Assay of lapatinib in murine models of cigarette smoke carcinogenesis

Abstract

Lapatinib, a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2), is prescribed for the treatment of patients with metastatic breast cancer overexpressing HER-2. Involvement of this drug in pulmonary carcinogenesis has been poorly investigated. We used murine models suitable to evaluate cigarette smoke-related molecular and histopathological alterations. A total of 481 Swiss H mice were used. The mice were exposed to mainstream cigarette smoke (MCS) during the first four months of life. After 10 weeks, MCS caused an elevation of bulky DNA adducts, oxidative DNA damage and an extensive downregulation of microRNAs in lung. After four months, an increase in micronucleus frequency was observed in peripheral blood erythrocytes. After 7.5 months, histopathological alterations were detected in the lung, also including benign tumors and malignant tumors, and in the urinary tract. A subchronic toxicity study assessed the non-toxic doses of lapatinib, administered daily with the diet after weaning. After 10 weeks, lapatinib significantly attenuated the MCS-related nucleotide changes and upregulated several low-intensity microRNAs in lung. The drug poorly affected the MCS systemic genotoxicity and had modest protective effects on MCS-induced preneoplastic lesions in lung and kidney, when administered under conditions that temporarily mimicked interventions either in current smokers or exsmokers. On the other hand, it caused some toxicity to the liver. Thus, on the whole, lapatinib appears to have a low impact in the smoke-related lung carcinogenesis models used, especially in terms of tumorigenic response.

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor

“…In agreement with the results of previous studies (21,22,(37)(38)(39)(40)(41), exposure of mice to MCS resulted in an evident oxidative DNA damage in lung. Moreover, high levels of bulky DNA adducts were detectable in the form of DRZ at 32 P postlabeling, which is typical for exposure to complex mixtures.…”

“…In line with previous studies (22,(39)(40)(41)(49)(50)(51)(52)(53)(54)(55), exposure of mice to MCS resulted in an extensive dysregulation of pulmonary miRNAs, which was oriented in the sense of downregulation. The reliability of microarrays for evaluating miRNA dysregulation in the lung of MCS-exposed mice was validated by means of qPCR analyses in the present study and in several previous studies investigating the effects of MCS and other putative chemopreventive agents (vorinostat, myoinositol, bexarotene, pioglitazone, metformin, lapatinib, aspirin, naproxen, and celecoxib) under experimental conditions similar to those used in the present study (22,(39)(40)(41)49,54,55). The 62 miRNAs downregulated by MCS in the present study are involved in a variety of functions, mainly including oncogene inhibition, stress response, apoptosis and angiogenesis.…”

Chromosome aberrations frequency in peripheral blood lymphocytes in young tobacco smoking and non-smoking people

“…The increase in MN frequency in normochromatic erythrocytes (NCE) was significantly higher in mice exposed to mainstream cigarette smoke compared to filtered air-exposed mice. Mainstream cigarette smoke also caused an elevation of bulky DNA adducts, oxidative DNA damage, and an extensive downregulation of microRNAs in lung (21). In our previous study conducted in Bosnia and Herzegovina, cigarette consumption increased the micronuclei frequency in peripheral blood lymphocytes in group of young smokers (22).…”

Pharmacological Modulation of Lung Carcinogenesis in Smokers: Preclinical and Clinical Evidence

“…After 10 weeks, lapatinib significantly attenuated the MCS-related nucleotide changes (bulky DNA adducts and oxidative DNA damage) and upregulated several low-intensity microRNAs in lung. At the end of the period of exposure to MCS (4 months), a decrease in the frequency of MN PCNE in MCS-exposed mice treated with lapatinib after weaning did not reach the statistical significance threshold [31]. After 7.5 months, lapatinib had poor effects on MCS-induced histopathological alterations.…”

“…However, this drug was hepatotoxic to MCS-exposed female mice. Thus, on the whole, lapatinib appears to have a low impact in the smoke-related lung carcinogenesis models used, especially in terms of modulation of the tumorigenic response [31]. …”