title: Effects of a new clinically relevant antiestrogen (GW5638) related to tamoxifen on breast and endometrial cancer growth in vivo.
abstract: OBJECTIVE
  Cross-resistance is an important issue for the evaluation of new antiestrogens to treat advanced breast cancer patients who have failed tamoxifen therapy. In addition, postmenopausal patients treated with long-term adjuvant tamoxifen show a 3-4-fold increase in the risk of developing endometrial cancer. Consequently, a new second line agent should be more antiestrogenic and less estrogen-like on the uterus, and be effective at controlling the growth of breast cancer after exposure to tamoxifen. The purpose was to evaluate the effects of the new tamoxifen analogue GW5638 on breast and endometrial cancer growth.
  
  
  METHODS
  Athymic mice were transplanted with an endometrial tumor model (ECC-1 E2) that is responsive to estrogen and has never been exposed to antiestrogen. In addition, we used three breast tumor models: a tamoxifen-naïve tumor (T47D-E2) and two tamoxifen-stimulated tumors (MT2 TAM and MCF-7 TAM LT). The antiestrogen GW5638 (1.5 mg daily), tamoxifen (0.5 mg or 1.5 mg daily), and raloxifene (1.5 mg daily) were given p.o. The pure antiestrogen ICI182,780 (5 mg once a week) was given s.c. Western blots from MCF-7 TAM breast tumors were performed to demonstrate the regulation of estrogen receptor alpha expression by different ligands.
  
  
  RESULTS
  Estradiol and GW5638 down-regulated the receptor compared with control. ICI182,780 completely degraded the receptor but tamoxifen had no effect. GW5638 did not promote tumor growth, and was effective in blocking the effects of postmenopausal estradiol on the growth of tamoxifen-naïve breast and endometrial tumors. However, raloxifene did not completely block the effects of postmenopausal estradiol on the growth of tamoxifen-naïve endometrial tumor after 14 weeks. GW5638 and ICI182,780 but not raloxifene were also effective in blocking the tamoxifen-stimulated breast tumor growth in athymic mice.
  
  
  CONCLUSIONS
  GW5638 is more effective than raloxifene in blocking the effect of estrogen on tamoxifen-naïve endometrial cancer. More importantly, GW5638, like the pure antiestrogen ICI182,780, is able to block the growth of breast cancer stimulated by tamoxifen differently from raloxifene. GW5638 down-regulates estrogen receptor but does not completely destroy the receptor. Therefore, based on our findings, GW5638 could be developed as a second line agent for advanced breast cancer patients and an important first line agent to evaluate as an adjuvant treatment or chemopreventive.
authors.affiliation: Department of Gynecology, Federal University of São Paulo, SP, Brazil 04023-900.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Dardes
authors.forename: Ruth M
authors.initials: RM
authors.lastname: O'Regan
authors.forename: Csaba
authors.initials: C
authors.lastname: Gajdos
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.forename: David
authors.initials: D
authors.lastname: Bentrem
authors.forename: Alex
authors.initials: A
authors.lastname: De Los Reyes
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
mesh_terms: D000818:Animals; D002934:Cinnamates / Q000494:pharmacology*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D002934:Cinnamates; D004965:Estrogen Antagonists; D004967:Estrogens; D011960:Receptors, Estrogen; D013267:Stilbenes; D013629:Tamoxifen; C087550:3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid; D020849:Raloxifene Hydrochloride