Safety and antitumor activity of recombinant soluble Apo2 ligand
Avi Ashkenazi,Roger Pai,Sharon Fong,Susan Leung,David A. Lawrence,Scot A. Marsters,Christine Blackie,Ling Chang,Amy E. McMurtrey,Andrea Hebert,Laura DeForge,Iphigenia Koumenis,Derf Lewis,Louise A. Harris,Jeanine L. Bussiere,Hartmut Koeppen,Zahra Shahrokh,Ralph H. Schwall +17 more
TLDR
Apo2L may have potent anticancer activity without significant toxicity toward normal tissues, and cooperated synergistically with the chemotherapeutic drugs 5-fluorouracil or CPT-11, causing substantial tumor regression or complete tumor ablation.Abstract:
TNF and Fas ligand induce apoptosis in tumor cells; however, their severe toxicity toward normal tissues hampers their application to cancer therapy. Apo2 ligand (Apo2L, or TRAIL) is a related molecule that triggers tumor cell apoptosis. Apo2L mRNA is expressed in many tissues, suggesting that the ligand may be nontoxic to normal cells. To investigate Apo2L’s therapeutic potential, we generated in bacteria a potently active soluble version of the native human protein. Several normal cell types were resistant in vitro to apoptosis induction by Apo2L. Repeated intravenous injections of Apo2L in nonhuman primates did not cause detectable toxicity to tissues and organs examined. Apo2L exerted cytostatic or cytotoxic effects in vitro on 32 of 39 cell lines from colon, lung, breast, kidney, brain, and skin cancer. Treatment of athymic mice with Apo2L shortly after tumor xenograft injection markedly reduced tumor incidence. Apo2L treatment of mice bearing solid tumors induced tumor cell apoptosis, suppressed tumor progression, and improved survival. Apo2L cooperated synergistically with the chemotherapeutic drugs 5-fluorouracil or CPT-11, causing substantial tumor regression or complete tumor ablation. Thus, Apo2L may have potent anticancer activity without significant toxicity toward normal tissues.read more
Citations
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Apoptosis: a link between cancer genetics and chemotherapy.
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Overview of cell death signaling pathways
Zhaoyu Jin,Wafik S. El-Deiry +1 more
TL;DR: Changing attention is being focused on alternative signaling pathways leading to cell death including necrosis, autophagy, and mitotic catastrophe.
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TL;DR: This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, and Culture of Japan and by a Research Grant from the Princess Takamatsu Cancer Research Fund, and performed in part through Special Coordination Funds of the Science and Technology Agency of the Japanese Government.
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TL;DR: A novel tumor necrosis factor (TNF) family member has been cloned and characterized, and the TRAIL gene is located on chromosome 3 at position 3q26, which is not close to any other known TNF ligand family members.