Preclinical Evaluation of JAB-2485, a Potent AURKA Inhibitor with High Selectivity and Favorable Pharmacokinetic Properties.

As a critical mitotic regulator, Aurora kinase A (AURKA) is aberrantly activated in a wide range of cancers. Therapeutic targeting of AUKRA is a promising strategy for the treatment of solid tumors. In this study, we evaluated the preclinical characteristics of JAB-2485, a small-molecule inhibitor of AURKA currently in Phase I/IIa clinical trial in the US (NCT05490472). Biochemical studies demonstrated that JAB-2485 is potent and highly selective on AURKA, with subnanomolar IC50 and around 1500-fold selectivity over AURKB or AURKC. In addition, JAB-2485 exhibited favorable pharmacokinetic properties featured by low clearance and good bioavailability, strong dose-response relationship, as well as low risk for hematotoxicity and off-target liability. As a single agent, JAB-2485 effectively induced G2/M cell cycle arrest and apoptosis and inhibited the proliferation of small cell lung cancer, triple-negative breast cancer, and neuroblastoma cells. Furthermore, JAB-2485 exhibited robust in vivo antitumor activity both as monotherapy and in combination with chemotherapies or the bromodomain inhibitor JAB-8263 in xenograft models of various cancer types. Together, these encouraging preclinical data provide a strong basis for safety and efficacy evaluations of JAB-2485 in the clinical setting.

TiO2 nanotube arrays-based photoelectrocatalyst: Tri-Doping engineering and carbon coating engineering boosting visible activity, and stable hydrogen evolution.

The integration of non-metallic doping and carbon coating for TiO2-based photoelectrocatalysts can be recognized as a promising strategy to enhance their hydrogen production performance. To this end, this study explored the carbon coating engineering to induce stable multi-element doping with an aim to develop high-performance TiO2 nanotube array-based photoelectrocatalysts. The resulting structures consisted of carbon-nitrogen-sulfur-tri-doped TiO2 nanotube arrays with a nitrogen-sulfur-codoped carbon coating (CNS-TNTA/NSC). The fabrication process involved a one-step, low-cost strategy of the carbon-coated tridoped reaction confined in vacuum space, utilizing polymer thiourea sealed in a controlled environment. Compared the photocurrent density of CNS-TNTA/NSC with pristine TNTA, the photocurrent enhancement of approximately 18.3-fold under simulated sunlight and a remarkable increase of 32.8-fold under simulated visible light conditions. The enhanced photocatalytic activity under visible light was ascribed to two factors: First, C, N, and S tri-doping and Ti3+ created a diverse array of impurity energy levels within the band gap, which synergistically narrowed the band gap and further enhanced response to the visible light range. Second, the presence of a carbon coating shell doped with N and S can greatly promote electron transfer and efficient electron-hole pair separation. This study could provide significant insights concerning the design of sophisticated photoanodes.

Functional properties and flavor characteristics of milk from cows supplemented with jujube powder.

Jujube has various functional properties and is a promising source of bioactive compounds and flavors. This study investigated the functional properties and flavor characteristics of milk from cows supplemented with jujube powder (JP). Here, milk volatile profiles and taste properties were analyzed by using an electronic nose, and headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS). Compared with the control group, the total antioxidant capacity, 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulphonic free radical scavenging activity, lactoferrin, and IgG levels increased significantly in the JP group. Volatile flavor analysis indicated that ketone levels increased, while acid abundance decreased, and toluene and dimethyl sulfone significantly increased in the JP group. Taste profile analyses demonstrated that jujube supplementation altered the taste of the milk. In summary, dietary jujube powder supplementation affects the volatile flavor composition and aroma of milk, as well as the bioactive component and antioxidant properties. These findings enhance our understanding of milk production using direct dietary supplementation to produce sustainable dairy products.

Fast pyrolysis kinetics of waste tires and its products studied by a wireless-powered thermo-balance.

Fast pyrolysis is commonly used in industrial reactors to convert waste tires into fine chemicals and fuels. However, current thermogravimetric analyzers are facing limitations that prevent the acquisition of kinetic information. To better understand the reaction kinetics, we designed a novel thermo-balance device that was capable of in-situ weight measurement during rapid heating. The results showed that the reaction rate substantially increased, with significant reductions in reaction time and apparent activation energy compared to slow pyrolysis. The change of reaction mechanism from the reaction order model to the nucleation and growth model was responsible for the increase in the degradation rate. Fast pyrolysis led to the generation of more trimers of isoprene as primary pyrolytic volatiles, which we further supported through density functional theory calculations. The findings suggested that fast pyrolysis has a higher chance of overcoming the high energy barrier to form trimers of isoprene. This comprehensive and in-depth understanding of fast pyrolysis kinetics and product distribution could reveal a more realistic process of waste pyrolysis, which benefited the industry.

Multiple sclerosis and pregnancy: Pathogenesis, influencing factors, and treatment options.

Multiple sclerosis (MS) is an autoimmune-mediated degenerative disease of the central nervous system, characterized by inflammatory demyelination. It is primarily found in women of childbearing age, making pregnancy a significant concern for both patients with MS and clinicians. To assist these patients in achieving their desire for pregnancy, reducing MS relapses during all stages of pregnancy, preventing the progression of MS, mitigating the impact of MS treatment on the course and outcome of pregnancy, and a thorough understanding of the relationship between pregnancy and MS, as well as specific management and the application of relevant medications for MS patients at each stage of pregnancy, are essential. This article provides an update on pregnancy-related issues in women with MS, including the general recommendations for management at each stage of pregnancy.

Cpt1a promoted ROS-induced oxidative stress and inflammation in liver injury via the Nrf2/HO-1 and NLRP3 inflammasome signaling pathway.

Various liver diseases caused by liver damage seriously affect people's health. The purpose of this study was to clarify the effects and the mechanisms of carnitine palmitoyltransferase 1 (Cpt1a) on oxidative stress and inflammation in liver injury. It was found that the expression of Cpt1a mRNA was upregulated in a model of liver injury in mice. Thus, overexpression of Cpt1a increased reactive oxygen species (ROS) production and malondialdehyde (MDA) levels and reduced superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-px) levels in an in vitro model of liver injury. It was also shown that overexpression of Cpt1a suppressed the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. In summary, these data indicate that Cpt1a promotes ROS-induced oxidative stress in liver injury via the Nrf2/HO-1 and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome signaling pathway.

Reprogramming of Mouse Calvarial Osteoblasts into Induced Pluripotent Stem Cells.

Previous studies have demonstrated the ability of reprogramming endochondral bone into induced pluripotent stem (iPS) cells, but whether similar phenomenon occurs in intramembranous bone remains to be determined. Here we adopted fluorescence-activated cell sorting-based strategy to isolate homogenous population of intramembranous calvarial osteoblasts from newborn transgenic mice carrying both Osx1-GFP::Cre and Oct4-EGFP transgenes. Following retroviral transduction of Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc), enriched population of osteoblasts underwent silencing of Osx1-GFP::Cre expression at early stage of reprogramming followed by late activation of Oct4-EGFP expression in the resulting iPS cells. These osteoblast-derived iPS cells exhibited gene expression profiles akin to embryonic stem cells and were pluripotent as demonstrated by their ability to form teratomas comprising tissues from all germ layers and also contribute to tail tissue in chimera embryos. These data demonstrate that iPS cells can be generated from intramembranous osteoblasts.

Reprogramming of Dermal Fibroblasts into Osteo-Chondrogenic Cells with Elevated Osteogenic Potency by Defined Transcription Factors.

Recent studies using defined transcription factors to convert skin fibroblasts into chondrocytes have raised the question of whether osteo-chondroprogenitors expressing SOX9 and RUNX2 could also be generated during the course of the reprogramming process. Here, we demonstrated that doxycycline-inducible expression of reprogramming factors (KLF4 [K] and c-MYC [M]) for 6 days were sufficient to convert murine fibroblasts into SOX9+/RUNX2+ cellular aggregates and together with SOX9 (S) promoted the conversion efficiency when cultured in a defined stem cell medium, mTeSR. KMS-reprogrammed cells possess gene expression profiles akin to those of native osteo-chondroprogenitors with elevated osteogenic properties and can differentiate into osteoblasts and chondrocytes in vitro, but form bone tissue upon transplantation under the skin and in the fracture site of mouse tibia. Altogether, we provide a reprogramming strategy to enable efficient derivation of osteo-chondrogenic cells that may hold promise for cell replacement therapy not limited to cartilage but also for bone tissues.

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer.

LESSONS LEARNED: This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. BACKGROUND: Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. METHODS: Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. RESULTS: Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. CONCLUSION: This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC.

The Efficacy and Safety of Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Previously Treated with Chemotherapy: A Single-Arm, Multi-Center, Prospective Study.

BACKGROUND: Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. METHODS: Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125 mg tablet, three times per day). The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety. RESULTS: From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9-6.6 m) and 5.4 months (95%CI 3.1-7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7% respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow-up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127). CONCLUSIONS: In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02486354.

A Retrospective Study of Stage I to IIIa Lung Adenocarcinoma After Resection: What Is the Optimal Adjuvant Modality for Patients With an EGFR Mutation?

UNLABELLED: We retrospectively reviewed a total of 257 stage I to IIIa lung adenocarcinoma after resection, tested them for the epidermal growth factor receptor (EGFR) mutation, and analyzed the effect of perioperative treatment on survival. The results showed that in patients with an EGFR mutation, adjuvant EGFR-tyrosine kinase inhibitor monotherapy after complete resection significantly prolongs disease-free survival compared with adjuvant chemotherapy and/or radiotherapy. BACKGROUND: Adjuvant cisplatin-based chemotherapy improves non-small-cell lung cancer (NSCLC) 5-year survival rates after resection. However, adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) efficacy and the optimal adjuvant treatment are unclear. PATIENTS AND METHODS: The clinical records of patients tested for EGFR mutation after complete NSCLC resection were reviewed and tested for significance; EGFR mutation and adjuvant therapy effects on survival were assessed using univariate and Cox regression analyses. RESULTS: We enrolled 257 patients (stage I, 126; stage II-IIIa, 131); 138 had EGFR mutation. EGFR mutation status was unrelated to recurrence (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.572-1.204; P = .326) or death (HR, 0.679; 95% CI, 0.406-1.136; P = .14). Thirty-one patients with EGFR mutation received adjuvant EGFR-TKIs; most (87.1%) received EGFR-TKI monotherapy. Patients who received adjuvant EGFR-TKIs had longer disease-free survival (DFS) than those who did not (P = .033) or received conventional adjuvant chemotherapy (P = .038). Adjuvant EGFR-TKIs did not affect overall survival (OS; P = .258), although the recipients had better 3-year OS (92.5% vs. 81%). Eight patients who received adjuvant EGFR-TKI developed disease recurrence, which occurred in 7 patients during adjuvant treatment. In the adjuvant EGFR-TKI group patients with a primary tumor EGFR mutation, EGFR mutation in the corresponding metastatic lymph nodes did not affect DFS, but patients who received EGFR-TKI after recurrence had longer progression-free survival (P = .087). CONCLUSION: In patients with an EGFR mutation, adjuvant EGFR-TKI monotherapy after complete resection significantly prolongs DFS compared with adjuvant chemotherapy and/or radiotherapy.

Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancer.

Advanced non-small-cell lung cancer (NSCLC) is the main cause for cancer-related mortality. Treatments for advanced NSCLC are largely palliative and a benefit plateau appears to have reached with the platinum-based chemotherapy regimens. EGF receptor (EGFR) tyrosine kinase inhibitors gefitinib, erlotinib and afatinib came up with prolonged progression-free survival and improved quality of life, especially in EGFR-mutated patients. Icotinib is an oral selective EGFR tyrosine kinase, which was approved by China Food and Drug administration in June 2011 for treating advanced NSCLC. Its approval was based on the registered Phase III trial (ICOGEN), which showed icotinib is noninferior to gefitinib. This review will discuss the role of icotinib in NSCLC, and its potential application and ongoing investigations.

A single-arm, multicenter, safety-monitoring, phase IV study of icotinib in treating advanced non-small cell lung cancer (NSCLC).

BACKGROUND: The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China. METHODS: This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125 mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients. RESULTS: Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21-95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively. CONCLUSIONS: The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting.

Therapeutic effects and adverse drug reactions are affected by icotinib exposure and CYP2C19 and EGFR genotypes in Chinese non-small cell lung cancer patients.

BACKGROUND: The aim of this study was to evaluate how CYP2C19 affects icotinib and metabolite' exposure, and to determine whether the exposure and EGFR genotype influences survival time, tumor metastasis and adverse drug reactions. MATERIALS AND METHODS: 274 NSCLC patients who accepted 125 mg icotinib/t.i.d. were chosen from a phase III study. Blood samples were obtained in 672 nd (4th week) and 1,680 th hours (10th week), and plasma was used to quantify the concentration of icotinib and blood cells were sampled to check the genotypes. Clinical data were also collected at the same time, including EGFR genotypes. Plasma concentrations were assessed by HPLC-MS/MS and genotype by sequencing. All data were analyzed through SPSS 17.0 and SAS 9.2. RESULTS: CYP 2C19 genotypes affected bio-transformation from icotinib to M24 and M26, especially in poor-metabolisers. Higher icotinib concentrations (>1000 ng/mL) not only increased patient PFS and OS but also reduced tumor metastasis. Patients with mutant EGFR experienced a higher median PFS and OS (234 and 627 days), especially those with the 19del genotype demonstrating higher PR ratio. Patients who suffered grade II skin toxicity had a higher icotinib exposure than those with grade I skin toxicity or no adverse effects. Liver toxic reactions might occur in patients with greater M20 and M23 plasma concentrations. CONCLUSIONS: CYP2C19 polymorphisms significantly affect icotinib, M24 and M26 exposure. Patients with mutant EGFR genotype and higher icotinib concentration might have increased PFS and OS and lower tumor metastasis. Liver ADR events and serious skin effects might be respectively induced by greater M20, M23 and icotinib concentrations.

Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial.

BACKGROUND: Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer. METHODS: In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18-75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506. FINDINGS: 400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67-1·05; median progression-free survival 4·6 months [95% CI 3·5-6·3] vs 3·4 months [2·3-3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033). INTERPRETATION: Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer.

Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors.

Crown ether fused anilinoquinazoline analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities in an in vitro EGFR kinase assay and an EGFR-mediated intracellular tyrosine phosphorylation assay. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these fused quinazoline compounds is reported.

Icotinib (BPI-2009H), a novel EGFR tyrosine kinase inhibitor, displays potent efficacy in preclinical studies.

Icotinib, one of the leading compounds selected from our compound library, was found to be a potent and specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an IC(50) of 5 nM. When profiled with 88 kinases, Icotinib only showed meaningful inhibitory activity to EGFR and its mutants. Icotinib blocked EGFR-mediated intracellular tyrosine phosphorylation (IC(50)=45 nM) in the human epidermoid carcinoma A431 cell line and inhibits tumor cell proliferation. In vivo studies demonstrated that Icotinib exhibited potent dose-dependent antitumor effects in nude mice carrying a variety of human tumor-derived xenografts. The drug was well tolerated at doses up to 120 mg/kg/day in mice without mortality or significant body weight loss during the treatment. A head to head randomized, double blind phase III trial using Gefitinib as an active control for patients with advanced non-small cell lung cancer (NSCLC) was finished recently (Trial registration ID: NCT01040780). The data shows that Icotinib was non-inferior to Gefitinib in terms of median progression free survival (PFS) and safety superior favor to Icotinib compared to Gefitinib.

Phase I trial of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in Chinese patients with non-small cell lung cancer.

BACKGROUND: The preclinical experiments and studies of congener drugs show icotinib, a new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, can specifically bind to the tyrosine kinase domain of the EGFR, block the EGFR related signal, thereby inhibit the growth of tumor cell. The objective of this study was to investigate the safety, tolerability and dose-related biologic effects of icotinib in patients with non-small cell lung cancer (NSCLC) in a Chinese patient population. METHODS: This was an open-label, phase I, dose escalation, safety/tolerability trial of oral icotinib (100 to 400 mg), administered twice per day for 28-continuous-day cycles until disease progression or undue toxicity. RESULTS: Forty patients with stage IIIB (15%) or IV (85%) NSCLC were included in the study. They had mainly adenocarcinoma (85%), with a performance status (PS) of 0 (45%) or 1 (55%) and less than half the patients (45%) had histories of smoking and all were pretreated by at least one regimen of chemotherapy. Patients were assigned to three dose levels of 150 mg b.i.d, 200 mg b.i.d, or 125 mg t.i.d. The follow-up periods ranged from 5 to 80 weeks. Adverse events were found in 35% patients, most of which were mild and reversible. The adverse events mainly occurred in the first 4 weeks and included rash (25%), diarrhea, nausea and abdominal distention. One definite interstitial lung disease (ILD) was found in a patient in the dose of 200 mg b.i.d. According to an 8-week assessment, one (2.5%) patient receiving 150 mg gained complete response (CR) that persisted for 44 weeks, seven (17.50%) patients had partial remission (PR), and 18 (45%) patients had stable disease (SD). The objective response including CR + PR was 20%. The median time of progression-free survival for the 40 patients was 20 weeks (range: 12 to 32 weeks). The response was not affected by pathological type, history of smoking, or numbers of previous therapeutic regimens. No relationship between dose, response, adverse effect, or duration of the study was observed. CONCLUSIONS: Icotinib, given as oral twice daily, showed favorable safety and tolerability. Mild and reversible rash, diarrhea, and nausea were the main adverse events. Antitumor activity was obvious at each dose in heavily pretreated patients. Pharmacodynamic evaluations and further phase II/III trials are in progress.

Metabolite identification of a new antitumor agent icotinib in rats using liquid chromatography/tandem mass spectrometry.

Icotinib, 4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline, is a new antitumor agent. The metabolic pathway of icotinib in rats was studied using liquid chromatography/tandem mass spectrometry (LC/MS(n)) analysis. Full scan and selected ion monitoring modes were used to profile the possible metabolites of icotinib in rat urine, feces and bile samples. Four phase I metabolites (M1-M4) and two phase II metabolites (M5, M6) were detected and characterized. Multiple-stage mass spectrometry and nuclear magnetic resonance (NMR) spectrometry were employed to elucidate structures of metabolites. Icotinib was metabolized to open the crown ether ring to form the main phase I metabolites. During metabolism, a reactive metabolite was formed. Using semicarbazide as a trapping agent, an intermediate arising from opening of the crown ether ring was detected as an aldehyde product by LC/MS/MS. These data indicated that ring opening of the crown ether was triggered by hydroxylation at the 8''-position of the ring to form a hemiacetal intermediate, which was further oxidized or reduced. Finally, the metabolic pathway of icotinib in rats was proposed.

The Abl-related gene (Arg) requires its F-actin-microtubule cross-linking activity to regulate lamellipodial dynamics during fibroblast adhesion.

Microtubules (MTs) help establish and maintain cell polarity by promoting actin-dependent membrane protrusion at the leading edge of the cell, but the molecular mechanisms that mediate cross-talk between actin and MTs during this process are unclear. We demonstrate that the Abl-related gene (Arg) nonreceptor tyrosine kinase is required for dynamic lamellipodial protrusions after adhesion to fibronectin. arg-/- fibroblasts exhibit reduced lamellipodial dynamics as compared with wild-type fibroblasts, and this defect can be rescued by reexpression of an Arg-yellow fluorescent protein fusion. We show that Arg can bind MTs with high affinity and cross-link filamentous actin (F-actin) bundles and MTs in vitro. MTs concentrate and insert into Arg-induced F-actin-rich cell protrusions. Arg requires both its F-actin-binding domains and its MT-binding domain to rescue the defects in lamellipodial dynamics of arg-/- fibroblasts. These findings demonstrate that Arg can mediate physical contact between F-actin and MTs at the cell periphery and that this cross-linking activity is required for Arg to regulate lamellipodial dynamics in fibroblasts.