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

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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.

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Acknowledgements

Financial support for this project was provided by Spirogen Ltd (UK) and Cancer Research UK programme grant C2259/A9994 to JAH. Dr Geoffrey Wells (The School of Pharmacy, London) is thanked for his comparative analysis of the NCI GI50 data for SG2000 and SG2057.

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Authors and Affiliations

  1. Spirogen Ltd, UCL Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK

    John A. Hartley, Anzu Hamaguchi & Marie Suggitt

  2. CR-UK Drug-DNA Interactions Research Group, UCL Cancer Institute, Paul O’Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK

    John A. Hartley & Anzu Hamaguchi

  3. Spirogen Ltd, The School of Pharmacy, University of London, London, WC1N 1AX, UK

    Stephen J. Gregson, David E. Thurston & Philip W. Howard

  4. UCL Cancer Institute, University College London, Paul O’Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK

    John A. Hartley

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  1. John A. Hartley
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  2. Anzu Hamaguchi
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  3. Marie Suggitt
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  4. Stephen J. Gregson
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  5. David E. Thurston
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  6. Philip W. Howard
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Correspondence to John A. Hartley.

Additional information

SG2057 is owned by Spirogen Ltd in which J.A. Hartley, P.W. Howard and D.E. Thurston have equity interests. The data contained in this paper have been presented in part at the 18th EORTC-NCI-AACR Symposium on “Molecular Targets and Cancer Therapeutics”, Prague, Czech Republic, 2006.

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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)

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Hartley, J.A., Hamaguchi, A., Suggitt, M. et al. DNA interstrand cross-linking and in vivo antitumor activity of the extended pyrrolo[2,1-c][1,4]benzodiazepine dimer SG2057. Invest New Drugs 30, 950–958 (2012). https://doi.org/10.1007/s10637-011-9647-z

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