Non-small-cell lung cancer: molecular targeted therapy and personalized medicine - drug resistance, mechanisms, and strategies.

Pharmgenomics Pers Med. 2013;6:25-36

Authors: Sechler M, Cizmic AD, Avasarala S, Van Scoyk M, Brzezinski C, Kelley N, Bikkavilli RK, Winn RA

Abstract
Targeted therapies for cancer bring the hope of specific treatment, providing high efficacy and in some cases lower toxicity than conventional treatment. Although targeted therapeutics have helped immensely in the treatment of several cancers, like chronic myelogenous leukemia, colon cancer, and breast cancer, the benefit of these agents in the treatment of lung cancer remains limited, in part due to the development of drug resistance. In this review, we discuss the mechanisms of drug resistance and the current strategies used to treat lung cancer. A better understanding of these drug-resistance mechanisms could potentially benefit from the development of a more robust personalized medicine approach for the treatment of lung cancer.

PMID: 23690695 [PubMed]

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Endotoxin and cancer chemo-prevention.

Cancer Epidemiol. 2013 May 18;

Authors: Mastrangelo G, Fadda E, Cegolon L

Abstract
Reduced rates of lung cancer have been observed in several occupational groups exposed to high levels of organic dusts contaminated by endotoxin. The underlying anti-neoplastic mechanism of endotoxin may be an increased secretion of endogenous anti-neoplastic mediators and activation of the toll-like receptors (TLR). A detoxified endotoxin derivative, Monophosphoryl Lipid A (MPL(®)) is marketed in Europe since 1999 as part of the adjuvant systems in allergy vaccines for treatment of allergic rhino-conjunctivitis and allergic asthma. Over 200,000 patients have used them to date (nearly 70% in Germany). Since detailed exposure (MPL(®) dose and timing of administration) and individual data are potentially available, an observational follow-up study could be conducted in Germany to investigate the protective effect of MPL(®) against cancer, comparing cancer incidence in two groups of patients with allergic rhinitis: those treated with allergoids plus MPL(®) and those treated with a vaccine including the same allergoids but not MPL(®). The protective effect of MPL(®) could be quantified in ever and never smokers. If this proposed observational study provides evidence of protective effects, MPL(®) could be immediately used as a chemo-preventive agent since it is already in use as adjuvant in human vaccines against cancer.

PMID: 23692704 [PubMed - as supplied by publisher]

Nedaplatin, a cisplatin analog, has been developed to decrease the toxicities induced by cisplatin, such as nephrotoxicity and gastrointestinal toxicity. The dose of nedaplatin is determined by body surface area, not by the area under the curve (AUC).

The recommended therapeutic dose is 80-100 mg/m(2), although the pharmacokinetic profile of nedaplatin is similar to that of carboplatin. In our preliminary study, there was a favorable correlation between AUC and creatinine clearance (CL), suggesting that renal function should be considered when nedaplatin is administered. Ishibashi's formula, ie, DoseNDP = AUC × CLNDP, where CLNDP = 0.0738 × creatinine clearance + 4.47, would be predictable and useful for estimating the individual dose of nedaplatin. Several Phase II studies have suggested that nedaplatin might be a useful second analog, especially for patients with non-small cell lung cancer, esophageal cancer, uterine cervical cancer, head and neck cancer, or urothelial cancer. Further, nedaplatin was reported to be a useful chemotherapeutic agent with radiosensitizing properties; however, there is no Phase III study of nedaplatin, neither with chemotherapy nor with concurrent chemoradiotherapy, because nedaplatin is not commonly used throughout the world.

Further evaluation in a randomized controlled trial is warranted to demonstrate definitively the activity of nedaplatin.