Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
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Drug Resist. Updat. · Jun 2011
ReviewErlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer: a systematic review.
Platinum-based chemotherapy is the standard of care for ovarian cancer and non-small cell lung cancer (NSCLC). However, resistance to platinum agents invariably develops. Targeted therapies, such as tyrosine kinase inhibitors (TKIs), have great potential here as they exert their anti-tumour effect via alternative mechanisms to platinum-based drugs and as such may remain unaffected by emergent resistance to platinum. ⋯ Preclinical models of platinum-resistant cancer were found which display a spectrum of cross-resistance profiles to EGFR-TKIs. Sensitivity to EGFR-TKIs is dependent on the activation of the EGFR pathway or EGFR interacting proteins such as HER-2. EGFR-TKIs show favourable response rates in platinum-pretreated NSCLC, 11.14% and 15.25% for 150mg/day erlotinib and 250mg/day gefitinib, respectively. These response rates significantly improve in patients of Asian descent (28.3% and 29.17%, respectively) and patients with EGFR activation mutations (41.6% and 63.89%, respectively) or increased copy number (33.3% and 45.45%, respectively). Gefitinib significantly outperformed erlotinib and should therefore be the EGFR-TKI of choice in platinum-pretreated relapsed NSCLC. In contrast, response rates are very poor to both erlotinib and gefitinib in platinum pretreated ovarian cancer, 0-5.9% and they should not be used in this cohort of patients. Preclinical models demonstrate that, while cross resistance can occur between platinums and EGFR-TKIs, there is not a generalised cross-resistance phenotype. Erlotinib and gefitinib are suitable for the treatment of platinum-pretreated NSCLC, particularly in patients with EGFR mutations or increases in copy number. Unfortunately, the high rates of EGFR protein overexpression in ovarian cancer are not translating to a clinically useful therapeutic target for EGFR-TKIs; EGFR mutations are rare in ovarian cancer. Newer TKIs may improve response rates in these cohorts and future clinical trials need to collect tumour biopsies from all patients to ensure the success of personalised chemotherapy.
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Drug Resist. Updat. · Jun 2011
ReviewNanomedicine for targeted cancer therapy: towards the overcoming of drug resistance.
Anticancer drug resistance almost invariably emerges and poses major obstacles towards curative therapy of various human malignancies. In the current review we will distinguish between mechanisms of chemoresistance that are predominantly mediated by ATP-driven multidrug resistance (MDR) efflux transporters, typically of the ATP-binding cassette (ABC) superfamily, and those that are independent of such drug efflux pumps. In recent years, multiple nanoparticle (NP)-based therapeutic systems have been developed that were rationally designed to overcome drug resistance by neutralizing, evading or exploiting various drug efflux pumps and other resistance mechanisms. ⋯ In the near future, it is anticipated that innovative theragnostic nanovehicles will be developed which will harbor four major components: (1) a selective targeting moiety, (2) a diagnostic imaging aid for the localization of the malignant tumor and its micro- or macrometastases, (3) a cytotoxic, small molecule drug(s) or novel therapeutic biological(s), and (4) a chemosensitizing agent aimed at neutralizing a resistance mechanism, or exploiting a molecular "Achilles hill" of drug resistant cells. We propose to name these envisioned four element-containing nanovehicle platform, "quadrugnostic" nanomedicine. This targeted strategy holds promise in paving the way for the introduction of highly effective nanoscopic vehicles for cancer therapeutics while overcoming drug resistance.