Investigational New Drugs

, Volume 30, Issue 3, pp 950–958

DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine dimer SG2057

Authors

    • Spirogen Ltd, UCL Cancer Institute
    • CR-UK Drug-DNA Interactions Research Group, UCL Cancer Institute
    • UCL Cancer Institute, University College London
  • Anzu Hamaguchi
    • Spirogen Ltd, UCL Cancer Institute
    • CR-UK Drug-DNA Interactions Research Group, UCL Cancer Institute
  • Marie Suggitt
    • Spirogen Ltd, UCL Cancer Institute
  • Stephen J. Gregson
    • Spirogen Ltd, The School of Pharmacy, University of London
  • David E. Thurston
    • Spirogen Ltd, The School of Pharmacy, University of London
  • Philip W. Howard
    • Spirogen Ltd, The School of Pharmacy, University of London
PRECLINICAL STUDIES

DOI: 10.1007/s10637-011-9647-z

Cite this article as:
Hartley, J.A., Hamaguchi, A., Suggitt, M. et al. Invest New Drugs (2012) 30: 950. doi:10.1007/s10637-011-9647-z

Summary

The pyrrolobenzodiazepines (PBDs) are naturally occurring antitumor antibiotics and a PBD dimer (SJG-136, SG2000) is in Phase II trials. SG2000 is a propyldioxy linked PBD dimer which binds sequence selectively in the minor groove of DNA forming DNA interstrand and intrastrand cross-linked adducts, and also mono-adducts depending on sequence. SG2057 is the corresponding dimer containing a pentyldioxy linkage. SG2057 has multilog differential in vitro cytotoxicity against a panel of human tumour cell lines with a mean GI50 of 212 pM. The agent is highly efficient at producing DNA interstrand cross-links in cells which form rapidly and persist over a 48 h period. Significant antitumor activity was demonstrated in several human tumor xenograft models. Cures were obtained in a LOX-IMVI melanoma model following a single administration and dose-dependent activity, including regression responses, observed in SKOV-3 ovarian and HL-60 promyelocytic leukemia models following repeat dose schedules. In the advanced stage LS174T model, SG2057 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. SG2057 is therefore a highly active antitumor agent, with more potent in vitro activity and superior in vivo activity to SG2000, warranting further development.

Keywords

Pyrrolobenzodiazepine dimer SG2057 DNA interstrand cross-linking DNA minor groove binding agent

Supplementary material

10637_2011_9647_MOESM1_ESM.doc (72 kb)
Figure 1 Comparison of the GI50 values derived from the NCI 60 cell line panel in vitro screen for SG2000 [12] and SG2057 [7]. (DOC 72 kb)

Copyright information

© Springer Science+Business Media, LLC 2011