title: Pharmacodynamic modeling of sequence-dependent antitumor activity of insulin-like growth factor blockade and gemcitabine.
abstract: Agents that block insulin-like growth factor (IGF) signaling are under investigation in clinical trials. Antitumor effects are likely to be enhanced when combined with other agents, but administration sequence effects on activity are not well-described. Three breast cancer cell lines (MCF-7, MDA-MB-231, and Hs-578T) were treated with Gemcitabine and small molecule receptor tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine (PQIP) as single agents and then in combination in the forward (Gemcitabine followed by PQIP) and reverse (PQIP followed by Gemcitabine) sequences. Antitumor effects were assessed longitudinally by Bayesian analysis using WinBUGS. The pharmacodynamic model adequately predicted the observed data. The differences in the cell-kill rate constants for the forward vs. reverse sequence ranged from 0.11 to 0.64 (day(-1)), and statistical significance was generally dependent on cell line and PQIP concentration. These data indicate that treatment with Gemcitabine first, followed by PQIP is superior to the reverse sequence in vitro.
authors.affiliation: Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, 55455, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Khatri
authors.forename: Richard C
authors.initials: RC
authors.lastname: Brundage
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Hull
authors.forename: Brent W
authors.initials: BW
authors.lastname: Williams
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
authors.forename: Mark N
authors.initials: MN
authors.lastname: Kirstein
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D001499:Bayes Theorem; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008954:Models, Biological; D011719:Pyrazines / Q000008:administration & dosage; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D013002:Somatomedins / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine
chemical_list: C523453:3-(3-(4-methylpiperazin-1-yl)cyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-8-ylamine; D007093:Imidazoles; D011719:Pyrazines; D013002:Somatomedins; D003841:Deoxycytidine; D017526:Receptor, IGF Type 1; D000093542:Gemcitabine
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