Loading

wait a moment

Chemoprevention of Lung Cancer in Transgenic Mice: Use of A/J Mice in Chemoprevention Studies

The A/J mouse lung model of chemical carcinogenesis has been the most frequently employed murine model both for testing for potential chemical carcinogens and to screen for agents that prevent carcinogenesis (chemopre-ventive agents). The model has been shown to respond to a wide variety of potential chemical carcinogens, including the tobacco-related carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(a)pyrene, yielding multiple peripheral adenomas. Among the agents tested in A/J mice, several groups of chemicals have shown significant efficacy against mouse lung tumor development.

For example, glucocorticoids, green tea, nonsteroidal anti-inflammatory drugs, isothiocyanates, and farnesyl-transferase inhibitors (FTIs) are among the most effective compounds. Table 1 summarizes the efficacy of glucocorticoids and FTIs that have been tested in A/J mice and transgenic mice. Glucocorticoids were found to be a strong inhibitor of carcinogenesis in skin, forestomach, and lung in rodents. Wattenberg and Estensen reported that dexamethasone, a synthetic glucocorticoid, inhibits lung tumorigenesis by 56%, and by 86% when dexamethasone was administered with myo-inositol. In order to minimize the systemic toxic effects, glucocorticoids such as budesonide can be successfully delivered by aerosol, and by this method inhibit lung tumor development by > 90%.” Recently, we have found that FTI is chemopreventive on both the established lung adenomas model and the complete carcinogenesis model from A/J mice induced by NNK. FTI-276 was used, which is a CAAX peptidomimetic of the carboxyl terminal of Ras proteins. FTI-276 inhibited lung tumor size by 58% in an established mouse lung tumor model, and by 79% in a complete chemoprevention model. These results demonstrated that FTI-276 is chemopreventive in both the established lung adenomas model and the complete carcinogenesis model. These studies support the importance of using animal models in testing and characterization of cancer chemopreventive agents. More recently, a specific farnesyltransferase inhibitor, R115777, was tested for its efficacy against lung tumor development in A/J mice using NNK, and was found to exhibit 58% inhibition of lung tumor multiplicity.
Table 1—Glucocorticoids and FTI Tested in Mouse Lung Tumor Models

Class/Agent

Animal Model

Route

Carcinogen

Effect,

%

Source

Glucocorticoids

Dexamethasone

a/j

Diet

Benzo(a)pyrene

56

Wattenberg and Estensen

Dexamethasone plus

a/j

Diet

Benzo(a)pyrene

86

Wattenberg and Estensen

myo-inositol

Budesonide

a/j

Diet

Benzo(a)pyrene

89

Herzog et al

Budesonide

a/j

Aerosol

Benzo(a)pyrene

90

Wattenberg et al

Dexamethasone plus

p53Val135/wt (A/JxFVB/J)Fj

Diet

NNK

70-73

Zhang et al

myo-inositol

Budesonide

p53+/~Ink4a/Arf+/~ (A/J)

Diet

Benzo(a)pyrene

40-95

Wang et al

FTI

Perillyl alcohol

A/J

IP

NNK

58

You and Bergman

D-Iimonene

A/J

IG

NNK

78

You and Bergman

Lovastatin

A/J

Diet

NNK

48

You and Bergman

Farnesol

A/J

Diet

NNK

35

You and Bergman

FTI-276

A/J

Time-release

NNK

40-60

Lantry et al and

pellet

Zhang et al

R115777

A/J

Diet

VC

58

Gunning et al

L778,123

p53+/~Ink4a/Arf+/~ (A/J)

SC

Benzo(a)pyrene

42-60

Zhang et al