence and prognosis of contralateral carcinoma of the breast. J. Am. Coll. Surg. 178, 390–396 (1994).

    CAS  PubMed  Google Scholar 

  64. Kelsey, J. L. & Gammon, M. D. The epidemiology of breast cancer. CA Cancer J. Clin. 41, 146–165 (1991).

    Article  CAS  Google Scholar 

  65. Lippman, S. M. & Hong, W. K. Molecular markers of the risk of oral cancer. N. Engl. J. Med. 344, 1323–1326 (2001).

    Article  CAS  Google Scholar 

  66. Schwartz, J. L. Biomarkers and molecular epidemiology and chemoprevention of oral carcinogenesis. Crit. Rev. Oral Biol. Med. 11, 92–122 (2000).

    Article  CAS  Google Scholar 

  67. Tucker, M. A. et al. Clinically recognized dysplastic nevi. A central risk factor for cutaneous melanoma. JAMA 277, 1439–1444 (1997).

    Article  CAS  Google Scholar 

  68. Collard, J. M. High-grade dysplasia in Barrett's esophagus. The case for esophagectomy. Chest Surg. Clin. N. Am. 12, 77–92 (2002).

    Article  Google Scholar 

  69. Chang, S. S. & Cookson, M. S. Radical cystectomy for bladder cancer: the case for early intervention. Urol. Clin. North Am. 32, 147–155 (2005).

    Article  Google Scholar 

  70. Benner, S. E., Hong, W. K., Lippman, S. M., Lee, J. S. & Hittelman, W. M. Intermediate biomarkers in upper aerodigestive tract and lung chemoprevention trials. J. Cell Biochem. Suppl. 16G, 33–38 (1992).

    Article  CAS  Google Scholar 

  71. Berry, D. A. et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J. Clin. Oncol. 20, 2701–2712 (2002).

    Article  CAS  Google Scholar 

  72. Evans, W. E. & McLeod, H. L. Pharmacogenomics — drug disposition, drug targets, and side effects. N. Engl. J. Med. 348, 538–549 (2003).

    Article  CAS  Google Scholar 

  73. Lesko, L. J. & Woodcock, J. Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nature Rev. Drug Discov. 3, 763–769 (2004).

    Article  CAS  Google Scholar 

  74. Kelloff, G. J. et al. Surrogate end-point biomarkers in chemopreventive drug development. IARC Sci. Publ. 154, 13–26 (2001).

    CAS  PubMed  Google Scholar 

  75. Rolan, P. The contribution of clinical pharmacology surrogates and models to drug development — a critical appraisal. Br. J. Clin. Pharmacol. 44, 219–225 (1997).

    Article  CAS  Google Scholar 

  76. Swanson, B. N. Delivery of high-quality biomarker assays. Dis. Markers 18, 47–56 (2002).

    Article  CAS  Google Scholar 

  77. Bossuyt, P. M. et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Ann. Intern. Med. 138, W1–W12 (2003).

    Article  Google Scholar 

  78. Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Ins.t 92, 205–216 (2000).

    Article  CAS  Google Scholar 

  79. McShane, L. M. et al. Reporting recommendations for tumor marker prognostic studies (REMARK). J. Natl Cancer Inst. 97, 1180–1184 (2005).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cancer Treatment and Diagnosis, National Institutes of Health, National Cancer Institute, Executive Plaza North Room 6058, 6130 Executive Boulevard, Rockville, 20852, Maryland, USA

    Gary J. Kelloff

  2. CCS Associates, 2005 Landings Drive, Mountain View, 94043, California, USA

    Caroline C. Sigman

Authors
  1. Gary J. Kelloff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline C. Sigman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary J. Kelloff.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Early Detection Research Network (NCI, Division of Cancer Prevention)

FDA Critical Path Initiative

International HapMap Project

Medsun — Medical Product Safety Network

Glossary

Intraepithelial neoplasia

(IEN: dysplasia or precancer). The histopathological abnormality of the epithelia of organs. IEN is characterized by changes in the size and shape of cell nuclei, and increases in the number of, and abnormalities in, cell mitoses. Abnormalities that are confined by the basement membrane distinguish this neoplastic state (precancer) from invasive neoplasia (cancer).

Clinical endpoints

(for preclinical and clinical studies). Events or outcomes, usually study objectives, which can be measured to determine the effectiveness of the intervention.

Gail risk model

An algorithm formulated by Mitchell Gail that uses personal and family history to estimate a womans absolute risk of developing breast cancer.

Hyperplasia

An abnormal increase in the number of cells in an organ or tissue.

Sigmoidoscopy

The examination of the lower (sigmoid) colon, which might also involve the removal of tissue for pathological examination.

Colonoscopy

The examination of the entirety of the colon, which might also involve the removal of tissue for pathological examination.

Oral leukoplakia

Leukoplakia (white patches in the mouth that cannot be rubbed off and are not diagnosable clinically or histologically as any other specific disease) is a pre-malignant lesion of which 2–5% over 10 years progress to squamous cell carcinoma. There is no clear correlation between the histological grading of dysplasia and the prognosis in individual cases.

Haplotype Mapping Project

(HapMaP). The National Human Genome Research Institute's project to catalogue the genetic variations that are of most importance to human health.

Familial adenomatous polyposis coli

(FAP). An inherited condition in which numerous polyps form on the inside walls of the colon and rectum, increasing the risk of colorectal cancer (to nearly 100% by age 50, if untreated).

Predictive Safety Testing Consortium

A collaboration of industry, academia and government to identify and clinically qualify safety biomarkers to better understand the safety profiles of compounds, develop methods to troubleshoot compounds that fail preclinical drug-safety assessment, predict and prevent post-marketing safety issues and speed and/or reduce the cost of preclinical drug-safety evaluation.

Cyclooxygenase 2

(COX2). An inducible enzyme that is involved in the formation of prostanoids, such as prostaglandin, and is found in activated macrophages and other cells at sites of inflammation.

Fine-needle aspiration

(FNA). The removal of tissue or fluid with a fine needle for microscopic examination. Also known as needle biopsy.

Barrett oesophagus

A change towards abnormality in the cells lining the lower oesophagus caused by long-term gastroesophageal reflux, which could lead to cancer of the oesophagus.

Loss of heterozygosity

(LOH). The loss of one of the two alleles at one or more loci in a cell lineage or cancer-cell population owing to chromosome loss, deletion, or mitotic crossing-over.

Relative risk

The ratio of risk of disease or death among in individuals who are exposed to a drug or other factors compared with those who are not exposed.

Near-infrared fluorescence

(NIRF). The induction and emission of fluorescence by exposure of specific substrates to near-infrared (700–900 nm) photon emissions. NIRF is useful for optical imaging of tissues because of low interference with haemoglobin and other biomolecules.

Spectral karyotyping

A visualization of all of an organism's chromosomes together, each labelled with a different colour, which is useful for identifying chromosome abnormalities.

18F-fluorodeoxyglucose positron-emission tomography

(FDG-PET). A radio-labelled imaging methodology for detecting cancers using increased glucose metabolism – a characteristic of cancers and other pathologies.

Glycolysis

The ability of cells to partially break down glucose in anaerobic enzyme reactions; when combined with aerobic enzyme reactions, a more complete breakdown occurs, producing more energy.

18F-Fluorodeoxythymidine PET

(FLT-PET). A radio-labelled imaging methodology using thymidine uptake to detect the abnormal cell proliferation that is characteristic of cancers.

Selective-oestrogenreceptor modulator

(SERM). A drug that acts like oestrogen on some tissues but blocks the effect of oestrogen on other tissues (tamoxifen and raloxifene are SERMs).

Ductal carcinoma in situ

(DCIS). A non-invasive condition in which abnormal cells in the lining of a breast duct remain encapsulated without spreading to other breast tissues; DCIS can progress to invasive cancer.

Polypectomy

Surgery to remove a polyp.

Hereditary non-polyposis colorectal cancer syndrome

(HNPCC). An inherited disorder carrying a higher-than-normal risk of developing colorectal cancer and other cancers, often before the age of 50; also called Lynch syndrome.

Dysplastic nevus syndrome

A disorder of the skin characterized by the presence of many mole-like tumours (nevi).

Li-Fraumeni syndrome

A rare, inherited predisposition to multiple cancers, caused by an alteration in the TP53 tumour-suppressor gene.

Genetic polymorphisms

Variations in DNA (observed in 1% or more of the population) that might alter protein structure and function or might increase or decrease gene expression. Sites in the DNA sequence where individuals differ at a single DNA base are called single-nucleotide polymorphisms (SNPs).

Prostate-specific antigen

(PSA). A protein produced by the prostate that is increased in the blood of men with prostate cancer, benign prostatic hyperplasia, or infection or inflammation of the prostate.

Antioxidant

Substances such as β-carotene, lycopene, and vitamins A, C, and E that protect cells from oxidative damage. Such damage is thought to have a role in cancer, heart disease, stroke and other diseases of ageing.

International Prostate Symptom Score

(IPSS). A questionnaire used in clinical trials to quantify urinary symptoms that are associated with benign prostatic hyperplasia.

Dysplastic nevi

Atypical moles, generally larger than ordinary moles, with irregular and indistinct borders and non-uniform color ranging from pink to dark brown, that are usually flat (but parts might be raised above the skin surface).

Cystectomy

Surgery to remove all or part of the bladder.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kelloff, G., Sigman, C. Assessing intraepithelial neoplasia and drug safety in cancer-preventive drug development. Nat Rev Cancer 7, 508–518 (2007). https://doi.org/10.1038/nrc2154

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2154

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing