This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hartley, J. A. Articles by Thurston, D. E Search for Related Content PubMed PubMed Citation Articles by Hartley, J. A. Articles by Thurston, D. E

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

¹ Cancer Research UK Drug-DNA Interactions Research Group and ² Cancer Research UK Targeting and Imaging Research Group, Department of Oncology, Royal Free and University College Medical School, London, United Kingdom; ³ Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom; ⁴ Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland; and ⁵ Cancer Research UK Gene Targeted Drug Design Research Group, School of Pharmacy, University of London, London, United Kingdom

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.

This article has been cited by other articles:

				Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents Mol. Cancer Ther., November 1, 2009; 8(11): 3015 - 3023.

				M. Zainol, J. Stoute, G. M. Almeida, A. Rapp, K. J. Bowman, G. D. D. Jones, and ECVAG Introducing a true internal standard for the Comet assay to minimize intra- and inter-experiment variability in measures of DNA damage and repair Nucleic Acids Res., October 14, 2009; (2009) gkp826v1. [Abstract] [Full Text] [PDF]

				D. Hochhauser, T. Meyer, V. J. Spanswick, J. Wu, P. H. Clingen, P. Loadman, M. Cobb, L. Gumbrell, R. H. Begent, J. A. Hartley, et al. Phase I Study of Sequence-Selective Minor Groove DNA Binding Agent SJG-136 in Patients with Advanced Solid Tumors Clin. Cancer Res., March 15, 2009; 15(6): 2140 - 2147. [Abstract] [Full Text] [PDF]

				S. Arnould, V. J. Spanswick, J. S. Macpherson, J. A. Hartley, D. E. Thurston, D. I. Jodrell, and S. M. Guichard Time-dependent cytotoxicity induced by SJG-136 (NSC 694501): influence of the rate of interstrand cross-link formation on DNA damage signaling. Mol. Cancer Ther., June 1, 2006; 5(6): 1602 - 1609. [Abstract] [Full Text] [PDF]

				P. H. Clingen, I. U. De Silva, P. J. McHugh, F. J Ghadessy, M. J. Tilby, D. E. Thurston, and J. A. Hartley The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136 Nucleic Acids Res., June 8, 2005; 33(10): 3283 - 3291. [Abstract] [Full Text] [PDF]

				M. C. Alley, M. G. Hollingshead, C. M. Pacula-Cox, W. R. Waud, J. A. Hartley, P. W. Howard, S. J. Gregson, D. E. Thurston, and E. A. Sausville SJG-136 (NSC 694501), A Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity: Part 2: Efficacy Evaluations Cancer Res., September 15, 2004; 64(18): 6700 - 6706. [Abstract] [Full Text] [PDF]