e-7010 and Carcinoma--Non-Small-Cell-Lung

Targeting vasculature, essential in oxygen and nutrient supply, represents a new frontier in the treatment of cancer. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of vascular disrupting agents (VDAs) targets endothelial cells and pericytes of the already established tumor vasculature, resulting in tumor ischemia and necrosis. VDAs have been divided into two types: ligand-directed VDAs and small molecules. Ligand-directed VDAs consist of targeting and effector moieties that are linked together. Their clinical efficacy appears limited because of cost and a lack of specificity and toxicity. Small molecules include two classes: the synthetic flavonoids, which work through induction of local cytokine production, and the tubulin-binding agents. The aim of this review is to discuss the hypothesized molecular mechanisms of action of VDAs and their early preclinical and clinical results, emphasizing ASA404, combretastatin A-4 disodium phosphate, ABT-751, and NPI-2358, reported in the treatment of non-small cell lung cancer, which is the leading cause of cancer death worldwide, and also to discuss future developments in this cancer population.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Diketopiperazines; Endothelial Cells; Humans; Imidazoles; Lung Neoplasms; Pericytes; Piperazines; Stilbenes; Sulfonamides; Xanthones

Despite developments in conventional (chemo)radiotherapy and surgery, survival of non-small cell lung cancer (NSCLC) patients remains poor. Treatments with targeted molecular drugs offer novel therapeutic strategies. Bevacizumab, a recombinant anti-vascular endothelial growth factor (VEGF) antibody, is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC. However, a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain. Furthermore, novel agents targeting the pre-existing NSCLC vasculature (i.e. vascular disrupting agents, VDAs) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies. Herein, we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Axitinib; Benzenesulfonates; Bevacizumab; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Indazoles; Indoles; Lung Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperidines; Pyridines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Sorafenib; Sulfonamides; Xanthones

Microtubules are among the most strategic subcellular targets of anticancer agents. Recently, new antimicrotubule agents have been introduced to clinical cancer chemotherapy. Navelbine is a new derivative of vinca alkaloids, which especially has an activity against NSCLC. Unlike classical anti-microtubules agents like colchitine and vinca alkaloids, which induce depolymerization of microtubules, taxol has an unique mechanism of action which induces tubulin polymerization. Taxotere, an analogue of taxol is slightly more active as a promoter of tubulin polymerization than Taxol. E7010 is a novel sulfonamide that inhibits tubulin polymerization. Results of preclinical and clinical studies of these agents are reviewed.

Topics: Aminophenols; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Docetaxel; Humans; Leukemia, Experimental; Lung Neoplasms; Mice; Microtubules; Paclitaxel; Sulfonamides; Taxoids; Vinblastine; Vinorelbine

ABT-751 is a novel antimitotic agent that exerted cytotoxic effects in preclinical studies. Carboplatin has efficacy in treating advanced non-small cell lung cancer (NSCLC) in combination with other drugs.. Lung cancer cell lines were treated with ABT-751 and/or carboplatin to investigate their impact on cell growth. A phase I study with an expansion cohort was conducted in previously treated NSCLC patients. The primary objective was the maximum tolerated dose (MTD); secondary objectives were objective response rates, median survival, time to tumor progression, dose-limiting toxicities (DLTs), and pharmacodynamic evaluation of buccal swabs.. Combining ABT-751 with carboplatin significantly reduced growth and induced apoptosis of lung cancer cell lines. Twenty advanced NSCLC patients were enrolled. MTD was ABT-751 125 mg orally twice daily for 7 days with carboplatin AUC 6. DLTs included fatigue, ileus, neutropenia and pneumonitis. Two patients had confirmed partial responses. Median overall survival was 11.7 months (95% CI 5.9-27.0). Time to tumor progression was 2.8 months (95% CI 2.0-2.7). Four of 6 patients showed decreased cyclin D1 protein in posttreatment versus pretreatment buccal swabs.. Combining ABT-751 with carboplatin suppressed growth of lung cancer cell lines and had modest clinical antitumor activity in advanced NSCLC previously treated predominantly with carboplatin. Further studies of this combination are not recommended while investigations of biomarkers in different patient populations, alternative schedules and combinations may be pursued.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Apoptosis; Area Under Curve; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cyclin D1; Drug Therapy, Combination; Fatigue; Female; Humans; Ileus; Lung Neoplasms; Male; Middle Aged; Neutropenia; Pneumonia; Sulfonamides; Survival Rate

ABT-751 is an antimitotic and vascular disrupting agent with potent preclinical anticancer activity. We conducted a phase I and randomized double-blind phase II study of pemetrexed with ABT-751 or placebo in patients with recurrent advanced or metastatic non-small-cell lung cancer (NSCLC).. One hundred seventy-one patients received intravenous pemetrexed 500 mg/m(2) day 1 and oral ABT-751 or placebo days 1 to 14 of 21-day cycles. The primary end point was progression-free survival (PFS). Secondary end point included overall survival (OS); pharmacokinetic and pharmacodynamic parameters were also analyzed.. The recommended phase II dose of ABT-751 with pemetrexed is 200 mg. Fatigue, constipation, anemia, nausea, and diarrhea were the most common toxicities in both study arms. No pharmacokinetic interactions were observed. Median PFS in the ABT-751 arm was 2.3 months versus 1.9 for placebo (P = .819, log-rank) for the intention-to-treat population. However, differences in PFS (P = .112, log-rank) and OS (P = .034, log-rank; median 3.3 v 8.1 months) favoring ABT-751 were seen in the squamous NSCLC subgroup. Baseline circulating tumor cell concentrations were predictive of improved OS (P = .013). Changes from baseline of greater than 20% in plasma levels of placenta growth factor (P = .056), squamous cell carcinoma antigen (P = .03), and cytokeratin 19 fragment antigen 21-1 (P = .01) were markers best associated with improved OS.. Addition of ABT-751 to pemetrexed is well-tolerated, but does not improve outcome in unselected patients with recurrent NSCLC. ABT-751 may have therapeutic potential in squamous NSCLC. Exploratory cellular and molecular analyses in this study identified biomarkers that may correlate with survival.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Czech Republic; Disease-Free Survival; Double-Blind Method; Female; Glutamates; Guanine; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Pemetrexed; Proportional Hazards Models; Risk Assessment; Risk Factors; Sulfonamides; Time Factors; Treatment Outcome; United States

To determine the tolerability and efficacy of ABT-751, an oral antimitotic agent that inhibits polymerization of microtubules, in patients with advanced taxane-refractory non-small cell lung carcinoma (NSCLC).. Eligibility was limited to patients with recurrent or metastatic NSCLC who had received one to two cytotoxic chemotherapy regimens, had a performance status of zero to one, and adequate organ function. Treatment included ABT-751 200 mg daily for 21 consecutive days, followed by 7 days off drug. Objectives were to determine response rate, time to tumor progression, survival, and tolerability of ABT-751.. All 35 enrolled patients were assessable for survival, response, and tolerability. Median time to tumor progression and overall survival were 2.1 and 8.4 months, respectively. The objective response rate was 2.9%. One patient achieved a partial response that was ongoing 567 days after initial documentation. Treatment was well tolerated; fatigue, constipation, and dehydration were the only treatment related, grade three adverse events occurring in more than one patient. Incidence of grade 3/4 hematologic and blood chemistry toxicities was acceptable, and ABT-751 was not associated with myelosuppression.. ABT-751 associated toxicity was acceptable. The median time to progression and overall survival as demonstrated for ABT-751 were comparable to other agents considered active in this patient population and to current treatments approved for second-line NSCLC. The novel antimitotic targeting of ABT-751 in combination with the compound's acceptable nonmyelosuppressive toxicity profile and efficacy similar to agents currently in use in this setting, warrant further evaluation of this compound in combination with other cytotoxic agents in advanced NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Severity of Illness Index; Sulfonamides; Surveys and Questionnaires; Survival Rate; Treatment Outcome; United States

We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC

Topics: A549 Cells; Animals; Antineoplastic Agents; Benzamides; Carcinoma, Non-Small-Cell Lung; Catalytic Domain; Cell Line, Tumor; Cell Proliferation; Heterografts; Histone Deacetylase Inhibitors; Humans; Indoles; Lymphoma, B-Cell; Mice; Models, Molecular; Protein Binding; Tubulin Modulators