A review of topoisomerase inhibition in lung cancer

Chhatriwala, Hatim; Jafri, Nazia F.; Salgia, Ravi

doi:10.4161/cbt.5.12.3546

Cited by 34 publications

(28 citation statements)

References 36 publications

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“…Topoisomerases can relax either negative supercoils, or both positive and negative supercoils of the DNA. These unique features are needed because of the double helical structure of DNA, in which TOPOs help access stored information for transcription, recombination and replication purposes (17).…”

Section: Introductionmentioning

confidence: 99%

ERCC1 and topoisomerase I expression in small cell lung cancer: Prognostic and predictive implications

et al. 2012

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Abstract. Small cell lung cancer is the most aggressive lung cancer subtype. The standard treatment approach is based on cisplatin regimens. Although response rates to treatment are approximately 60-80%, the median survival is still very poor. Excision repair cross complementation group 1 (ERCC1) is an enzyme that removes cisplatin-induced DNA adducts and has been related with prognosis and cisplatin response. Topotecan is the standard treatment as second-line therapy and it is an inhibitor of topoisomerase I (TOP I). We selected 76 patients with small cell lung (SCLC) to analyze the ERCC1 and TOP I mRNA expression. ERCC1 was studied both by quantitative PCR and immunohistochemistry. A significant association was found between the inmunohistochemistry expression of ERCC1 and the lack of platinum response (p=0.001). Moreover, low levels of TOP I RNA were shown to be linked to cisplatin response (p=0.002). In the survival analysis, a significant correlation between a better PFS with a low TOP I RNA expression as well as a negative ERCC1 inmunostaining were found, in both cases with a significant p-value (p=0.02 and 0.009, respectively). In summary, our results suggest the use of ERCC1 immunohistochemistry and TOP I mRNA analysis to predict cisplatin response and prognosis in SCLC patients. IntroductionSmall cell lung cancer (SCLC) is the most aggressive lung cancer subtype, with a strong tendency for early dissemination as well as high frequency of metastasis. SCLC accounts for 14% of new lung cancer cases diagnosed in USA and Europe (1) and staging determines prognosis and treatment. The standard treatment approach to patients with limited stage (SCLC) and good performance status is a combination of chest radiation and chemotherapy based on cisplatin (P) and etoposide (E), which results in complete response rate of 50-80% and a 5-year survival probability of 12-25% (2). In case of extensive disease (ED), the main treatment is a combination of cisplatin with either etoposide or irinotecan. Reponses rates are approximately 60-80% and the median survival reaches 7-12 months.Cisplatin causes monoadducts and intrastrand or interstrand cross-links in DNA (3,4). Nucleotide excision repair plays a central role among DNA repair pathways and has been associated with resistance to cisplatin-based chemotherapy. The excision repair cross complementation group 1 (ERCC1) enzyme, plays a rate-limiting role in the nucleotide excision repair pathway which recognizes and removes cisplatininduced DNA adducts (5). The role of ERCC1 in resolving DNA interstrand cross-link-induced double-strand breaks has been clearly shown (6-8). Various studies have reported the relationship between ERCC1 expression and the effect of cisplatin-induced DNA adducts in human ovarian cancer cells in vitro (9), in primary gastric adenocarcinomas (10), colorectal cancer (11) and, more recently, in esophageal cancer (12). Pivotal data from primary non-small cell lung cancer (NSCLC) specimens have suggested a link between ERCC1 immunoexpression and cisplatin...

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Section: Introductionmentioning

confidence: 99%

ERCC1 and topoisomerase I expression in small cell lung cancer: Prognostic and predictive implications

et al. 2012

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“…Transient breakages allow rotation of the DNA double helix around the intact phosphodiester bonds opposite to the enzymemediated DNA cleavages. Once the DNA is relaxed, the enzyme readily relegates the break and restores intact duplex DNA (15). These enzymes are classified as type I and type II topoisomerases according to their reaction mechanisms; Type I topoisomerases make a single-stranded break in a DNA duplex, mediate passage of the intact strand through the break, and then reseal it.…”

Section: Introductionmentioning

confidence: 99%

The interference of piperidinopropionaphthone hydrochloride in mammalian type I and type II DNA topoisomerase reactions

Istanbullu

2015

mpj

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“…Those differences were confirmed in primary tumour cells but little is known about metastatic cells that are the real cause of treatment failure and disease progress. The major mechanisms involved in the multi-drug resistance to chemotherapy of cancer cells are up-regulation of resistance molecules or down-regulation of target molecules [3,8]. The first mechanism that could contribute to several structural and functional unrelated cytotoxic agents, such as epipodophyllotoxins, Vinca alkaloids, anthracyclines, taxanes, colchicines and others, is associated with altered cytotoxic drug transport that is mediated by members of the ABC superfamily of transport proteins.…”

Section: Introductionmentioning

confidence: 99%

“…Lung resistance protein (LRP), which is an integral part of the major vault protein and is found in the cytoplasm and nuclear membrane, is involved in the intracellular distribution of cytotoxic agents [13][14][15]. Several chemotherapeutic agents involved in treating cancer interfere with topoisomerase IIα activity, such as anthracyclines and etoposide, or microtubule stabilisation, such as taxanes [8]. Therefore, another mechanism of drug resistance is associated with altered expression of the target (e.g., topoisomerase IIα).…”

Section: Introductionmentioning

confidence: 99%

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Expressions of Topoisomerase IIα and BCRP in Metastatic Cells are Associated with Overall Survival in Small Cell Lung Cancer Patients

Rijavec

Šilar

Triller

et al. 2011

Pathol. Oncol. Res.

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The aim of this study was to investigate the mRNA expression levels of multidrug resistance-associated proteins in chemo-naïve metastatic lung cancer cells and to determine the correlation with response to chemotherapy and overall survival. Metastatic cells were obtained by transbronchial fine needle aspiration biopsy of enlarged mediastinal lymph nodes in 14 patients with small cell lung cancer (SCLC) and 7 patients with non-small cell lung cancer (NSCLC). After cytological confirmation of lung cancer type, total RNA was extracted from biopsy samples and reverse transcribed to cDNA, and real-time PCR for the genes of interest [P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance protein (LRP) and topoisomerase IIα (TOPIIα)], was performed. We observed significantly decreased expression of BCRP and significantly increased expression of TOPIIα in metastatic SCLC cells compared to NSCLC. Furthermore, in SCLC high topoisomerase IIα and low BCRP expression levels positively correlated with longer overall survival. Our results showed higher expression levels of BCRP as well as lower levels of topoisomerase IIα in chemo-naïve metastatic cells in NSCLC than in SCLC. These results correlate with previous observations that metastatic SCLC cells at the beginning of chemotherapy are potentially more sensitive to chemotherapeutic agents while in metastatic NSCLC cells resistance is usually inherent. We also showed that altered levels of topoisomerase IIα and BCRP in SCLC are important factors that contribute to resistance to chemotherapeutics that interfere with the enzyme and/or DNA and are highly associated with overall survival.

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A review of topoisomerase inhibition in lung cancer

Cited by 34 publications

References 36 publications

ERCC1 and topoisomerase I expression in small cell lung cancer: Prognostic and predictive implications

ERCC1 and topoisomerase I expression in small cell lung cancer: Prognostic and predictive implications

The interference of piperidinopropionaphthone hydrochloride in mammalian type I and type II DNA topoisomerase reactions

Expressions of Topoisomerase IIα and BCRP in Metastatic Cells are Associated with Overall Survival in Small Cell Lung Cancer Patients

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