Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer

Abstract

While chemotherapy provides useful palliation, advanced lung cancer remains incurable since those tumors that are initially sensitive to therapy rapidly develop acquired resistance. Resistance may arise from impaired drug delivery, extracellular factors, decreased drug uptake into tumor cells, increased drug efflux, drug inactivation by detoxifying factors, decreased drug activation or binding to target, altered target, increased damage repair, tolerance of damage, decreased proapoptotic factors, increased antiapoptotic factors, or altered cell cycling or transcription factors. Factors for which there is now substantial clinical evidence of a link to small cell lung cancer (SCLC) resistance to chemotherapy include MRP (for platinum-based combination chemotherapy) and MDR1/P-gp (for non-platinum agents). SPECT MIBI and Tc-TF scanning appears to predict chemotherapy benefit in SCLC. In non-small cell lung cancer (NSCLC), the strongest clinical evidence is for taxane resistance with elevated expression or mutation of class III β-tubulin (and possibly α tubulin), platinum resistance and expression of ERCC1 or BCRP, gemcitabine resistance and RRM1 expression, and resistance to several agents and COX-2 expression (although COX-2 inhibitors have had minimal impact on drug efficacy clinically). Tumors expressing high BRCA1 may have increased resistance to platinums but increased sensitivity to taxanes. Limited early clinical data suggest that chemotherapy resistance in NSCLC may also be increased with decreased expression of cyclin B1 or of Eg5, or with increased expression of ICAM, matrilysin, osteopontin, DDH, survivin, PCDGF, caveolin-1, p21WAF1/CIP1, or 14-3-3sigma, and that IGF-1R inhibitors may increase efficacy of chemotherapy, particularly in squamous cell carcinomas. Equivocal data (with some positive studies but other negative studies) suggest that NSCLC tumors with some EGFR mutations may have increased sensitivity to chemotherapy, while K-ras mutations and expression of GST-pi, RB or p27kip1 may possibly confer resistance. While limited clinical data suggest that p53 mutations are associated with resistance to platinum-based therapies in NSCLC, data on p53 IHC positivity are equivocal. To date, resistance-modulating strategies have generally not proven clinically useful in lung cancer, although small randomized trials suggest a modest benefit of verapamil and related agents in NSCLC.

Excision repair cross complementation group 1 is a chemotherapy-tolerating gene in cisplatin-based treatment for non-small cell lung cancer

“…As further confirmation of the above, we detected the expression of the associated membrane proteins, P-gp and MRP, which have been reported to participate in drug resistance (12). The FCM result showed that there was no significant difference in the expression of P-gp and MRP proteins between H1299/E and H1299/V cells.…”

“…Without efficient DNA repair, the platinum-induced DNA damage eventually leads to cell apoptosis (5). Although the platinum containing agents greatly increase the effectiveness of NSCLC treatment compared with other drugs, platinum-based chemotherapy has apparently reached a therapeutic plateau with limited response to treatment as well as little improvement of survival for patients (10,11), due to the tumors rapidly developing acquired drug resistance which has not yet been overcome (12). Many published reports suggest that the emergence of platinum resistance, not only intrinsic, but also acquired primarily attribute to the nucleotide excision repair (NER) system (6,13).…”

Use of an Artificial Neural Network to Predict Risk Factors of Nosocomial Infection in Lung Cancer Patients

“…Despite surgical resection, chemotherapy and radiation therapy technology are continuously improving, patientswith lung cancer remains extremely vulnerable to relapse and fatal (Gridelli et al, 2003). The cure rate of lung cancer is very low and the average 5-year survival of patients with lung cancer is below 15 % ( Ogawa et al, 2008;Rachet et al, 2008;Chen et al, 2009;Stewart et al, 2010). The nosocomial infection rate of patients with lung cancer showed high trend (Kamboj et al, 2009).…”

Regulatory Mechanisms of Annexin-Induced Chemotherapy Resistance in Cisplatin Resistant Lung Adenocarcinoma

“…However, the drug resistance produced by tumor cells marks not only the most universal and difficult problem that influences the curative effect of chemotherapy, but also the main reason that leads to chemotherapy failure. However, no therapeutic schedule or drug effectively inhibits the tolerance of adenocarcinoma and extend the life of patients have been developed so far (Zhang and Hu, 2006;Stewart et al, 2007;Stewart, 2010). Therefore, conducting indepth research on the new action mechanism of cisplatin on adenocarcinoma and discovering key molecules that play significant roles may lead to more effective candidate targets and treatment plans for adenocarcinoma.…”