STX140 is efficacious in vitro and in vivo in taxane-resistant breast carcinoma cells.
OBJECTIVE
The aim of these studies was to characterize the action of STX140 in a P-glycoprotein-overexpressing tumor cell line both in vitro and in vivo. In addition, its efficacy was determined against xenografts derived from patients who failed docetaxel therapy.


METHODS
The effects of STX140, Taxol, and 2-methoxyestradiol (2-MeOE2) on cell proliferation, cell cycle, and apoptosis were assessed in vitro in drug-resistant cells (MCF-7(DOX)) and the parental cell line (MCF-7(WT)). Mice bearing an MCF-7(DOX) tumor on one flank and an MCF-7(WT) tumor on the other flank were used to assess the in vivo efficacy. Furthermore, the responses to STX140 of three xenografts, derived from drug-resistant patients, were assessed.


RESULTS
In this study, STX140 caused cell cycle arrest, cyclin B1 induction, and subsequent apoptosis of both MCF-7(DOX) and MCF-7(WT) cells. Taxol and 2-MeOE2 were only active in the MCF-7(WT) parental cell line. Although both STX140 and Taxol inhibited the growth of xenografts derived from MCF-7(WT) cells, only STX140 inhibited the growth of tumors derived from MCF-7(DOX) cells. 2-MeOE2 was ineffective at the dose tested against both tumor types. Two out of the three newly derived docetaxel-resistant xenografts, including a metastatic triple-negative tumor, responded to STX140 but not to docetaxel treatment.


CONCLUSIONS
STX140 shows excellent efficacy in both MCF-7(WT) and MCF-7(DOX) breast cancer xenograft models, in contrast to Taxol and 2-MeOE2. The clinical potential of STX140 was further highlighted by the efficacy seen in xenografts recently derived from patients who had failed on taxane therapy.
Newman
Simon P
SP
Endocrinology and Metabolic Medicine, Faculty of Medicine, Imperial College London, St Mary's Hospital, London, UK. simon.newman@imperial.ac.uk
Foster
Paul A
PA
Stengel
Chloe
C
Day
Joanna M
JM
Ho
Yaik T
YT
Judde
Jean-Gabriel
JG
Lassalle
Myriam
M
Prevost
Gregoire
G
Leese
Mathew P
MP
Potter
Barry V L
BV
Reed
Michael J
MJ
Purohit
Atul
A
D000077584:2-Methoxyestradiol; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D004963:Estrenes / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000627:therapeutic use*; D050257:Tubulin Modulators / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
C526438:2-methoxyestradiol-3,17-O,O-bis(sulfamate); D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004963:Estrenes; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D017239:Paclitaxel