Tissue Distribution, Stability, and Pharmacokinetics of Apo2 Ligand/Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Human Colon Carcinoma Colo205 Tumor-Bearing Nude Mice

Xiang, Hong; Nguyen, Cindy B.; Kelley, Sean K.; Dybdal, Noël; Escandón, Enrique

doi:10.1124/dmd.104.000323

Cited by 64 publications

(50 citation statements)

References 9 publications

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“…The high kidney activity confirms the function of the kidney as main site of rhTRAIL clearance, which is not influenced by intraperitoneal administration. Activity in most organs followed that of blood pool activity, suggesting that distribution to normal tissues was limited, which corresponds to previous studies (39). Our results indicate that intraperitoneal administration of rhTRAIL may result in favorable tumor uptake in intraperitoneally growing tumors.…”

Section: Discussionsupporting

confidence: 71%

Enhanced Antitumor Efficacy of a DR5-Specific TRAIL Variant over Recombinant Human TRAIL in a Bioluminescent Ovarian Cancer Xenograft Model

Duiker¹,

Vries²,

Mahalingam

et al. 2009

Clinical Cancer Research

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Purpose: Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) is clinically evaluated as novel anticancer drug. rhTRAIL-DR5, a rhTRAIL variant that specifically binds to DR5 receptor, has recently been developed. We investigated whether rhTRAIL-DR5 is more efficient than rhTRAIL in combination with cisplatin in DR5-expressing human A2780 ovarian cancer cells. Design: Effect of cisplatin alone or in combination with rhTRAIL or rhTRAIL-DR5 on DR5 surface expression, apoptosis, and cell survival of A2780 was measured. Biodistribution analysis was done in mice with 125 I-rhTRAIL administered intravenously versus intraperitoneally. Antitumor efficacy of rhTRAIL-DR5 versus rhTRAIL was determined in an intraperitoneally growing bioluminescent A2780 xenograft model. Results: Cisplatin strongly enhanced DR5 surface expression. Both rhTRAIL and rhTRAIL-DR5 in combination with cisplatin induced high levels of caspase-3 activation, apoptosis, and cell kill, with rhTRAIL-DR5 being most potent. Intraperitoneal administration of 125 I-rhTRAIL resulted in a 1.7-fold higher area under the curve in serum, increased tumor exposure, and more caspase-3 activation in the tumor than intravenous administration. Intraperitoneal administration of rhTRAIL-DR5 delayed A2780 tumor progression, reflected in a mean light reduction of 68.3% (P = 0.015), whereas rhTRAIL or rhTRAIL-DR5 plus cisplatin resulted in 85% (P = 0.003) and 97% (P = 0.002) reduction compared with A2780 tumor progression in vehicle-treated animals. Combination of rhTRAIL-DR5 with cisplatin was more effective than cisplatin alone (P = 0.027). Conclusion: rhTRAIL-DR5 was superior over rhTRAIL in vitro and in vivo against DR5-expressing ovarian cancer also in combination with cisplatin. Intraperitoneal administration of rhTRAIL-DR5 warrants further exploration in ovarian cancer.

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Section: Discussionsupporting

confidence: 71%

Enhanced Antitumor Efficacy of a DR5-Specific TRAIL Variant over Recombinant Human TRAIL in a Bioluminescent Ovarian Cancer Xenograft Model

Duiker¹,

Vries²,

Mahalingam

et al. 2009

Clinical Cancer Research

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“…The decreased PEG-mIL-10 kidney uptake was correlated to the slower clearance and enhanced systemic exposure. In agreement with our results, it has been shown that renal uptake is the major route of nonspecific disposition for recombinant cytokines with high isoelectric points such as IL-11, Apo2 ligand, and TNF-␣ (Miyazaki et al, 1998;Takagi et al, 1995Takagi et al, , 1997Xiang et al, 2004) or relative small molecular weight such as insulin (Maack et al, 1979;Rabkin et al, 1984). Of interest, the biodistribution pattern of labeled hIL-10 present in immune complexes indicated that the liver instead of the kidney has become the major route of clearance and disposition for antibodybound IL-10.…”

Section: Discussionsupporting

confidence: 81%

Effects of PEGylation and Immune Complex Formation on the Pharmacokinetics and Biodistribution of Recombinant Interleukin 10 in Mice

Alvarez¹,

So²,

Hsieh³

et al. 2011

Drug Metab Dispos

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“…40,41 Higher concentrations did not differ in their ability to induce apoptosis in the presence of BZB. For BZB treatment, we chose a concentration of 500 ng/mL, which, when combined with TRAIL, has been shown to be nontoxic in PHHs.…”

Section: Discussionmentioning

confidence: 96%

Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib

et al. 2013

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As the result of an increasing incidence and a prevalent therapy resistance of hepatocellular carcinoma (HCC), there is a strong need for novel strategies to enhance treatment responses in HCC. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising anticancer drug because it can selectively induce apoptosis in cancer cells, but not in healthy cells. Nevertheless, most tumor cells show TRAIL resistance, emphasizing the requirement for apoptosis-sensitizing agents and TRAIL molecules with improved tumor specificity. In this study, we employed a recombinant TRAIL molecule, in which three TRAIL protomers were expressed as a single polypeptide chain (scTRAIL), and a novel TRAIL variant, in which scTRAIL was additionally fused to an antibody fragment recognizing epidermal growth factor receptor (EGFR) to improve its HCC-targeting properties. We analyzed the proapoptotic effects of both TRAIL versions in combination with the proteasome inhibitor bortezomib (BZB) in hepatoma cells and primary human hepatocytes as well as in intact explants from HCC and healthy liver tissue. We demonstrate that EGFR-targeted TRAIL in combination with BZB induced significantly higher caspase activation and cell death in hepatoma cells, but not in primary hepatocytes. Importantly, when incubated with fresh liver explants, the combination of EGFR-targeted TRAIL and BZB displayed selective cytotoxicity for HCC, but not for tumor-free liver tissue, which could even be verified in liver explants from the same individuals. Unlike nontargeted TRAIL, EGFR-targeted TRAIL combined with BZB exerted no toxicity in liver tissues from nonalcoholic fatty liver disease patients. Conclusion: EGFRtargeted TRAIL reveals increased antitumor activity toward HCC without inducing toxicity to tumor-free liver tissue and might therefore represent a promising novel strategy for HCC treatment. (HEPATOLOGY 2013;57:625-636) H epatocellular carcinoma (HCC) is a global health problem with increasing incidence. 1 In western countries, less than 50% of patients are eligible for potential curative treatment, including resection, transplantation, or local ablation. The limited therapeutic options and its resistance to systemic chemotherapy have triggered the search for moleculartargeted therapies for liver cancer. There is evidence of aberrant activation of several signaling cascades, such as the epidermal growth factor receptor (EGFR)/

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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

Cited by 64 publications

References 9 publications

Enhanced Antitumor Efficacy of a DR5-Specific TRAIL Variant over Recombinant Human TRAIL in a Bioluminescent Ovarian Cancer Xenograft Model

Enhanced Antitumor Efficacy of a DR5-Specific TRAIL Variant over Recombinant Human TRAIL in a Bioluminescent Ovarian Cancer Xenograft Model

Effects of PEGylation and Immune Complex Formation on the Pharmacokinetics and Biodistribution of Recombinant Interleukin 10 in Mice

Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib

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