In vivo inhibition of angiogenesis by sulphamoylated derivatives of 2-methoxyoestradiol.
Drugs that inhibit growth of tumours and their blood supply could have considerable therapeutic potential. 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate (2-MeOE2bisMATE) has been shown to inhibit the proliferation of MCF-7 (ER+) breast cancer cells and angiogenesis in vitro. 2-MeOE2bisMATE and its analogue, 17-Cym-2-MeOE2MATE, were investigated for their ability to inhibit in vivo angiogenesis and tumour growth. The mouse Matrigel plug assay for angiogenesis was used to investigate the effect of compounds on neovascularisation and was quantified using a FITC-dextran injection technique. Nude mice bearing tumours derived from MCF-7 cells were used to assess efficacy on tumour growth. Tumour sections were stained for VEGFR-2 and Ki67 to assess tumour angiogenesis and cell proliferation respectively. Matrigel plugs supplemented with basic fibroblast growth factor resulted in increased neovascularisation over 7 days. Oral administration of 2-MeOE2bisMATE for 7 days at 10 or 50 mg kg(-1) significantly reduced neovascularisation to or below control levels respectively. 17-Cym-2-MeOE2MATE at 20 mg kg(-1) was equally effective. 2-MeOE2bisMATE, dosed daily for 21 days, caused a 52% reduction in tumour growth at 5 mg kg(-1) and 38% regression at 20 mg kg(-1). 17-Cym-2-MeOE2MATE (20 mg kg(-1)) reduced tumour growth by 92%. Immunohistochemistry revealed a reduction in angiogenesis and proliferation. Matrigel plug and tumour imaging after FITC-dextran injection indicated that 2-MeOE2bisMATE caused a marked disruption of vasculature. These sulphamoylated oestrogen derivatives have been shown to be potent inhibitors of angiogenesis in vivo. This, together with their ability to inhibit tumour growth, indicates the potential of this new class of drugs for further development for cancer therapy.
Chander
S K
SK
Endocrinology and Metabolic Medicine and Sterix Ltd, Imperial College, St Mary's Hospital, London W2 1NY, UK. s.chander@imperial.ac.uk
Foster
P A
PA
Leese
M P
MP
Newman
S P
SP
Potter
B V L
BV
Purohit
A
A
Reed
M J
MJ
D000077584:2-Methoxyestradiol; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003094:Collagen; D004338:Drug Combinations; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007797:Laminin; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011509:Proteoglycans; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators / Q000627:therapeutic use
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D050257:Tubulin Modulators; C059485:matrigel; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003094:Collagen