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BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure.

Abstract
The anti-proliferative and anti-angiogenic properties of the endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2), are enhanced in a series of sulphamoylated derivatives of 2-MeOE2. To investigate possible mechanisms of resistance to these compounds, a cell line, A2780.140, eightfold less sensitive to the 3,17-O,O-bis-sulphamoylated derivative, STX140, was derived from the A2780 ovarian cancer cell line by dose escalation. Other cell lines tested did not develop STX140 resistance. RT-PCR and immunoblot analysis demonstrated that breast cancer resistance protein (BCRP) expression is dramatically increased in A2780.140 cells. The cells are cross-resistant to the most structurally similar bis-sulphamates, and to BCRP substrates, mitoxantrone and doxorubicin; but they remain sensitive to taxol, an MDR1 substrate, and to all other sulphamates tested. Sensitivity can be restored using a BCRP inhibitor, and this pattern of resistance is also seen in a BCRP-expressing MCF-7-derived cell line, MCF-7.MR. In mice bearing wild-type (wt) and BCRP-expressing tumours on either flank, both STX140 and mitoxantrone inhibited the growth of the MCF-7wt xenografts, but only STX140 inhibited growth of the MCF-7.MR tumours. In conclusion, STX140, a promising orally bioavailable anti-cancer agent in pre-clinical development, is highly efficacious in BCRP-expressing xenografts. This is despite an increase in BCRP expression in A2780 cells in vitro after chronic dosing with STX140.
AuthorsJ M Day, P A Foster, H J Tutill, S P Newman, Y T Ho, M P Leese, B V L Potter, M J Reed, A Purohit
JournalBritish journal of cancer (Br J Cancer) Vol. 100 Issue 3 Pg. 476-86 (Feb 10 2009) ISSN: 1532-1827 [Electronic] England
PMID19156141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 2-methoxyestradiol-3,17-O,O-bis(sulfamate)
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • DNA Primers
  • Estrenes
  • Neoplasm Proteins
Topics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters (genetics)
  • Animals
  • Base Sequence
  • Blotting, Western
  • Breast Neoplasms (pathology)
  • Cell Cycle
  • Cell Line, Tumor
  • DNA Primers
  • Drug Resistance, Neoplasm
  • Estrenes (pharmacology)
  • Female
  • Flow Cytometry
  • Humans
  • Mice
  • Neoplasm Proteins (genetics)
  • Ovarian Neoplasms (pathology)
  • Reverse Transcriptase Polymerase Chain Reaction

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