Smit E.F.,Netherlands Cancer Institute |
Wu Y.-L.,Guangdong General Hospital and Guangdong Academy of Medical science |
Gervais R.,Center Francois Baclesse |
Zhou C.,Shanghai Pulmonary Hospital |
And 10 more authors.
Lung Cancer | Year: 2016
Objectives Active smokers with non-small-cell lung cancer (NSCLC) have increased erlotinib metabolism versus non-smoking patients, which reduces exposure. Therefore, an increased erlotinib dose may be beneficial. The CurrentS study (NCT01183858) assessed efficacy and safety of 300 mg erlotinib (E300) as second-line therapy in current smokers with locally advanced or metastatic NSCLC versus the standard 150 mg dose (E150). Materials and methods Patients with stage IIIB/IV NSCLC (current smokers who failed first-line platinum-based chemotherapy) were randomized to receive E150 or E300 until progression/death/unacceptable toxicity. Primary endpoint: progression-free survival (PFS). Secondary endpoints: overall survival (OS), disease control rate and safety. Results A total of 342 patients were screened; the intent-to-treat population comprised 159 E300 patients and 154 E150 patients. Median PFS was 7.0 versus 6.9 weeks with E300 versus E150, respectively (unstratified hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 0.83–1.33; unstratified log-rank P = 0.671). Median OS was 6.8 months in both arms (unstratified HR = 1.03, 95% CI: 0.80–1.32; unstratified log-rank P = 0.846). Overall, 89.2% (E300 arm) and 84.4% (E150 arm) experienced ≥1 adverse event (AE) of any grade (44.3% and 37%, respectively, experienced grade ≥3 AEs); AEs of special interest were reported in 67.7% and 47.4% of patients, respectively. E300 resulted in higher mean plasma concentrations versus E150, however, this did not improve efficacy. Conclusions Despite the difference in erlotinib exposure, there was no evidence of an incremental efficacy benefit of a higher erlotinib dose versus the standard dose in this population of highly active smokers. © 2016 Elsevier Ireland Ltd
Ullrich N.,University of Duisburg - Essen |
Loffek S.,University of Duisburg - Essen |
Horn S.,University of Duisburg - Essen |
Ennen M.,Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire |
And 9 more authors.
Pigment Cell and Melanoma Research | Year: 2015
The multifunctional Ig-like carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is neo-expressed in the majority of malignant melanoma lesions. CEACAM1 acts as a driver of tumor cell invasion, and its expression correlates with poor patient prognosis. Despite its importance in melanoma progression, how CEACAM1 expression is regulated is largely unknown. Here, we show that CEACAM1 expression in melanoma cell lines and melanoma tissue strongly correlates with that of the microphthalmia-associated transcription factor (MITF), a key regulator of melanoma proliferation and invasiveness. MITF is revealed as a direct and positive regulator for CEACAM1 expression via binding to an M-box motif located in the CEACAM1 promoter. Taken together, our study provides novel insights into the regulation of CEACAM1 expression and suggests an MITF-CEACAM1 axis as a potential determinant of melanoma progression. © 2015 John Wiley & Sons A/S.
Kinsella P.,Trinity College Dublin |
Greene L.M.,Trinity College Dublin |
Bright S.A.,Trinity College Dublin |
Pollock J.K.,Trinity College Dublin |
And 5 more authors.
Investigational New Drugs | Year: 2016
Summary: The C-KIT receptor tyrosine kinase is constitutively activated in the majority of gastrointestinal stromal tumours (GIST). Imatinib (IM) a selective inhibitor of C-KIT, is indicated for the treatment of KIT-positive unresectable and/or metastatic GIST, and has tripled the survival time of patients with metastatic GIST. However, the majority of patients develop IM-resistance and progress. Although IM elicits strong antiproliferative effects, it fails to induce sufficient levels of apoptosis; acquired IM-resistance and disease recurrence remain an issue, a more effective drug treatment is greatly needed. We examined the effect of a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-15 in combination with IM on GIST cells. PBOX-15 decreased viability and in combination with IM synergistically enhanced apoptosis in both IM-sensitive and IM-resistant GIST cells, decreased the anti-apoptotic protein Mcl-1, and enhanced activation of pro-caspase-3 and PARP cleavage. The combination treatment also led to an enhanced inhibition of C-KIT-phosphorylation and inactivation of C-KIT-dependent signalling in comparison to either drug alone; CDC37, a key regulator of C-KIT in GIST was also dramatically decreased. Furthermore, PBOX-15 reduced CKII expression, an enzyme which regulates the expression of CDC37. In conclusion, our findings indicate the potential of PBOX-15 to improve the apoptotic response of IM in GIST cells and provide a more effective treatment option for GIST patients. © 2016 Springer Science+Business Media New York.
Diaz-Carballo D.,Ruhr University Bochum |
Ueberla K.,Ruhr University Bochum |
Kleff V.,Institute of Anatomy |
Ergun S.,Institute of Anatomy |
And 6 more authors.
International Journal of Clinical Pharmacology and Therapeutics | Year: 2010
Objectives: Polyisoprenylated acylphloroglucinols have recently emerged as antitumoral agents. This study aims at elucidating the antiretroviral activity of two such compounds which were isolated from Caribbean propolis: 7-epi-nemorosone and plukenetione A, the structure of which is based on an adamantane moiety. Plukenetione A is for the first time shown to have antiretroviral activity. Material and methods: The isolation of both small molecules was carried out using RP-HPLC. Their antiretroviral activity was studied based on lentiviral particles produced in HEK293T cells from the SIV-based vector VLΔBH; their cytotoxicity was monitored by MTT proliferation assay. The antiviral activity of 7-epi-nemorosone was studied in CEMx174-SEAP infected with the HIV-1-strain pNL4.3wt. Reverse transcriptase inhibition was determined by a standard two-step RT-PCR using MMLV RT. Results: 7-epinemorosone and plukenetione A were found to be potent antilentiviral agents in the employed system, inhibiting viral infection at concentrations below 1 μM/2 μM, respectively. Whereas 7-epi-nemorosone was not able to inhibit the reverse transcriptase in vitro (IC50 > 25 μM), plukenetione A effectively inhibited its enzymatic activity at an IC50 of 1.75 μM. Conclusions: Despite 7-epi-nemorosone and plukenetione A sharing some structural core elements, the mechanism of action involved in their antiretroviral activity seems to be different. We propose that 7-epinemorosone inhibits the viral replication by interrupting the Akt/PKB signaling cascade, as was demonstrated previously in various cell lines. Since plukenetione A effectively inhibits the enzymatic activity of MMLV reverse transcriptase at concentrations that show antilentiviral activity, we suggest that this small molecule acts by interfering with the enzyme's catalytic site. ©2010 Dustri-Verlag Dr. K. Feistle.
10-year long-term survival (LTS) of induction chemotherapy with three cycles cisplatin/paclitaxel followed by concurrent chemoradiation cisplatin/etoposide/45Gy (1.5Gy bid) plus surgery in locally advanced non-small-cell lung cancer (NSCLC)-A multicenter phase-II trial (CISTAXOL)
Eberhardt W.E.E.,West German Cancer Center |
Gauler T.C.,West German Cancer Center |
LePechoux C.,Institute Gustave Roussy |
Stamatis G.,Ruhrlandclinic |
And 10 more authors.
Lung Cancer | Year: 2013
Background: Induction chemoradiotherapy plus surgery remains an option to study in IIIA(N2) and selected IIIB NSCLC. Here we report ten-year long-term survival of a prospective multicenter German-French phase-II trial with trimodality. Patients and methods: Mediastinoscopically proven IIIA(N2)/selected IIIB NSCLC received three cycles cisplatin (50mg/m2 day 1+8) and paclitaxel (175mg/m2d1) qd 22. Concurrent CTx/RTx followed: 45Gy (1.5Gy bid) with cisplatin 50mg/m2 day 2+9 and etoposide 100mg/m2 d 4-6. Surgery was planned three to five weeks after RTx. If evaluated inoperable/irresectable at the end of RTx, definitive RTx-boost (20Gy; 2Gy qd) followed. Here we report 10-year-LTS for this cohort. Results: All 64 patients were accrued 3/99 to 2/02. Patients characteristics: IIIA(N2)/IIIB 25/39; m/f 48/16; adeno/squamous/large-cell/adenosquamous/NOS 15/26/18/3/2; age: median 52.5 (range 33-69). 36 operated: R0 32/36 (89%); pCR 16/36 (44%). 10-year-LTS%; all 26.0; IIIA(N2) 37.1; IIIB 17.9; relevant prognostic factors (exploratory): pretreatment - histopathology (squamous/adeno) - age (<50/≥50) - Charlson-CI: 1/>1 - BMI (≥25/<25) - pack years smoking (≥10/<10); treatment-dependent - R0/no-R0. Conclusions: This regimen achieves substantial LTS. Interestingly, adenocarcinomas, older patients, unfavorable comorbidity scores, higher BMI and light smokers demonstrate poor long-term outcome even with aggressive trimodality. This dataset defines the rationale for our ongoing randomized trial with surgery after induction therapy in IIIA(N2)/selected IIIB (ESPATÜ). © 2013.