| | |  | | | | Record from Web of Science® | | | | | | |
| Safety and antitumor activity of recombinant soluble Apo2 ligand |
|
|
| Author(s): Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Masters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z, Schwall RH |
| Source: JOURNAL OF CLINICAL INVESTIGATION Volume: 104 Issue: 2 Pages: 155-162 Published: JUL 1999 |
| Times Cited: 1,037 References: 38 |
| 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Ashkenazi, A (reprint author), Genentech Inc, Dept Mol Oncol, 1 DNA Way, S San Francisco, CA 94080 USA |
Addresses:
1. Genentech Inc, Dept Mol Oncol, S San Francisco, CA 94080 USA
2. Genentech Inc, Dept Proc Sci, S San Francisco, CA 94080 USA
3. Genentech Inc, Dept Cell Biol & Technol, S San Francisco, CA 94080 USA
4. Genentech Inc, Dept Res Bioassays, S San Francisco, CA 94080 USA
5. Genentech Inc, Dept Analyt Chem, S San Francisco, CA 94080 USA
6. Genentech Inc, Dept Pharmacol Sci, S San Francisco, CA 94080 USA
7. Genentech Inc, Dept Pathol, S San Francisco, CA 94080 USA |
| Publisher: AMER SOC CLINICAL INVESTIGATION INC, ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA |
| Subject Category: Medicine, Research & Experimental |
| IDS Number: 251WB |
| ISSN: 0021-9738 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |