title: Pharmacokinetic/pharmacodynamic model-guided identification of hypoxia-selective 1,2,4-benzotriazine 1,4-dioxides with antitumor activity: the role of extravascular transport.
abstract: Pharmacokinetic/pharmacodynamic (PK/PD) modeling has shown the antitumor activity of tirapazamine (TPZ), a bioreductive hypoxia-selective cytotoxin, to be limited by poor penetration through hypoxic tumor tissue. We have prepared a series of 1,2,4-benzotriazine 1,4-dioxide (BTO) analogues of TPZ to improve activity against hypoxic cells by increasing extravascular transport. The 6 substituents modified lipophilicity and rates of hypoxic metabolism. 3-Alkylamino substituents increased aqueous solubility and also influenced lipophilicity and hypoxic metabolism. PK/PD model-guided screening was used to select six BTOs for evaluation against hypoxic cells in HT29 human tumor xenografts. All six BTOs were active in vivo, and two provided greater hypoxic cell killing than TPZ because of improved transport and/or plasma PK. This PK/PD model considers two causes of therapeutic failure (limited tumor penetration and poor plasma pharmacokinetics) often not addressed early in drug development and provides a general strategy for selecting candidates for in vivo evaluation during lead optimization.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1003, New Zealand. m.hay@auckland.ac.nz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hay
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Hicks
authors.forename: Frederik B
authors.initials: FB
authors.lastname: Pruijn
authors.forename: Karin
authors.initials: K
authors.lastname: Pchalek
authors.forename: Bronwyn G
authors.initials: BG
authors.lastname: Siim
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000465:Algorithms; D000818:Animals; D001692:Biological Transport; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D014227:Triazines