Reckamp KL, Krysan K, Morrow JD, Milne GL, Newman RA, Tucker C et al.. A phase I trial to determine the optimal biological dose of celecoxib when combined with erlotinib in advanced non-small cell lung cancer. Clin Cancer Res 12: 3381-3388
Overexpression of cyclooxygenase-2 (COX-2) activates extracellular signal-regulated kinase/mitogen-activated protein kinase signaling in an epidermal growth factor receptor (EGFR) tyrosine kinase inhibition (TKI)-resistant manner. Because preclinical data indicated that tumor COX-2 expression caused resistance to EGFR TKI, a phase I trial to establish the optimal biological dose (OBD), defined as the maximal decrease in urinary prostaglandin E-M (PGE-M), and toxicity profile of the combination of celecoxib and erlotinib in advanced non-small cell lung cancer was done.
Twenty-two subjects with stage IIIB and/or IV non-small cell lung cancer received increasing doses of celecoxib from 200 to 800 mg twice daily (bid) and a fixed dose of erlotinib. Primary end points included evaluation of toxicity and determination of the OBD of celecoxib when combined with erlotinib. Secondary end points investigate exploratory biological markers and clinical response.
Twenty-two subjects were enrolled, and 21 were evaluable for the determination of the OBD, toxicity, and response. Rash and skin-related effects were the most commonly reported toxicities and occurred in 86%. There were no dose-limiting toxicities and no cardiovascular toxicities related to study treatment. All subjects were evaluated on intent to treat. Seven patients showed partial responses (33%), and five patients developed stable disease (24%). Responses were seen in patients both with and without EGFR-activating mutations. A significant decline in urinary PGE-M was shown after 8 weeks of treatment, with an OBD of celecoxib of 600 mg bid.
This study defines the OBD of celecoxib when combined with a fixed dose of EGFR TKI. These results show objective responses with an acceptable toxicity profile. Future trials using COX-2 inhibition strategies should use the OBD of celecoxib at 600 mg bid.
"The majority of resistance to EGFR-TKIs are seen with: 1) the second-site exon 20 EGFR gatekeeper mutation plasmid T790M that reduces drug binding in ~50% of all cases of EGFR mutation;21 2) the plasmid T790M mutation plus EGFR amplification in ~8% of cases;22 3) tyrosine kinase switching or receptor dimerization through MET (proto-oncogene that encodes a protein known as hepatocyte growth factor receptor) amplification in ~5%–19% of cases;23 4) overexpression of AXL (encodes tyrosine-protein kinase receptor UFO in human) and its ligand GAS6 in 20% and 25% of cases, respectively;24 and 5) activating mutation of the phosphatidylinositol 3-kinase (PI3K) p110α-encoding gene PIK3CA in ~5% of cases.25–27 There is also evidence of nuclear factor-κB(NF-κB) signaling being implicated as a resistance mechanism to avoid TKI-induced apoptosis, possibly through the low expression of the NF-κB inhibitory protein IκB.25 "
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.
Drug Design, Development and Therapy 06/2014; 8:735-744. DOI:10.2147/DDDT.S60672 · 3.03 Impact Factor
"In this study, dead BCC cells were prepared by mixing 80 μM celecoxib with a cell suspension for 16 hours to induce cell death. Celecoxib has been used in combination with other chemotherapeutic agents, including docetaxel and erlotinib, in clinical trials for non–small-cell lung cancers [36,37]. A previous report demonstrated the important role of cyclooxygenase-2 in the progression of BCC. "
[Show abstract][Hide abstract] ABSTRACT: Ultrahigh-resolution optical coherence tomography (UR-OCT) has been used for the first time to our knowledge to study single-cell basal cell carcinoma (BCC) in vitro. This noninvasive, in situ, label-free technique with deep imaging depth enables three-dimensional analysis of scattering properties of single cells with cellular spatial resolution. From three-dimensional UR-OCT imaging, live and dead BCC cells can be easily identified based on morphological observation. We developed a novel method to automatically extract characteristic parameters of a single cell from data volume, and quantitative comparison and parametric analysis were performed. The results demonstrate the capability of UR-OCT to detect cell death at the cellular level.
"Celecoxib has been approved to be used in chemopreventive treatment of FAP by FDA [Steinbach et al., 2000] because of its proved anticancer effects and the lowest level of adverse cardiovascular events among all COX-2 specific inhibitors [Kimmel et al., 2005; Ulrich et al., 2006]. Its application to chemotherapy of lung, prostate, and breast cancers has also been widely investigated in clinic [Dang et al., 2004; Csiki et al., 2005; Reckamp et al., 2006; Smith et al., 2006]. Therefore, celecoxib is a good candidate for investigation of the role of COX-2 inhibitors in drug resistance. "
[Show abstract][Hide abstract] ABSTRACT: The P-glycoprotein (p170, P-gp) encoded by human MDR1 gene functions as a pump to extrude anticancer drugs from cancer cells. Over-expression of p170 is closely related to primary and induced drug resistance phenotype of tumor cells. Recent studies have demonstrated that expression of cyclooxygenase-2 (COX-2) is positively correlated with the p170 level, suggesting a potential of COX-2 specific inhibitors in regulation of cytotoxicity of anticancer agents. Celecoxib is one of the specific inhibitors of COX-2 and has been widely used in clinic. However, its function in the response of cancer cells to anticancer drugs and the related mechanism are still waiting to be investigated. To explore the correlation of celecoxib and the p170-mediated drug resistance, the role of celecoxib in drug response of cancer cells was analyzed with flow cytometry, high performance liquid chromatography (HPLC), and colony formation experiments. Celecoxib (50 microM) was found to significantly enhance the sensitivity of MCF-7 and JAR/VP16 cells to tamoxifen and etoposide, respectively, by inhibition of p170 expression and increase in intracellular accumulation of the drugs. However, celecoxib did not affect pump function of p170. Enzyme activity and methylation analyses demonstrated that the inhibitory effect of celecoxib on p170 was independent on COX-2 but closely related to hypermethylation of MDR1 gene promoter. Our study suggested that celecoxib was a potential agent for enhancement of the sensitivity of cancer cells to anticancer drugs. It also provided a links between epigenetic change of MDR1 and drug response of cancer cells.
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