Preclinical Mouse Models for Cancer Chemoprevention Studies

Lipkin, Martin; Yang, Kan; Edelmann, Winfried; Xue, Lexun; Fan, Kunhua; Risio, Mauro; Newmark, Harold L.; Kucherapati, Raju

doi:10.1111/j.1749-6632.1999.tb08719.x

Cited by 36 publications

(21 citation statements)

References 10 publications

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“…To this end, we determined the effect of equimolar amounts of the meta-and para-isomers of NO-ASA on the development of gastrointestinal tumors in the Min (Apc min/ϩ ) mouse model of intestinal cancer. Min mice have a truncating mutation in the Apc gene that predisposes them to the development of gastrointestinal tumors, mainly in the small intestine (Lipkin et al, 1999). In many important ways, this model system recapitulates the salient steps of colon carcinogenesis and thus represents a useful (and extensively utilized) experimental system.…”

Section: Resultsmentioning

confidence: 99%

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Positional Isomerism Markedly Affects the Growth Inhibition of Colon Cancer Cells by Nitric Oxide-Donating Aspirin in Vitro and in Vivo

Kashfi¹,

Borgo²,

Williams³

et al. 2004

J Pharmacol Exp Ther

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NO-donating aspirin (NO-ASA), a novel pharmacological agent currently undergoing clinical testing, consists of ASA to which a nitrate group is covalently linked via a spacer molecule. We synthesized the three positional isomers of NO-ASA with respect to the -CH 2 ONO 2 group (ortho, meta, and para) and examined whether this isomerism affects the biological activity of NO-ASA on HT-29 human colon cancer cells. The ortho-and para-isomers showed similar IC 50 values (1-5 M) for cell growth inhibition over 72 h, whereas the IC 50 of the metaisomer was 200 to 500 M. The ortho-and para-isomers inhibited cell proliferation more potently than the meta-isomer. All three induced apoptosis but the ortho-and para-isomers also induced atypical cells (they maintain their shape but have diminished or absent nuclear material). Treatment for 3 weeks of Min (Apc min/ϩ ) mice, a model of intestinal cancer, with equimolar amounts of meta-and para-NO-ASA decreased the number of tumors in the small intestine by 36 and 59% (P Ͻ 0.01), respectively, compared with vehicle-treated controls, thus confirming their in vitro differences in potency. A structure-activity study of the three isomers revealed that substituting an aliphatic for the aromatic spacer or removing the -ONO 2 group profoundly diminished NO-ASA's ability to inhibit cell growth, whereas removal of the acetyl group on the ASA moiety did not affect cell growth inhibition. Thus, positional isomerism is critical for the pharmacological properties of NO-ASA against colon cancer and it should be taken into consideration in rational drug design.

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Section: Resultsmentioning

confidence: 99%

“…This is the reason why we assessed their validity in an animal model system of colon cancer. Min mice offered such a model (Lipkin et al, 1999). The para-isomer was twice as potent as the meta-isomer in reducing the number of intestinal tumors in these mice, even after a relatively brief treatment period.…”

Section: Discussionmentioning

confidence: 99%

Positional Isomerism Markedly Affects the Growth Inhibition of Colon Cancer Cells by Nitric Oxide-Donating Aspirin in Vitro and in Vivo

Kashfi¹,

Borgo²,

Williams³

et al. 2004

J Pharmacol Exp Ther

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“…Vitamin D intake and sunlight exposure play a protective role against colorectal carcinogenesis [180]. It has been reported that a Western-style diet with decreased levels of calcium and vitamin D increases the incidence of pre-neoplasic intestinal lesions in mouse models of intestinal tumorigenesis [181]. Addition of dietary calcium and vitamin D significantly suppresses Western-diet induced changes, both in normal and Apc mutant mice [181].…”

Section: Vdrmentioning

confidence: 99%

Nuclear receptors, intestinal architecture and colon cancer: an intriguing link

D'Errico

Moschetta

2008

Cell. Mol. Life Sci.

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The intestinal epithelium is structured in crypt-villus units which are responsible for its continuous renewal. These units are organized in a dynamic scenario in which proliferating progenitor cells are generated from stem cells in the crypts and migrate along the villus axis until their extrusion as differentiated cells at the surface epithelium. The mechanisms controlling cell transition involve transcription factors that switch on and off compartment-specific genes. The Wnt cascade represents the dominant force controlling cell fate in the crypt-villus axis. Mutations in this cascade result in the development of colorectal cancer. Life-style modifications and dietary regimens are epidemiologically recognized contributing factors for intestinal tumorigenesis. Nuclear receptors are a family of transcription factors functioning as sensors of dietary and endogenous molecules, thus translating nutritional and hormonal stimuli into transcriptional modifications. This review presents the role of nuclear receptors in intestinal carcinogenesis and explores their influence in maintenance of intestinal epithelium architecture.

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“…Molecular studies of the well-known relationship between polyunsaturated fatty acid metabolism and carcinogenesis have revealed novel molecular targets for cancer chemoprevention and treatment (Lipkin et al, 1999;Willett, 1997;Klurfeld & Bull, 1997;Guthrie & Carroll, 1999). The role of lipoxygenase in the development and progression of cancer is complex due to the variety of lipoxygenase genes that have been identified in humans, in addition to different profiles of lipoxygenase observed between studies on human tumor biopsies and experimentally induced animal tumor models (Pidgeon et al, 2007).…”

Section: Lox Inhibition In Cancermentioning

confidence: 99%