Prevention of mouse lung tumors by budesonide and its modulation of biomarkers

Pereira, Michael A.; Li, Yingzhe; Gunning, William T.; Kramer, Paula M.; Alyaqoub, Fadel S.; Lubet, Ronald A.; Steele, Vernon E.; Szabó, Éva; Tao, Lianhui

doi:10.1093/carcin/23.7.1185

Cited by 54 publications

(53 citation statements)

References 27 publications

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“…Neither the multiplicity nor the incidence of lung adenomas in the carcinogentreated groups with and without test compound differed significantly. As expected in the A/J mouse model, a few spontaneous lung adenomas with incidence ranging from 0% to 25% were observed in groups not treated with carcinogens (groups [10][11][12][13][14]. The only exception was group 10, which had a 40% incidence.…”

Section: Resultssupporting

confidence: 58%

“…Again, there were no significant differences of these lesions among the carcinogen-treated control group and groups 2 to 9. Among the control groups not treated with carcinogens (groups [10][11][12][13][14], no significant differences in the multiplicity and incidence of adenomas were observed.…”

Section: Resultsmentioning

confidence: 99%

“…Part of the reason for this is the scarcity of information from studies in animals. To our knowledge, only a limited number of agents, i.e., black tea polyphenol constituents (9), budesonide (10,11), lycopene (12), and myoinositol (11) have been studied for their chemopreventive activity during the progression phase after benign lung tumors had already developed.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

et al. 2005

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We have shown previously that naturally occurring isothiocyanates derived from cruciferous vegetables and their N-acetylcysteine conjugates inhibit lung adenoma formation induced by tobacco carcinogens in A/J mice at the postinitiation stage. The tumor-inhibitory activity by these compounds is linked with activation of activator protein and induction of apoptosis in lung tissues, suggesting that these compounds may also inhibit the development of adenomas to adenocarcinomas in lung. In this study, the chemopreventive activity of phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates during progression of lung adenomas to malignant tumors was investigated in A/J mice. Mice were divided into 14 groups and treated with a mixture of 3 Mmol benzo(a)pyrene [B(a)P] and 3 Mmol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) given by gavage once weekly for 8 weeks. Twenty weeks after the beginning of carcinogen administration, a total of 20 mice in the treatment groups were sacrificed with an average yield of 7.3 F 4.5 lung adenomas per mouse. The remaining mice in each group were fed diets containing phenethyl isothiocyanate (3 and 1.5 mmol/kg diet), sulforaphane (3 and 1.5 mmol/kg diet), phenethyl isothiocyanate-N-acetylcysteine (8 and 4 mmol/kg diet), sulforaphane-N-acetylcysteine (8 and 4 mmol/kg diet) during weeks 21 to 42. Four mice in each of the high-dose treatment groups were sacrificed during weeks 28 and 36 and the bioassay was terminated during week 42; lung tissues were harvested for histopathologic examination of tumors and for cell proliferation (proliferating cell nuclear antigen) and apoptosis (caspase-3) assays using immunohistochemical staining. At termination, the incidence of adenocarcinoma in the 3 mmol/kg diet phenethyl isothiocyanate group and 8 mmol/kg diet phenethyl isothiocyanate-N-acetylcysteine group was reduced to 19% and 13%, respectively, compared with 42% in the carcinogen-treated control group. At the lower doses, phenethyl isothiocyanate and its N-acetylcysteine conjugate also inhibited the incidences of lung adenocarcinoma, however, the decreases were not statistically significant. The lung tumor incidences in groups treated with sulforaphane-N-acetylcysteine in the diet were also significantly reduced to 11% or 16%. Furthermore, the malignant lung tumor multiplicity was significantly reduced from 1.0 tumor/ mouse in the carcinogen-treated control group to 0.3 in the sulforaphane low-dose group, 0.3 and 0.4 in the two sulforaphane-N-acetylcysteine groups, and 0.4 in the phenethyl isothiocyanate high-dose group. The malignant tumor multiplicities in other treatment groups were also reduced (0.5-0.8 tumors/mouse), but not significantly. Unlike lung adenocarcinomas, both incidences and multiplicities of lung adenomas were not much affected by treatment with isothiocyanates or their conjugates. Immunohistochemical examination of the lung tumors from all time points indicated that significant reduction in proliferating cell nuclear antigen and induction...

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Section: Resultssupporting

confidence: 58%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

et al. 2005

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“…The tumors from mice administered the control diet had an average diameter of 0.951 6 0.0082 and an area of 0.551 6 0.026. The longer duration of treatment for 21 weeks (4-25) that lasted until the mice were killed was more effective in reducing tumor size than a shorter duration of treatment for 15 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) weeks that was terminated 6 weeks prior to killing. Treatment for only 9 (4-13) weeks followed by a holding period of 12 weeks was not effective in decreasing the size of the tumors.…”

Section: Prevention Of Vinyl Carbamate-induced Lung Tumorsmentioning

confidence: 99%

Prevention of mouse lung tumors by targretin

Pereira

Kramer

Nines

et al. 2005

Intl Journal of Cancer

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Targretin has indicated chemotherapeutic activity against nonsmall-cell lung cancer and chemoprevention in rat mammary gland. Therefore, targretin was evaluated for the prevention of 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNK) and vinyl carbamate-induced lung tumors in female strain A mice. Three experiments were performed: (i) a dose-response study with vinyl carbamate-induced tumors; (ii) a limited treatment study also with vinyl carbamate and (iii) prevention of NNK-induced tumors. In the dose-response study, 0, 10, 30, 100 and 300 mg/kg targretin were administered after vinyl carbamate. Dose levels of 30 mg/kg and greater significantly decreased tumor multiplicity by >19%. However, the efficacy of 30 and 300 mg/kg was not significantly different demonstrating a shallow dose-response relationship. In the limited treatment study, 200 mg/kg targretin was administered to the mice from 4-13, 4-19, 4-25 and 23-25 weeks after vinyl carbamate. Administering targretin from weeks 4-19 and 4-25 decreased the multiplicity of tumors from 35.3 6 1.43 to 29.1 6 1.51 and 25.0 6 0.93, respectively, and along with administering it from weeks 23-25 decreased tumor size. In the third study, when targretin (100 and 300 mg/kg) was administered for 3 weeks after NNK followed by a 20 weeks holding period, tumor multiplicity was reduced from 10.6 6 1.13 to 6.38 6 0.75 and 4.60 6 0.70, respectively. Hence, targretin demonstrated both preventive and therapeutic activity with respect to mouse lung tumors supporting its further development as a preventive and therapeutic agent for lung cancer. ' 2005 Wiley-Liss, Inc.

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“…Budesonide is a glucocorticoid, a family of compounds that are effective cancer chemopreventive agents in animal models but can have side effects in humans (24). Several studies showed that budesonide, given either in diet or by aerosol, inhibits the formation of lung tumors in the lung of mice treated either with benzo(a)pyrene (24)(25)(26)(27)(28)(29)(30) or vinyl carbamate (31). In addition, budesonide was found to modulate gene expression during mouse lung tumorigenesis (28).…”

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confidence: 99%

Modulation by Phenethyl Isothiocyanate and Budesonide of Molecular and Histopathologic Alterations Induced by Environmental Cigarette Smoke in Mice

D’Agostini

Mastracci

Izzotti

et al. 2009

Cancer Prevention Research

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Our discovery that the perinatal period involves nucleotide modifications and gene overexpression in mouse lung prompted us to evaluate whether mice may become more susceptible to cigarette smoke when exposure starts immediately after birth. We previously showed that mainstream cigarette smoke is a quite potent carcinogen in neonatal mice. Further on, we showed that exposure of mice to environmental cigarette smoke (ECS), starting at birth, results in alterations of a variety of intermediate biomarkers. However, after 4 months of exposure to ECS followed by 7 months of recovery in filtered air, the lung tumor yield was rather low. In the present study, we evaluated the protective effects of the glucocorticoid budesonide and of the dietary agent phenethyl isothiocyanate in mice exposed to ECS for 9 months followed by 2 months of recovery. After weanling, the mice exposed to ECS since birth underwent a variety of alterations of molecular and cytogenetical end points, and 11 months after birth, they exhibited significant histopathologic changes, such as pulmonary anthracosis, emphysema, hemorrhagic areas, alveolar bronchiolarization, bronchial hyperplasia, and tumors, both benign and malignant. The carcinogenic response was less evident in dams exposed to ECS under identical conditions. Both phenethyl isothiocyanate and budesonide, administered daily with the diet after weanling, attenuated several alterations of ECS-related biomarkers and moderately protected the lungs from histopathologic alterations, including tumors. Thus, although not as efficiently as the bioassay in mainstream cigarette smoke-exposed mice, the model in neonatal mice is suitable to evaluate both ECS carcinogenicity and its modulation by chemopreventive agents.

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Prevention of mouse lung tumors by budesonide and its modulation of biomarkers

Cited by 54 publications

References 27 publications

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

Phenethyl Isothiocyanate and Sulforaphane and their N-Acetylcysteine Conjugates Inhibit Malignant Progression of Lung Adenomas Induced by Tobacco Carcinogens in A/J Mice

Prevention of mouse lung tumors by targretin

Modulation by Phenethyl Isothiocyanate and Budesonide of Molecular and Histopathologic Alterations Induced by Environmental Cigarette Smoke in Mice

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