Toremifene-atamestane; alone or in combination: predictions from the preclinical intratumoral aromatase model.
Since most breast cancers occur in postmenopausal women and are hormone dependent, we developed a model system that mimics this situation. In this model, tumors of human estrogen receptor (ER) positive breast cancer cells stably transfected with aromatase (Ac-1) are grown in immune-compromised mice. Using this model we have explored a number of therapeutic strategies to maximize the antitumor efficacy of antiestrogens (AEs) and aromatase inhibitors (AIs). This intratumoral aromatase xenograft model has proved accurate in predicting the outcome of several clinical trials. In this current study we compared the effect of an AE toremifene and steroidal AI atamestane, alone or in combination, on growth of hormone-dependent human breast cancer. We have also compared toremifene plus atamestane combination with tamoxifen in this study. The growth of Ac-1 cells was inhibited by tamoxifen, toremifene and atamestane in vitro with IC(50) values of 1.8+/-1.3 microM, 1+/-0.3 microM and 60.4+/-17.2 microM, respectively. The combination of toremifene plus atamestane was found to be better than toremifene or atamestane alone in vitro. The effect of this combination was then studied in vivo using Ac-1 xenografts grown in ovariectomized female SCID mice. The mice were injected with toremifene (1000 microg/day), atamestane (1000 microg/day), tamoxifen (100 microg/day), or the combination of toremifene plus atamestane. In this study, our results indicate that the combination of toremifene plus atamestane was as effective as toremifene or tamoxifen alone but may not provide any additional benefit over toremifene alone or tamoxifen alone.
Sabnis
Gauri J
GJ
Department of Pharmacology and Experimental Therapeutics, University of Maryland-Baltimore, Baltimore, MD 21201, USA.
Macedo
Luciana
L
Goloubeva
Olga
O
Schayowitz
Adam
A
Zhu
Yue
Y
Brodie
Angela
A
D000735:Androstenedione / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011379:Prognosis; D017312:Toremifene / Q000008:administration & dosage*; D014162:Transfection; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D000735:Androstenedione; C048751:atamestane; D017312:Toremifene; D001141:Aromatase