E. Izbicka et al., 5,6-dihydro-5 '-azacytidine (DHAC) affects estrogen sensitivity in estrogen-refractory human breast carcinoma cell lines, ANTICANC R, 19(2A), 1999, pp. 1293-1298
Background; There is litde effective therapy for patients with hormone-refr
actory breast cancer. Hormone resistance is frequently due to the transcrip
tional inactivation of the estrogen receptor (ER) gene. We,determined the e
ffect of DHAC, a cytosine DNA methyltransferase (CMT) inhibitor, on the est
rogen sensitivity in three human breast carcinoma cell lines with intermedi
ate to low levels of estrogen receptor (EB) expression: MCF7 (adriamycin-se
nsitive), MCF7M/Adr (adriamycin-resistant), and MDA-435, and one ER+ cell l
ine ZR75-1. Materials and Methods: Cells maintained in culture were exposed
to DHAC or vehicle continuously for 14 days, then exposed to estradiol or
tamoxifen and counted on day 21. Results: Exposure to DHAC did not affect e
strogen sensitivity in ZR-75-1 and MCF7M/Adr cells. DHAC treatment of MCF7
and MDA-435 cells resulted in significant (p<0.05) growth stimulation in re
sponse to estrogen at 10(-6) M, and to growth modulation by tamoxifen at 10
(-5) to 10(-7) M. Conclusions: These data suggest that DHAC can restore the
estrogen sensitivity in ER-breast cancer. Thus, DHAC and other novel CMT i
nhibitors may have a clinical application in treating estrogen-refractory b
reast cancer patients by restoring the estrogen sensitivity and allowing th
ese patients to respond again to conventional therapy with estrogen antagon
ists.