piperidines and Small-Cell-Lung-Carcinoma

Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinases. It is approved for the treatment of unresectable or metastatic medullary thyroid cancer. Its use may be hindered due to adverse events, including rash. The reported incidence and risk of rash to vandetanib varies widely and has not been more closely investigated. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing a rash.. Databases from PubMed from 1996 through July 2011 and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through July 2011 were searched for relevant studies.. Eligible studies were prospective trials that described side effects of all-grade or high-grade rash for patients who received vandetanib 300 mg as a single agent. The incidence of all-grade and high-grade rash and relative risk were calculated using random-effects or fixed-effects models.. Of 63 studies initially identified, nine met the selection criteria and were included for the study. A total of 2961 patients were included for analysis. The summary incidences of all-grade and high-grade rash were 46.1% [95% confidence interval (CI), 40.6-51.8%] and 3.5% (95% CI, 2.5-4.7%), respectively. From randomized controlled trials, patients who received vandetanib 300 mg had a significantly increased risk of developing all-grade rash in comparison with controls, with a relative risk of 2.43 (95% CI, 1.37-4.29; P = 0.002).. There is a significant risk of developing rash in cancer patients receiving vandetanib. Awareness and treatment of this adverse event is critical to ensure adherence and maximize dosing, guaranteeing the best possible clinical benefit.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Eruptions; ErbB Receptors; Female; Humans; Incidence; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Risk; Severity of Illness Index; Small Cell Lung Carcinoma; Thyroid Neoplasms

Vandetanib is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis: vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and REarranged during Transfection tyrosine kinase activity. Phase I clinical trials have shown that vandetanib is well tolerated as a single agent at daily doses < or =300 mg. In the phase II setting, negative results were observed with vandetanib in small cell lung cancer, metastatic breast cancer, and multiple myeloma. In contrast, three randomized phase II studies showed that vandetanib prolonged the progression-free survival (PFS) time of patients with non-small cell lung cancer (NSCLC) as a single agent when compared with gefitinib or when added to chemotherapy. Rash, diarrhea, hypertension, fatigue, and asymptomatic QTc prolongation were the most common adverse events. Antitumor activity was also observed in medullary thyroid cancer. Four randomized phase III clinical trials in NSCLC are exploring the efficacy of vandetanib in combination with docetaxel, the Zactima in cOmbination with Docetaxel In non-small cell lung Cancer (ZODIAC) trial, or with pemetrexed, the Zactima Efficacy with Alimta in Lung cancer (ZEAL) trial, or as a single agent, the Zactima Efficacy when Studied versus Tarceva (ZEST) and the Zactima Efficacy trial for NSCLC Patients with History of EGFR-TKI chemo-Resistance (ZEPHYR) trials. Based on a press release by the sponsor of these trials, the PFS time was longer with vandetanib in the ZODIAC and ZEAL trials; the ZEST trial was negative for its primary superiority analysis, but was successful according to a preplanned noninferiority analysis of PFS. Ongoing phase II and III clinical trials will better define the appropriate schedule, the optimal setting of evaluation, and the safety of long-term use of vandetanib.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Docetaxel; Drug Therapy; ErbB Receptors; Glutamates; Guanine; Humans; Lung Neoplasms; Pemetrexed; Piperidines; Quinazolines; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Small Cell Lung Carcinoma; Taxoids; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-1

This randomized, double-blind, phase 2 trial evaluated whether the addition of vandetanib to platinum plus etoposide for previously untreated extensive-stage small cell lung cancer (SCLC) prolonged the time to disease progression in comparison with chemotherapy alone.. Patients with previously untreated extensive-stage SCLC received platinum (cisplatin or carboplatin) with etoposide in combination with vandetanib (100 mg daily) or a placebo for up to 4 total cycles (no maintenance therapy). An initial safety run-in phase was conducted with the first 6 patients enrolled; all these patients received vandetanib with cisplatin and etoposide. With an overall sample size of 68 patients, the study had 80% power to detect a 3-month difference in the time to progression (TTP) from 4 to 7 months (significance level,.10 [1-sided log-rank test]).. Seventy-four patients were enrolled between April 2008 and May 2013. Thirty-three patients were ultimately randomized to each arm. The baseline characteristics were well balanced, and the median number of treatment cycles was 4 for each arm. Thirty-one patients in each arm were evaluable for TTP; the median TTP was 5.62 months with vandetanib and 5.68 months with the placebo (P = .9518). The median overall survival was 13.24 months with vandetanib and 9.23 months with the placebo (P = .4577; 33 evaluable patients in each arm). Nonhematologic toxicity was increased with vandetanib versus the placebo. No correlation was seen between vascular endothelial growth factor polymorphisms and outcomes.. The addition of vandetanib to platinum and etoposide did not improve outcomes for patients with newly diagnosed extensive-stage SCLC. Toxicity was increased in comparison with chemotherapy alone. Cancer 2017;123:303-311. © 2016 American Cancer Society.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Disease Progression; Double-Blind Method; Etoposide; Female; Humans; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Piperidines; Quinazolines; Small Cell Lung Carcinoma

A 56-year-old woman, a never-smoker, had postoperative recurrence of anaplastic lymphoma kinase rearranged lung cancer. She achieved a partial response to treatment with an anaplastic lymphoma kinase tyrosine kinase inhibitor, crizotinib. After the tumor regrowth, crizotinib was switched to alectinib; once again a partial response was observed. At the second recurrence, transbronchial needle aspiration of the right paratracheal node was performed, which revealed cytological findings of small-cell carcinoma. While treatment with cisplatin-irinotecan chemotherapy made reduction of some tumor shadows, including the biopsied mediastinal lymph nodes, new, small, nodular shadows, highly suggestive of pulmonary metastases, were detected in both lung fields. This case may show proof of the transformation to small-cell lung cancer as a mechanism of resistance to anaplastic lymphoma kinase tyrosine kinase inhibitors in anaplastic lymphoma kinase rearranged tumor. However, this transformation may also be only one part of the resistance mechanism of the heterogeneous tumor.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Lymph Nodes; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Small Cell Lung Carcinoma

We report an anaplastic lymphoma receptor tyrosine kinase gene (ALK)-positive patient who showed a paradoxical response to the ALK inhibitor alectinib; the primary lesion increased in size, whereas other metastatic lesions decreased markedly. A biopsy of the primary lesion confirmed an ALK rearrangement; however, the tumor had transformed histologically into small cell lung cancer. The lack of reports of small cell lung cancer transformation in ALK-positive patients implies that this outcome was unusual; this patient was treated with alectinib, which is more selective and has a greater inhibitory effect than crizotinib. This case may reveal resistance mechanisms that differ according to the agent used for treatment.

Topics: Adenocarcinoma; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Cell Transformation, Neoplastic; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Small Cell Lung Carcinoma

Topics: Adenocarcinoma; Adult; Anaplastic Lymphoma Kinase; Carbazoles; Cell Transformation, Neoplastic; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Small Cell Lung Carcinoma

Studies have shown that muscarinic receptors 3 (M3R) plays key roles in regulating tumorigenesis and tumor growth. The aim of this study is to investigate the expression of M3R in human small cell lung cancer (SCLC) cell line SBC3 and to explore the effect of M3R antagonist on cell proliferation, apoptosis and adhesion.. SBC3 cells were cultured in vitro. RT-PCR and Western blot were used to detect the expression of M3R in SBC-3. MTT assay and flow cytometry were used to determine the effects of M3R antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) on the proliferation and apoptosis of SBC-3 cells. Flow cytometry was used to detect the integrin expression in SBC3 and alteration of integrin expression after treating the cells with cholinergic receptor agonist acetylcholine iodide (acetylcholine iodide, Ach) and 4-DAMP. Fibronectin (Fn) coated 96-well plates were used to detect the effect of Ach, 4-DAMP and anti-integrin antibody on cell adhesion.. M3R was expressed in SBC3 cells. 4-DAMP significantly inhibited SBC3 cells proliferation in a dose-dependent manner. 4-DAMP promoted cell apoptosis at a concentration of 10-4 M of 4-DAMP compared with control. αvβ1 and α5β1 integrin were expressed in SBC3 cells. 10-4 M Ach stimulated cell adhesion toward Fn significantly (P<0.01). This effect was completely abrogated by 10-5 M 4-DAMP, 5 μg/mL anti-β1 integrin antibody or anti-αv and anti-α5 integrin antibodies (P<0.01) and partially abrogated by 5 μg/mL anti-αv or anti-α5 integrin antibody (P<0.05). But Ach and 4-DAMP did not alter Fn receptor (αvβ1 or α5β1 integrin) expression.. M3R is expressed in SBC3 cell. The M3R antagonist inhibits SBC3 cell proliferation, adhesion and enhances cell apoptosis. M3R antagonist inhibiting SBC3 cell adhesion is presumably modulated by functional alteration of β1 containing integrins (αvβ1 and α5β1), but not by any variation in their expression.
.. 背景与目的 研究表明毒蕈碱胆碱受体3（muscarinic receptor 3, M3R）在多种肿瘤的发生、发展中发挥重要的作用。本研究旨在探讨M3R在人小细胞肺癌（small cell lung cancer, SCLC）细胞株SBC3的表达，M3R拮抗剂对细胞增殖、凋亡及粘附的影响。方法 体外培养SBC3细胞，RT-PCR和Western blot检测M3R的表达。MTT法及流式细胞法检测M3R拮抗剂（4-diphenylacetoxy-N-methylpiperidine methiodide, 4-DAMP）对细胞增殖和凋亡的影响。流式细胞法检测细胞整合素的表达及碘化乙酰胆碱（acetylcholine iodide, Ach）和4-DAMP对整合素表达的影响。纤维结合蛋白（Fn）包被的96孔板用以研究Ach、4-DAMP及整合素抗体对细胞粘附的作用。结果 SBC3细胞表达M3R，4-DAMP浓度依懒性抑制细胞增殖。与对照组比较，10-4 M 4-DAMP能够明显地增加SBC3细胞凋亡。SBC3细胞表达αvβ1和α5β1整合素，10-4 M Ach刺激细胞粘附（P<0.01）的作用几乎被10-5 M 4-DAMP、5 μg/mL抗-β1抗体或抗-αv和α5抗体完全阻断（P<0.01），但Ach及4-DAMP不影响αv、α5和β1的表达水平。结论 SBC3细胞表达M3R，M3R拮抗剂能抑制细胞的增殖并促进凋亡。其抑制粘附的作用是通过抑制细胞含β1的整合素（αvβ1 和 α5β1）的功能实现的。.

Topics: Apoptosis; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Humans; Lung Neoplasms; Piperidines; Receptor, Muscarinic M3; Small Cell Lung Carcinoma

Met receptor phosphorylation is associated with poor prognosis in human small cell lung cancer (SCLC). The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met-mediated epithelial-to-mesenchymal transition (EMT) in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models.. SCLC models of HGF-induced EMT were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice) for chemosensitivity and response to Met inhibition with PF-2341066 (crizotinib). Human SCLC samples at diagnosis (N = 87) and relapse (N = 5) were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and these were correlated with patient outcome.. We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype, and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival, and were upregulated in chemorefractory disease.. These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease.

Topics: Animals; Antineoplastic Agents; Carcinogenesis; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Drug Synergism; Epithelial-Mesenchymal Transition; Etoposide; Gene Expression; Hepatocyte Growth Factor; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Piperidines; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Small Cell Lung Carcinoma; Snail Family Transcription Factors; Transcription Factors; Xenograft Model Antitumor Assays

Benjakul, a Thai traditional herbal preparation, comnprises five plants: Piper chaba, Piper sarmentosum, Piper interruptum, Plumbago indica, and Zingiber officinale. It has widely been used to treat cancer patients in folk medicine in Thailand. Benjakul extract, and its isolated compounds should be investigated for cytotoxic activity and analysis isolated compounds from chemical fingerprinting.. To study cytotoxicity ofBenjakul extract and its isolatedpure compounds against human small cell lung cancer cell line (NCI-HI 688) and in normal human lungfibroblast cell line (MRC-5) and analysis the content ofisolated compounds for quality control of Benjakul extract.. Bioassay-guided fractionation was used for isolated active compounds from ethanolic extract of Benjakul. Cytotoxic activity was carried using the SRB assay. HPLC method was applied to analyze six isolated compound contentfrom Benjakul extract.. The ethanolic extract ofBenjakul showed cytotoxicity against NCI-H1688 with IC50 value = 36.15±4.35 μg/ml. Hexane fraction as semi-separation by VLC showed the best cytotoxic activity (21.1 7±7.42 μg/ml). Six isolated compounds were identified as myristicin, plumbagin, methyl piperate, 6-shogaol, 6-gingerol and piperine. Plumbagin exhibited the highest cytotoxic activity and 6-shogaol was the second most effective cytotoxic constituent (IC50 values = 1.41±0.01 and 6.45±0.19 μg/ml, respectively). Piperine showed the highest content in both ofHPLC analysis and column chromatography separation.. Benjakul extract exhibited cytotoxicity against NCI-HI 688. Plumbagin and 6-shogaol are bioactive markers for cytotoxicity against this small cell lung cancer cell line. Chromatographic fingerprinting can be used to analyze six cytotoxic compounds isolatedfrom the ethanolic extract ofBenjakul.

Topics: Alkaloids; Benzodioxoles; Catechols; Cell Line, Tumor; Chromatography, High Pressure Liquid; Drug Screening Assays, Antitumor; Ethanol; Fatty Alcohols; Humans; Lung Neoplasms; Medicine, Traditional; Naphthoquinones; Piper; Piperidines; Plant Extracts; Plumbaginaceae; Polyunsaturated Alkamides; Small Cell Lung Carcinoma; Thailand; Zingiber officinale

HERG (human ether-à-go-go-related gene) K(+) currents fulfill important ionic functions in cardiac and other excitable cells. In addition, HERG channels influence cell growth and migration in various types of tumor cells. The mechanisms underlying these functions are still not resolved. Here, we investigated the role of HERG channels for cell growth in a cell line (SW2) derived from small cell lung cancer (SCLC), a malignant variant of lung cancer. The two HERG1 isoforms (HERG1a, HERG1b) as well as HERG2 and HERG3 are expressed in SW2 cells. Inhibition of HERG currents by acute or sustained application of E-4031, a specific ERG channel blocker, depolarized SW2 cells by 10-15 mV. This result indicated that HERG K(+) conductance contributes considerably to the maintenance of the resting potential of about -45 mV. Blockage of HERG channels by E-4031 for up to 72 h did not affect cell proliferation. In contrast, siRNA-induced inhibition of HERG1 protein expression decreased cell proliferation by about 50%. Reduction of HERG1 protein expression was confirmed by Western blots. HERG current was almost absent in SW2 cells transfected with siRNA against HERG1. Qualitatively similar results were obtained in three other SCLC cell lines (OH1, OH3, H82), suggesting that the HERG1 channel protein is involved in SCLC cell growth, whereas the ion-conducting function of HERG1 seems not to be important for cell growth.

Topics: Cell Line, Tumor; Cell Proliferation; Ether-A-Go-Go Potassium Channels; Humans; Lung Neoplasms; Membrane Potentials; Piperidines; Pyridines; RNA, Small Interfering; Small Cell Lung Carcinoma

In small cell lung carcinoma (SCLC), acetylcholine (ACh) is synthesized and secreted, and it acts as an autocrine growth factor through activation of its receptors, muscarinic receptor (mAChR) and nicotinic receptor (nAChR). Alteration of tumor growth by blockade of M(3) mAChR in a human SCLC cell line, NCI-H82, was investigated in the present study. We used a highly selective M(3) muscarinic antagonist, N-(2-[3-([3R]-1-(cyclohexylmethyl)-3-piperidinyl]methylamino)-3-oxopropyl]amino-2-oxoethyl)-3,3,3-triphenyl-propioamide (J-115311). Our results show that J-115311 inhibited the increased intracellular calcium elicited by carbachol, a muscarinic agonist, in SCLC cells. J-115311 also inhibited SCLC cell growth in vitro. In a mouse orthotopic xenograft model, J-115311 dose-dependently reduced tumor growth when NCI-H82 cells were inoculated into the upper left lobe of the lung. These findings indicate that blockade of M(3) mAChR can suppress tumor growth in SCLC, suggesting the potential therapeutic utility of M(3) muscarinic antagonists as anti-cancer agents.

Topics: Animals; Antineoplastic Agents; Calcium Signaling; Carbachol; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dipeptides; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred ICR; Mice, SCID; Muscarinic Agonists; Muscarinic Antagonists; Piperidines; Receptor, Muscarinic M3; Small Cell Lung Carcinoma; Tumor Burden; Xenograft Model Antitumor Assays