BACKGROUND: Lung cancer is the major cause of cancer-related death in the United States, with small-cell lung cancer (SCLC) constituting approximately 20% of all cases of lung cancer. Numerous epidemiologic and molecular studies have suggested that alterations in retinoid-signaling pathways play a role in the pathogenesis of lung cancer. Fenretinide [N-(4-hydroxyphenyl)retinamide; HPR] is a synthetic retinoid with minimal toxicity and favorable pharmacokinetics during long-term administration to patients in clinical trials. PURPOSE: The aim of this investigation was to study the effect of HPR on the growth of SCLC cells in vitro. METHODS: Seven SCLC cell lines (NCI-H69, NCI-H82, NCI-H146, NCI-H209, NCI-H345, NCI-H446, and NCI-H510A) were exposed continuously to a broad range of concentrations of HPR or all-trans-retinoic acid (RA), and cell viability was determined on day 3 and day 7 by the trypan blue dye exclusion assay. The growth of these cells was compared with that of control vehicle-treated cells to determine survival fraction and the dose resulting in a 50% inhibition of growth when compared with growth of control cells (IC50). The induction of apoptosis was evaluated by fluorescent microscopy, DNA content analysis, and a terminal deoxyribonucleotidyl transferase-based assay that labels 3'-hydroxyl ends of DNA fragments (TUNEL assay) combined with flow cytometric analysis. RESULTS: HPR inhibited growth of a panel of SCLC cell lines at IC50 values that ranged from 0.1 to 3.0 microM (concentrations that are clinically achievable). In all cell lines tested, HPR was a more potent growth inhibitor than RA. By use of fluorescent microscopy, HPR was found to induce morphologic changes consistent with apoptosis in NCI-H82 SCLC cells, including cellular shrinkage, chromatin condensation, and nuclear fragmentation. Flow cytometric analysis revealed decreased DNA content, and TUNEL assay showed increased digoxigenin-uridine triphosphate incorporation in HPR-treated NCI-H82 SCLC cells; these findings are consistent with the induction of apoptosis. CONCLUSIONS: HPR inhibited the in vitro growth of SCLC cells. In NCI-H82 cells, HPR inhibited growth via the induction of apoptosis.
BACKGROUND:Lung cancer is the major cause of cancer-related death in the United States, with small-cell lung cancer (SCLC) constituting approximately 20% of all cases of lung cancer. Numerous epidemiologic and molecular studies have suggested that alterations in retinoid-signaling pathways play a role in the pathogenesis of lung cancer. Fenretinide [N-(4-hydroxyphenyl)retinamide; HPR] is a synthetic retinoid with minimal toxicity and favorable pharmacokinetics during long-term administration to patients in clinical trials. PURPOSE: The aim of this investigation was to study the effect of HPR on the growth of SCLC cells in vitro. METHODS: Seven SCLC cell lines (NCI-H69, NCI-H82, NCI-H146, NCI-H209, NCI-H345, NCI-H446, and NCI-H510A) were exposed continuously to a broad range of concentrations of HPR or all-trans-retinoic acid (RA), and cell viability was determined on day 3 and day 7 by the trypan blue dye exclusion assay. The growth of these cells was compared with that of control vehicle-treated cells to determine survival fraction and the dose resulting in a 50% inhibition of growth when compared with growth of control cells (IC50). The induction of apoptosis was evaluated by fluorescent microscopy, DNA content analysis, and a terminal deoxyribonucleotidyl transferase-based assay that labels 3'-hydroxyl ends of DNA fragments (TUNEL assay) combined with flow cytometric analysis. RESULTS:HPR inhibited growth of a panel of SCLC cell lines at IC50 values that ranged from 0.1 to 3.0 microM (concentrations that are clinically achievable). In all cell lines tested, HPR was a more potent growth inhibitor than RA. By use of fluorescent microscopy, HPR was found to induce morphologic changes consistent with apoptosis in NCI-H82 SCLC cells, including cellular shrinkage, chromatin condensation, and nuclear fragmentation. Flow cytometric analysis revealed decreased DNA content, and TUNEL assay showed increased digoxigenin-uridine triphosphate incorporation in HPR-treated NCI-H82 SCLC cells; these findings are consistent with the induction of apoptosis. CONCLUSIONS:HPR inhibited the in vitro growth of SCLC cells. In NCI-H82 cells, HPR inhibited growth via the induction of apoptosis.
Authors: Judith G Villablanca; Wendy B London; Arlene Naranjo; Patrick McGrady; Matthew M Ames; Joel M Reid; Renee M McGovern; Sarah A Buhrow; Hollie Jackson; Enno Stranzinger; Brenda J Kitchen; Paul M Sondel; Marguerite T Parisi; Barry Shulkin; Gregory A Yanik; Susan L Cohn; C Patrick Reynolds Journal: Clin Cancer Res Date: 2011-09-09 Impact factor: 12.531
Authors: Byungdo B Han; Suyang Li; Meng Tong; Andrew S Holpuch; Richard Spinney; Daren Wang; Michael B Border; Zhongfa Liu; Sachin Sarode; Ping Pei; Steven P Schwendeman; Susan R Mallery Journal: Cancer Prev Res (Phila) Date: 2015-02-24
Authors: Ulka Vaishampayan; Lance K Heilbrun; Ralph E Parchment; Vikash Jain; James Zwiebel; Ramesh R Boinpally; Patricia LoRusso; Maha Hussain Journal: Invest New Drugs Date: 2005-03 Impact factor: 3.850
Authors: Bryan J Schneider; Francis P Worden; Shirish M Gadgeel; Ralph E Parchment; Collette M Hodges; James Zwiebel; Rodney L Dunn; Antoinette J Wozniak; Michael J Kraut; Gregory P Kalemkerian Journal: Invest New Drugs Date: 2009-02-19 Impact factor: 3.850