Selective estrogen receptor modulators as inhibitors of repopulation of human breast cancer cell lines after chemotherapy.
OBJECTIVE
Repopulation of surviving tumor cells between courses of chemotherapy might lead to effective drug resistance. Here we study inhibition of repopulation of hormone-responsive human breast cancer cell lines by selective estrogen receptor (ER) modulators (SERMs) during courses of chemotherapy.


METHODS
Hormone responsive breast cancer cell lines MCF-7 and T47D, and the ER- cell line MDA-231, were treated with either 4-hydroxy tamoxifen (4OHT) or arzoxifene during weekly courses of treatment with 5-fluorouracil (5-FU) or methotrexate (MTX). Clonogenic assays were performed to determine the overall survival of tumor cells after treatment with the SERMs alone, after one to three doses of 5-FU or MTX alone, and after 5-FU or MTX followed by each of the SERMs.


RESULTS
Both SERMs inhibited the growth of ER+ cells MCF-7 and T47D but had no effect on the ER-cell line MDA-231. Arzoxifene was more effective than 4OHT. Between courses of treatment with either 5-FU or MTX, repopulation of ER+ cells was specifically inhibited by the SERMs, whereas repopulation of ER- MDA-231 was not affected.


CONCLUSIONS
Arzoxifene and 4OHT can inhibit specifically the repopulation of ER+ breast cancer cells between courses of chemotherapy. Scheduling of short-acting SERMs between courses of chemotherapy has the potential to improve therapeutic index.
Licun
Wu
W
Division of Experimental Therapeutics and Department of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, Toronto, Ontario M5G 2M9 Canada.
Tannock
Ian F
IF
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage; D011960:Receptors, Estrogen / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000008:administration & dosage; D013876:Thiophenes / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D018931:Antineoplastic Agents, Hormonal; D010880:Piperidines; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; D013629:Tamoxifen; C115121:LY 353381; D005472:Fluorouracil; D008727:Methotrexate