Intracellular-signaling tumor-regression modeling of the pro-apoptotic receptor agonists dulanermin and conatumumab.

Abstract

Dulanermin (rhApo2L/TRAIL) and conatumumab bind to transmembrane death receptors and trigger the extrinsic cellular apoptotic pathway through a caspase-signaling cascade resulting in cell death. Tumor size time series data from rodent tumor xenograft (COLO205) studies following administration of either of these two pro-apoptotic receptor agonists (PARAs) were combined to develop a intracellular-signaling tumor-regression model that includes two levels of signaling: upstream signals unique to each compound (representing initiator caspases), and a common downstream apoptosis signal (representing executioner caspases) shared by the two agents. Pharmacokinetic (PK) models for each drug were developed based on plasma concentration data following intravenous and/or intraperitoneal administration of the compounds and were used in the subsequent intracellular-signaling tumor-regression modeling. A model relating the PK of the two PARAs to their respective and common downstream signals, and to the resulting tumor burden was developed using mouse xenograft tumor size measurements from 448 experiments that included a wide range of dose sizes and dosing schedules. Incorporation of a pro-survival signal--consistent with the hypothesis that PARAs may also result in the upregulation of pro-survival factors that can lead to a reduction in effectiveness of PARAs with treatment--resulted in improved predictions of tumor volume data, especially for data from the long-term dosing experiments.

• Authors: Brittany P Kay, Cheng-Pang Hsu, Jian-Feng Lu, Yu-Nien Sun, Shuang Bai, Yan Xin, David Z D'Argenio
• Journal: Journal of pharmacokinetics and pharmacodynamics (J Pharmacokinet Pharmacodyn) Vol. 39 Issue 5 Pg. 577-90 (Oct 2012) ISSN: 1573-8744 [Electronic] United States
• PMID: 22932917 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Apoptosis Regulatory Proteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• conatumumab

Topics

• Animals
• Antibodies, Monoclonal (physiology)
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins (agonists, physiology)
• Cell Line, Tumor
• Female
• Humans
• Intracellular Fluid (drug effects, physiology)
• Mice
• Mice, Nude
• Models, Biological
• Random Allocation
• Rats
• Remission Induction (methods)
• Signal Transduction (drug effects, physiology)
• TNF-Related Apoptosis-Inducing Ligand (metabolism, physiology)
• Xenograft Model Antitumor Assays (methods)