The relative importance of predictive factors for single first-generation EGFR-TKI use for more than 5 years in patients with advanced non-small cell lung cancer: Taiwan multicenter TIPS-5 study.

BACKGROUND: The relative importance of predictive factors for advanced non-small cell lung cancer (NSCLC) patients on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment remains unclear. MATERIALS AND METHODS: We retrospectively enrolled advanced NSCLC patients with single first-generation EGFR-TKI treatment for ⩾5 years (Y) in Taiwan. Clinical data was collected and compared with those of another cohort with single first-line EGFR-TKI treatment for <5 Y. Plasma cell-free DNA (cfDNA) samples were collected from patient subsets, pre- and post-TKI, in the >5 Y group. RESULTS: Overall, 128 and 278 patients were enrolled in the ⩾5 Y and <5 Y groups, respectively. Significant factors in the multivariate analysis of patients' characteristics including Eastern Cooperative Oncology Group performance status 0-1, postoperative recurrence, without brain metastasis, oligometastasis (each score of 2), female sex, erlotinib use, and without bone metastasis (each score of 1), were incorporated into a risk scoring system. The area under the receiver operating characteristic curve was 0.82 [95% confidence interval (CI): 0.78-0.86]. Of the plasma cfDNA samples from 33 patients in the ⩾5 Y group, only 1 had a T790M in 25 patients without progressive disease. In 27 patients with single agent use for ⩾96 months, 22 (81.5%) received local treatment (surgery or radiotherapy) for the primary lung tumor before and during TKI treatment. CONCLUSION: For NSCLC patients with single first-generation EGFR-TKI use for ⩾5 Y, factors with different relative importance exist and the risk-scoring model is feasible with modest accuracy. The role of local treatment for primary tumors in patients with long-term TKI use requires further investigation.

Synthesis, anticancer activity and molecular docking studies on 1,2-diarylbenzimidazole analogues as anti-tubulin agents.

Twenty-four 1,2-diarylbenzimidazole derivatives were designed, synthesized and biologically evaluated. It turned out that most of them were potential anticancer drugs. Among them, compound c24 showed the highest anti-tumor activity (GI50 = 0.71-2.41 µM against HeLa, HepG2, A549 and MCF-7 cells), and low toxicity to normal cells (CC50 > 100 µM against L02 cells). In the microtubule binding assay, c24 showed the most potent inhibition of microtubule polymerization (IC50 = 8.47 µM). The binding ability of compound c24 to tubulin crystal was verified by molecular docking simulation experiment. Further studies on HepG2 and HeLa cells showed that compound c24 could cause mitotic arrest of tumor cells to G2/M phase then inducing apoptosis. To sum up, compound c24 is a promising microtubule assembly inhibitor.

Design, synthesis, and biological evaluation of 2,3-diphenyl-cycloalkyl pyrazole derivatives as potential tubulin polymerization inhibitors.

Several novel cycloalkyl-fused 2,3-diaryl pyrazole derivatives were designed, synthesized, and evaluated as potential anti-tubulin agents. Compound A10 exhibited the most potent antiproliferative activity against a panel of cancer lines (IC50  = 0.78-2.42 µM) and low cytotoxicity against 293T & L02 (CC50 values of 131.74 and 174.89 µM, respectively). Moreover, A10 displayed inhibition of tubulin polymerization in vitro, arrested the G2/M phase of the cell cycle, changed morphology of tubulin, increased intracellular reactive oxygen species, and induced apoptosis of HeLa cells. Docking simulation and 3D-QSAR models were performed to elaborate on the anti-tubulin mechanism of the derivatives. The inhibition of monoclonal colony formation provided more intuitional data to verify the possibility of A10 as a novel tubulin assembling inhibitor.

A class of novel tubulin polymerization inhibitors exert effective anti-tumor activity via mitotic catastrophe.

In current work, a class of novel 4,5-dihydro-1H-pyrazole-1-carboxylate derivatives (E01-E28) were designed, synthesized and evaluated. Among them, the most potent compound E24 exhibited comparable activity against a panel of cancer cells (GI50 ranging 0.05-0.98 µM) and tubulin polymerization inhibition (IC50 = 1.49 µM) with reference drug CA-4(P) (GI50 ranging 0.019-0.32 µM, IC50 = 2.18 µM). The following assays indicated that compound E24 disturbed the dynamics of tubulin catastrophe and rescue, which triggered G2/M arrest, leading to ROS accumulation, cleavage of PARP and apoptosis. Molecular dynamics simulation validated that compound E24 could tightly bind into tubulin heterodimers with ß Lys 254 and ß Cys 241 of tubulin in the docking pose. Metabolic stability and pharmacokinetics parameters were also determined. The half time (t1/2) displayed species differences in three microsomes. The plasma elimination half-life (t1/2), peak plasma concentration (Cmax), mean retention time (MRT), the area under the curve (AUC0-∞) and distribution volume (Vz) of E24 after intravenous administration were 0.90 ± 0.22 h, 594.50 ± 97.23 ng/mL, 1.09 ± 0.22 h, 413.67 ± 105.64 ng/mL*h and 5.03 ± 1.82 L/kg, respectively. In HeLa-xenografts, compound E24 exhibited obvious antitumor efficacy via the suppression of tumor growth without weight loss of body or organ. In brief, compound E24 might be a hopeful candidate with excellent properties for oncotherapy as tubulin polymerization inhibitor.

Novel Podophyllotoxin Derivatives as Potential Tubulin Inhibitors: Design, Synthesis, and Antiproliferative Activity Evaluation.

A number of podophyllotoxin derivatives (3A-3J) had been designed and synthesized, and their biological activities were evaluated in this study. Moreover, the antiproliferation activities of these compounds against four human cancer cell lines (HepG2, HeLa, A549, and MCF-7) were also tested. The results indicated that the most promising compound 3D displayed potent inhibitory activity over the four human cancer cell lines and was further demonstrated to have potent tubulin polymerization inhibitory effects without damaging the non-cancer cells. Additionally, 3D was verified to effectively interfere with tubulin and could prevent the mitosis of cancer cells, leading to cell cycle arrest and eventually inducing apoptosis in a dose- and time-dependent manner. Moreover, the Western blotting and siRNA results showed that Bcl-2 was downregulated in HepG2 cells treated with 3D. Finally, the molecular docking simulation results revealed that 3D could fit well in the colchicine-binding pocket. Taken together, this study has provided certain novel antitubulin agents for possible cancer chemotherapy.

CHA2DS2-VASc scores predict major adverse cardiovascular events in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) frequently experience concurrent comorbidities; therefore, risk assessment for major adverse cardiovascular events (MACEs) is very important. OBJECTIVES: We explored the association between COPD and risk of MACEs with three common clinical events: acute myocardial infarction (AMI), ischemic stroke (IS), and cardiovascular death (CVD). METHODS: We evaluated the predictive value of the CHA2DS2-VASc score (congestive heart failure [C], hypertension [H], age [A], diabetes [D], stroke [S], and vascular disease [VASc]) for MACEs in COPD patients. In this observational study, we retrospectively reviewed the records of 29 258 patients with COPD between 2005 and 2009 in relation to MACE risk using the CHA2DS2-VASc score. We calculated the hazard ratios (HR) and 95% confidence intervals (CI) using a significance level of .05. RESULTS: Patients with COPD had significantly (P < .001) increased risk of MACEs, and a high prevalence of CHA2DS2-VASc scores ≥ 6, predicting MACEs (16.1%), AMI (3.3%), IS (8.7%), and CVD (4.0%). A good discrimination was found for MACEs, IS events, and CVD events (AUC = 0.740, 0.739, and 0.778, respectively) but poorer discrimination for AMI events (AUC = 0.697). CONCLUSION: Early lifestyle modifications and antithrombotic therapy may be essential for COPD patients at a high risk of MACEs, that is, those with CHA2DS2-VASc scores ≥ 6.