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Modulation of Biomarkers During Chemoprevention of Mouse Lung Tumorigenesis by d-glucarate*

Margaret Hanausek, PhD; Zbigniew Walaszek, PhD; Janusz Szemraj, PhD; Robert Zoltaszek, MS; Thomas J. Slaga, PhD
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*From the AMC Cancer Research Center, Denver, CO.

Correspondence to: Margaret Hanausek, PhD, AMC Cancer Research Center, 1600 Pierce St, Denver, CO 80214; e-mail: hanausekm@amc.org



Chest. 2004;125(5_suppl):149S. doi:10.1378/chest.125.5_suppl.149S-a
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Several new potential serologic biomarkers for carcinogenesis are under development. The recently discovered oncofetal protein p65 has the potential to be used not only as a tumor marker, but also as a marker in chemoprevention trials for early detection of breast, prostate, and lung cancers. With a view toward early detection of cancer risk, we have studied strain-dependent differences in the expression of p65 in different organs of mice highly susceptible (C3H/HeJ, A/HeJ) and relatively resistant (C57BL/6N) to chemical carcinogenesis. Using reverse transcription polymerase chain reaction, we detected the p65-specific messenger RNA in mammary glands or lungs of young, 7- to 8-week-old female mice of the C3H/HeJ and A/HeJ strains known to spontaneously develop mammary gland or lung tumors, respectively. No p65-specific messenger RNA was detected in a control group of C57BL/6N mice resistant to chemical carcinogenesis. The occurrence of p65-specific messenger RNA in the susceptible organs or mononuclear cell populations of young C3H/HeJ and A/HeJ mice correlated well with the mammary gland and lung tumor incidence, respectively, reported for adult mice of these strains. Thus, expression of p65 examined by reverse transcription polymerase chain reaction may be used for lung cancer risk assessment. The p65 gene expression in A/J mice susceptible to lung cancer development was down-regulated by β-glucuronidase inhibitors from a group of d-glucaric acid derivatives. Postinitiation treatment with calcium d-glucarate markedly reduced the number of benzo[a]pyrene-induced lung lesions in A/J mice, with mutated K-ras and p53 genes, ie, by 60% and 50%, respectively. Calcium d-glucarate may inhibit promotion and progression of lung tumorigenesis in A/J mice by facilitating DNA adduct removal, as well as by suppressing chronic inflammation and mutagenesis in benzo[a]pyrene-induced lesions.

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