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Drug Metabolism and Disposition Fast Forward
First published on July 28, 2004; DOI: 10.1124/dmd.104.000323

0090-9556/04/3211-1230-1238$20.00
DMD 32:1230-1238, 2004

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TISSUE DISTRIBUTION, STABILITY, AND PHARMACOKINETICS OF APO2 LIGAND/TUMOR NECROSIS FACTOR-RELATED APOPTOSIS-INDUCING LIGAND IN HUMAN COLON CARCINOMA COLO205 TUMOR-BEARING NUDE MICE

Hong Xiang1, Cindy B. Nguyen, Sean K. Kelley, Noel Dybdal, and Enrique Escandón

Departments of Pharmacokinetic and Pharmacodynamic Sciences(H.X.,C.B.N., S.K.K.,E.E.)and Pathology(N.D.), Genentech, Inc., South San Francisco, California

Apo2L/TRAIL [Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand], a member of the TNF cytokine superfamily, induces cell death by apoptosis in a number of human cancer cells and is a potential agent for cancer therapy. We have characterized the in vitro stability of Apo2L/TRAIL in human serum and the tissue distribution and metabolism of Apo2L/TRAIL in a xenograft model of human colon carcinoma (COLO205). Apo2L/TRAIL was stable after incubation in human serum, with no significant high molecular weight complexes or degradation products observed. After i.v. administration of 125I-Apo2L/TRAIL to mice, a small percentage of the radiolabeled drug was seen as high molecular weight complex or as low molecular weight degradation products in plasma. However, the most abundant radioactive species corresponded to the intact Apo2L/TRAIL monomer, indicative of the relative stability of this recombinant protein in blood. Distribution of 125I-Apo2L/TRAIL to organs and solid xenograft tumors was limited. Intact 125I-Apo2L/TRAIL was detectable in the solid tumor at all time points and was the only tissue in which radioactivity transiently increased over time. Kidney contained the highest levels of radioactivity. Radioactive signal reached a tissue-to-blood ratio of 18 in the kidney cortex region when 125I-Apo2L/TRAIL was given in the presence of excess unlabeled ligand. In contrast to blood, extensive 125I-Apo2L/TRAIL degradation was observed in the kidney and, to a lesser degree, in the solid tumor and other organs, including liver, spleen, and lung. Our studies demonstrated that Apo2L/TRAIL is stable in the circulation, localizes to human solid xenograft tumors, and is primarily eliminated through the kidney.

Address correspondence to: Dr. Enrique Escandón, Genencor International, Inc, 925 Page Mill Road, Palo Alto CA 94304. E-mail: EEscandon{at}genencor.com




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