title: SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity.
abstract: SJG-136 (NSC 694501) is a rationally designed pyrrolobenzodiazepine dimer that binds in the minor groove of DNA. It spans 6 bp with a preference for binding to purine-GATC-pyrimidine sequences. The agent has potent activity in the National Cancer Institute (NCI) anticancer drug screen with 50% net growth inhibition conferred by 0.14 to 320 nmol/L (7.4 nmol/L mean). Sensitive cell lines exhibit total growth inhibition and 50% lethality after treatment with as little as 0.83 and 7.1 nmol/L SJG-136, respectively. COMPARE and molecular target analysis of SJG-136 data versus that of >60,000 compounds tested in the NCI 60 cell line screen shows that, although the agent has similarity to other DNA binding agents, the pattern of activity for SJG-136 does not fit within the clusters of any known agents, suggesting that SJG-136 possesses a distinct mechanism of action. Testing in the NCI standard hollow fiber assay produced prominent growth inhibition in 20 of 24 i.p. and 7 of 24 s.c. test combinations with 5 of 12 cell lines exhibiting cell kill. In addition, SJG-136 produced antitumor activity in mice bearing CH1 and CH1cisR xenografts, a cisplatin-resistant human ovarian tumor model, and also in mice bearing LS174T xenografts, a human colon tumor model. SJG-136 produces DNA interstrand cross-links between two N-2 guanine positions on opposite strands and separated by 2 bp. In human tumor cell lines, the cross-links form rapidly and persist compared with those produced by conventional cross-linking agents such as nitrogen mustards. In mice bearing the LS174T human colon xenograft, DNA interstrand cross-links can be detected in tumor cells using a modification of the single cell gel electrophoresis (comet) assay after administration of a therapeutic dose. Cross-links in the tumor increase with dose and are clearly detectable at 1 hour after i.v. administration. The level of cross-linking persists over a 24-hour period in this tumor in contrast to cross-links produced by conventional cross-linking agents observed over the same time period.
authors.affiliation: Cancer Research UK Drug-DNA Interactions Research Group, Department of Oncology, Royal Free and University College Medical School, London, United Kingdom. john.hartley@ucl.ac.uk
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Spanswick
authors.forename: Natalie
authors.initials: N
authors.lastname: Brooks
authors.forename: Peter H
authors.initials: PH
authors.lastname: Clingen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McHugh
authors.forename: Daniel
authors.initials: D
authors.lastname: Hochhauser
authors.forename: R Barbara
authors.initials: RB
authors.lastname: Pedley
authors.forename: Lloyd R
authors.initials: LR
authors.lastname: Kelland
authors.forename: Michael C
authors.initials: MC
authors.lastname: Alley
authors.forename: Robert
authors.initials: R
authors.lastname: Schultz
authors.forename: Melinda G
authors.initials: MG
authors.lastname: Hollingshead
authors.forename: Karen M
authors.initials: KM
authors.lastname: Schweikart
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Tomaszewski
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gregson
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D020552:Comet Assay; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
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; D003432:Cross-Linking Reagents; D011758:Pyrroles; D001569:Benzodiazepines; D004247:DNA