Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand cooperates with chemotherapy to inhibit orthotopic lung tumor growth and improve survival

• Published in: Cancer research (Chicago, Ill.) Ill.), 2004-07, Vol.64 (14), p.4900-4905
• Main Authors: HONGKUI JIN, RENHUI YANG, SHARON FONG, TOTPAL, Klara, LAWRENCE, David, ZHONG ZHENG, ROSS, Jed, KOEPPEN, Hartmut, SCHWALL, Ralph, ASHKENAZI, Avi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis Regulatory Proteins; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell Division - drug effects; Cell Line, Tumor; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical sciences; Membrane Glycoproteins - administration & dosage; Membrane Glycoproteins - pharmacology; Mice; Mice, Nude; Pharmacology. Drug treatments; Recombinant Proteins - pharmacology; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha - administration & dosage; Tumor Necrosis Factor-alpha - pharmacology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-0408

Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a tumor necrosis factor superfamily member that induces apoptosis through the death receptors DR4 and/or DR5 in various cancer cell types but not in most normal cells. Several lung cancer cell lines express DR4 and DR5 and undergo apoptosis in vitro in response to Apo2L/TRAIL. We investigated the efficacy of recombinant soluble human Apo2L/TRAIL and its interaction with chemotherapy in xenograft models based on human NCI-H460 non-small cell lung carcinoma cells. In vitro, Taxol enhanced caspase activation and apoptosis induction by Apo2L/TRAIL. In vivo, Apo2L/TRAIL or Taxol plus carboplatin chemotherapy partially delayed progression of established subcutaneous tumor xenografts, whereas combined treatment caused tumor regression and a substantially longer growth delay. Apo2L/TRAIL, chemotherapy, or the combination of both inhibited growth of preformed orthotopic lung parenchymal tumors versus control by 60%, 57%, or 97%, respectively (all P < 0.01; n = 8-10). Furthermore, combination treatment improved day-90 survival relative to control (7 of 15 versus 1 of 15; P = 0.0003 by Mantel-Cox) as well as to Apo2L/TRAIL (3 of 14; P = 0.031) or chemotherapy (3 of 15; P = 0.035). These studies provide evidence for in vivo activity of Apo2L/TRAIL against lung tumor xenografts and underscore the potential of this ligand for advancing current lung cancer treatment strategies.