title: Preliminary pharmacokinetic and bioanalytical studies of SJG-136 (NSC 694501), a sequence-selective pyrrolobenzodiazepine dimer DNA-cross-linking agent.
abstract: SJG-136 is a synthetic pyrrolobenzodiazepine (PBD) dimer in which two DNA-alkylating subunits are linked through an inert propanedioxy tether. Biophysical and biochemical studies of SJG-136 have shown a remarkable affinity for DNA and potent cytotoxicity in vitro. On this basis, together with its unique sequence selectivity and interstrand DNA cross-linking activity, SJG-136 has been selected for clinical trials. This study examines the pharmacological characteristics of SJG-136 and provides the first report of pharmacokinetic properties for this agent. A sensitive, selective and reproducible reversed-phase gradient LC/MS assay has been developed for detection and analysis, where a molecular ion ( m / z 557.2) is detectable for the SJG-136 parent imine. Fluorescence detection (260 nm excitation, 420 nm emission) gives a limit of sensitivity of 5 nM (2.5 ng ml(-1)) for analysis of SJG-136 in mouse plasma. Extraction efficiencies from plasma were >65% across a range of concentrations (5-1000 nM). Following administration to mice at the MTD (i.p., 0.2 mg kg(-1)), high peak plasma concentrations of SJG-136 were seen ( C (max) = 336 nM) at 30 min after dosing. A calculated terminal t (1/2) of 0.98 h and AUC of 0.34 microM.h resulted in a clearance rate of 17.7 ml min(-1) kg(-1). The PBD dimer binds only moderately to proteins (65-75%), and in vitro cytotoxicity studies confirmed IC(50) values of 4-30 nM with a panel of human cell lines. This finding demonstrates that plasma concentrations achieved in the mouse are substantially higher than those required to elicit an anti tumour response in vitro. This report forms an important phase in the pre-clinical characterization of the compound.
authors.affiliation: Cancer Research UK Cancer Research Unit, Tom Connors Cancer Research Centre, University of Bradford, All Saints Road, Bradford, West Yorkshire, BD7 3AY, UK.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Wilkinson
authors.forename: James P
authors.initials: JP
authors.lastname: Taylor
authors.forename: Steve
authors.initials: S
authors.lastname: Shnyder
authors.forename: Patricia
authors.initials: P
authors.lastname: Cooper
authors.forename: Phil W
authors.initials: PW
authors.lastname: Howard
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
authors.forename: Terence C
authors.initials: TC
authors.lastname: Jenkins
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000737:chemistry*; D001570:Benzodiazepinones / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000493:pharmacokinetics*; D004247:DNA / Q000737:chemistry*; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding; D011758:Pyrroles / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: C423343:1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione); D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D001798:Blood Proteins; D003432:Cross-Linking Reagents; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D004247:DNA