title: Pharmacodynamic modeling of anti-cancer activity of tetraiodothyroacetic acid in a perfused cell culture system.
abstract: Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations.
authors.affiliation: Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
authors.forename: David
authors.initials: D
authors.lastname: London
authors.forename: Ran
authors.initials: R
authors.lastname: Meng
authors.forename: Chang-Uk
authors.initials: CU
authors.lastname: Lim
authors.forename: Cassie
authors.initials: C
authors.lastname: Lin
authors.forename: Sharon
authors.initials: S
authors.lastname: Lin
authors.forename: Heng-Yuan
authors.initials: HY
authors.lastname: Tang
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: Brian
authors.initials: B
authors.lastname: Van Scoy
authors.forename: Robert
authors.initials: R
authors.lastname: Kulawy
authors.forename: Lurdes
authors.initials: L
authors.lastname: Queimado
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
authors.forename: Faith B
authors.initials: FB
authors.lastname: Davis
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D018929:Cell Culture Techniques / Q000295:instrumentation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D019295:Computational Biology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008954:Models, Biological; D009010:Monte Carlo Method; D053758:Nanoparticles / Q000008:administration & dosage; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage; D013974:Thyroxine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D013267:Stilbenes; C011126:tetraiodothyroacetic acid; D000068818:Cetuximab; D000077185:Resveratrol; D013974:Thyroxine