Further thoughts on preclinical animal models for cancer prevention: When is it best to start treatment? What are potential histopathologic endpoints?

Division of Cancer Prevention, Gastrointestinal and Other Cancers Research Group, National Cancer Institute, Bethesda, MD, USA.
Seminars in Oncology (Impact Factor: 3.9). 08/2010; 37(4):339-44. DOI: 10.1053/j.seminoncol.2010.07.001
Source: PubMed


One of the major questions in preclinical testing of potential cancer preventive agents is how to most closely approximate the testing protocol to be employed in phase III prevention trials. The nature of tumors arising in situ in animals allows one to initiate agent exposure from the time of tumor initiation until the time that preinvasive lesions already exist. The large phase III prevention trials have routinely followed participants for 3 to 7 years until a cancer endpoint, which generally implies that the timing of the intervention occurs further along during tumor progression. The objective of preclinical testing is to identify agents for large-scale phase III trials. Accordingly, initiating the tested intervention in preclinical studies later in the tumor progression process is more appropriate for any agent being proposed for phase III clinical trials. Furthermore, cancer, rather than advanced dysplastic lesions or other molecular markers (gene or protein expression), is the preferred primary endpoint. However, simultaneous examination of earlier designated "intermediate" endpoints (hyperplasias, dysplasias, or molecular markers) to determine whether their modulation correlates with that of the primary tumor endpoint would be useful, since these latter endpoints may be employed in phase II prevention trials.

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    ABSTRACT: The epidermal growth factor receptor inhibitor Iressa has shown strong preventive efficacy in the N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) model of bladder cancer in the rat. To explore its antitumor mechanism, we implemented a systems biology approach to characterize gene expression and signaling pathways in rat urinary bladder cancers treated with Iressa. Eleven bladder tumors from control rats, seven tumors from rats treated with Iressa, and seven normal bladder epithelia were profiled by the Affymetrix Rat Exon 1.0 ST Arrays. We identified 713 downregulated and 641 upregulated genes in comparing bladder tumors versus normal bladder epithelia. In addition, 178 genes were downregulated and 96 genes were upregulated when comparing control tumors versus Iressa-treated tumors. Two coexpression modules that were significantly correlated with tumor status and treatment status were identified [r = 0.70, P = 2.80 × 10(-15) (bladder tumor vs. normal bladder epithelium) and r = 0.63, P = 2.00 × 10(-42) (Iressa-treated tumor vs. control tumor), respectively]. Both tumor module and treatment module were enriched for genes involved in cell-cycle processes. Twenty-four and twenty-one highly connected hub genes likely to be key drivers in cell cycle were identified in the tumor module and treatment module, respectively. Analysis of microRNA genes on the array chips showed that tumor module and treatment module were significantly associated with expression levels of let-7c (r = 0.54, P = 3.70 × 10(-8) and r = 0.73, P = 1.50 × 10(-65), respectively). These results suggest that let-7c downregulation and its regulated cell-cycle pathway may play an integral role in governing bladder tumor suppression or collaborative oncogenesis and that Iressa exhibits its preventive efficacy on bladder tumorigenesis by upregulating let-7 and inhibiting the cell cycle. Cell culture study confirmed that the increased expression of let-7c decreases Iressa-treated bladder tumor cell growth. The identified hub genes may also serve as pharmacodynamic or efficacy biomarkers in clinical trials of chemoprevention in human bladder cancer.
    Cancer Prevention Research 02/2012; 5(2):248-59. DOI:10.1158/1940-6207.CAPR-10-0363 · 4.44 Impact Factor
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    Readings in Advanced Pharmacokinetics - Theory, Methods and Applications, 04/2012; , ISBN: 978-953-51-0533-6
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    ABSTRACT: Urinary bladder cancer prevention studies were performed with the nonsteroidal anti-inflammatory drugs (NSAIDs) naproxen (standard NSAID with a good cardiovascular profile), sulindac, and their nitric oxide (NO) derivatives. Additionally, the effects of the ornithine decarboxylase inhibitor, difluoromethylornithine (DFMO), alone or combined with a suboptimal dose of naproxen or sulindac was examined. Agents were evaluated at their human equivalent doses (HEDs), as well as at lower doses. In the hydroxybutyl(butyl)nitrosamine (OH-BBN) model of urinary bladder cancer, naproxen (400 or 75 ppm) and sulindac (400 ppm) reduced the incidence of large bladder cancers by 82, 68 and 44%, respectively, when the agents were initially given 3 months after the final dose of the carcinogen; microscopic cancers already existed. NO-naproxen was highly effective, while NO-sulindac was inactive. To further compare naproxen and NO-naproxen, we examined their effects on gene expression in rat livers following a 7 day exposure. Limited, but similar, gene expression changes in the liver were induced by both agents, implying that the primary effects of both are mediated by the parent NSAID. When agents were initiated 2 weeks after the last administration of OH-BBN, DFMO at 1000 ppm had limited activity, a low dose of naproxen (75 ppm) and sulindac (150 ppm) were highly and marginally effective. Combining DFMO with suboptimal doses of naproxen had minimal effects whereas the combination of DMFO and sulindac was more active than either agent alone. Thus, naproxen and NO-naproxen were highly effective, while sulindac was moderately effective in the OH-BBN model at their HEDs.
    Cancer Prevention Research 12/2013; 7(2). DOI:10.1158/1940-6207.CAPR-13-0164 · 4.44 Impact Factor
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