Growth inhibition of multi-drug-resistant breast cancer cells by 2-methoxyoestradiol-bis-sulphamate and 2-ethyloestradiol-bis-sulphamate.
There is currently considerable interest in the use of the endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2) for the treatment and prevention of breast cancer. We have previously shown that sulphamoylation of 2-MeOE2 and related derivatives greatly enhances their ability to inhibit the proliferation of ER+ and ER- breast cancer cells. In this study, we have compared the abilities of 2-methoxyoestradiol-bis-sulphamate (2-MeOE2bisMATE) and 2-ethyloestradiol-bis-sulphamate (2-EtE2bisMATE) with that of 2-MeOE2 to inhibit the proliferation of breast cancer cells when grown on three different substrata: plastic, collagen I and Matrigel. The human breast cell line MCF-7 was utilised for these studies together with its doxorubicin resistant variant, MCF-7 DOX40 and mitoxantrone resistant variant, MCF-7 MR, as a longitudinal model of in vitro drug resistance. On a plastic substratum all three cell lines were sensitive to the effects of 2-MeOE2bisMATE and 2-EtE2bisMATE whereas MCF-7 cells and the MCF-MR variant cells were resistant to the effects of 2-MeOE2 at 1 microM. The sensitivity of the cell lines to those compounds also remained significant when grown on more physiological substrata. All of the drugs tested arrested cells in the G2/M phase of the cell cycle. The finding that breast cancer cells that are resistant to conventional chemotherapeutic agents remain sensitive to 2-substituted oestrogen sulphamates offers considerable potential for the treatment of women with drug-resistant breast cancer.
Suzuki
R N
RN
Endocrinology and Metabolic Medicine and Sterix Ltd., Faculty of Medicine, Imperial College, St. Mary's Hospital, London W2 1NY, UK.
Newman
S P
SP
Purohit
A
A
Leese
M P
MP
Potter
B V L
BV
Reed
M J
MJ
D000077584:2-Methoxyestradiol; D001672:Biocompatible Materials / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle; D002455:Cell Division; D003094:Collagen / Q000494:pharmacology; D004338:Drug Combinations; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D004964:Estriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016195:G2 Phase; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D008938:Mitosis; D008956:Models, Chemical; D010969:Plastics / Q000494:pharmacology; D011509:Proteoglycans / Q000494:pharmacology; D013451:Sulfonic Acids / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C475284:2-ethyloestradiol-bis-sulfamate; D001672:Biocompatible Materials; D004338:Drug Combinations; D007797:Laminin; D010969:Plastics; D011509:Proteoglycans; D013451:Sulfonic Acids; C059485:matrigel; C053615:2-methoxyestriol; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003094:Collagen; C005741:sulfamic acid; D004964:Estriol