BACKGROUND: Although MAGE-3 has been detected in approximately 40% of lung and esophageal cancers, expression of this cancer testis antigen appears to be below the threshold for immune recognition in patients with these malignancies. The aim of this study was to determine if the demethylating agent, 5-Aza-2'-deoxycytidine (DAC) and if the histone deacetylase inhibitor Depsipeptide FR901228 (DP) could enhance MAGE-3 expression in lung and esophageal cancer cells. METHODS: Eleven lung and esophageal cancer lines and cultured normal human bronchial epithelial (NHBE) cells were exposed to normal media (NM), DAC, DP, or combination DAC/DP at varying concentrations and exposure durations. MAGE-3 expression was evaluated by quantitative RT-PCR (TaqMan) and immunohistochemistry techniques. Trypan blue exclusion techniques were used to examine the proliferation of cancer cells after drug exposure. RESULTS: Relative to untreated controls, MAGE-3 expression was enhanced 32-fold (range 3.9 to 110) by DAC alone (0.1 micromol/L x 72 h), 2.1-fold (0.4 to 4.2) by DP alone (25 ng/mL x 6h), and 57-fold (4.6 to 209) by sequential DAC/DP exposure. Increased MAGE-3 mRNA copy numbers coincided with enhanced protein levels in these cells. MAGE-3 expression persisted after drug exposure. Flow cytometry confirmed the presence of functional HLA class I expression in these cells. Sequential DAC/DP treatment mediated pronounced growth inhibition in cancer cells but not NHBE. CONCLUSIONS: Sequential DAC/DP treatment may be a novel strategy to simultaneously augment MAGE-3 expression and induce growth arrest in thoracic malignancies.
BACKGROUND: Although MAGE-3 has been detected in approximately 40% of lung and esophageal cancers, expression of this cancer testis antigen appears to be below the threshold for immune recognition in patients with these malignancies. The aim of this study was to determine if the demethylating agent, 5-Aza-2'-deoxycytidine (DAC) and if the histone deacetylase inhibitor Depsipeptide FR901228 (DP) could enhance MAGE-3 expression in lung and esophageal cancer cells. METHODS: Eleven lung and esophageal cancer lines and cultured normal human bronchial epithelial (NHBE) cells were exposed to normal media (NM), DAC, DP, or combination DAC/DP at varying concentrations and exposure durations. MAGE-3 expression was evaluated by quantitative RT-PCR (TaqMan) and immunohistochemistry techniques. Trypan blue exclusion techniques were used to examine the proliferation of cancer cells after drug exposure. RESULTS: Relative to untreated controls, MAGE-3 expression was enhanced 32-fold (range 3.9 to 110) by DAC alone (0.1 micromol/L x 72 h), 2.1-fold (0.4 to 4.2) by DP alone (25 ng/mL x 6h), and 57-fold (4.6 to 209) by sequential DAC/DP exposure. Increased MAGE-3 mRNA copy numbers coincided with enhanced protein levels in these cells. MAGE-3 expression persisted after drug exposure. Flow cytometry confirmed the presence of functional HLA class I expression in these cells. Sequential DAC/DP treatment mediated pronounced growth inhibition in cancer cells but not NHBE. CONCLUSIONS: Sequential DAC/DP treatment may be a novel strategy to simultaneously augment MAGE-3 expression and induce growth arrest in thoracic malignancies.
Authors: Susan E Bates; Zhirong Zhan; Kenneth Steadman; Tomasz Obrzut; Victoria Luchenko; Robin Frye; Robert W Robey; Maria Turner; Erin R Gardner; William D Figg; Seth M Steinberg; Alex Ling; Tito Fojo; Kin Wah To; Richard L Piekarz Journal: Br J Haematol Date: 2009-10-28 Impact factor: 6.998
Authors: Z Sheng Guo; Julie A Hong; Kari R Irvine; G Aaron Chen; Paul J Spiess; Yang Liu; Gang Zeng; John R Wunderlich; Dao M Nguyen; Nicholas P Restifo; David S Schrump Journal: Cancer Res Date: 2006-01-15 Impact factor: 12.701
Authors: Nachimuthu Chinnasamy; Jennifer A Wargo; Zhiya Yu; Mahadev Rao; Timothy L Frankel; John P Riley; Jenny J Hong; Maria R Parkhurst; Steven A Feldman; David S Schrump; Nicholas P Restifo; Paul F Robbins; Steven A Rosenberg; Richard A Morgan Journal: J Immunol Date: 2010-12-13 Impact factor: 5.422
Authors: Robert P Whitehead; Cathryn Rankin; Paulo M G Hoff; Philip J Gold; Kevin G Billingsley; Robert A Chapman; Lucas Wong; John H Ward; James L Abbruzzese; Charles D Blanke Journal: Invest New Drugs Date: 2008-10-22 Impact factor: 3.850