title: 4-Fluorobenzylamine and phenylalanine methyl ester conjugates of 2-nitroimidazole: evaluation as hypoxic cell radiosensitizers.
abstract: We have synthesized two 2-nitroimidazole derivatives and evaluated their hypoxic radiosensitization properties. The first, a 4-fluorobenzylamine conjugate of 2-nitroimidazole (PK-110), was designed so that it could also be labeled with the F-18 and used for positron emission tomographic imaging of hypoxia. The second, the L-phenylalanine methyl ester conjugate of 2-nitroimidazole (PK-130), was designed in an attempt to exploit amino acid transport channels to enhance drug transport into the tumor. The effects of these drugs (and SR-2508, for comparison) in vitro on the aerobic and hypoxic radiosensitivity of Chinese hamster V79 cells were evaluated using clonogenic assays. PK-130 and PK-110 at 0.1 and 1.0 mM were more efficient hypoxic cell radiosensitizers than obtained with 1.0 mM SR-2508. Marginal aerobic radiosensitization was observed for 1.0 mM treatment with PK-130 and PK-110, however, no aerobic radiosensitization was observed at 0.1 mM. Glutathione (GSH) depletion (less than 5% of control levels) by L-buthionine sulfoximine (BSO) further enhanced the SER for both PK-130 and PK-110 at 0.1 mM to 3.2 +/- 0.63 and 2.4 +/- 0.16, respectively. The results of this study encourage the in vivo tumor radiosensitization evaluation of PK-130 and PK-110.
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC 27710.
authors.forename: P K
authors.initials: PK
authors.lastname: Garg
authors.forename: S
authors.initials: S
authors.lastname: Garg
authors.forename: W G
authors.initials: WG
authors.lastname: Degraff
authors.forename: M R
authors.initials: MR
authors.lastname: Zalutsky
authors.forename: J B
authors.initials: JB
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D006224:Cricetinae; D003412:Cricetulus; D004307:Dose-Response Relationship, Radiation; D004341:Drug Evaluation; D017341:Etanidazole; D066298:In Vitro Techniques; D009593:Nitroimidazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C072692:PK 130; C072691:PK 110; D017341:Etanidazole