INHIBITION OF GROWTH OF ESTROGEN-RECEPTOR POSITIVE AND ESTROGEN-RECEPTOR NEGATIVE BREAST-CANCER CELLS IN CULTURE BY AA-ETHERA, A STABLE 2-5A DERIVATIVE
Ke. Latham et al., INHIBITION OF GROWTH OF ESTROGEN-RECEPTOR POSITIVE AND ESTROGEN-RECEPTOR NEGATIVE BREAST-CANCER CELLS IN CULTURE BY AA-ETHERA, A STABLE 2-5A DERIVATIVE, Oncogene, 12(4), 1996, pp. 827-837
The design, chemical synthesis and biological activities of a nuclease
-resistant, nontoxic bioactive 2-5A derivative, AA-etherA [i.e., adeny
lyl-(2'-5')-adenylyl-(2'-2 '')-9-[(2'-hydroxyethoxy)-methyl]adenine],
are described as a new approach to the inhibition of breast cancer cel
l growth, AA-etherA inhibits DNA replication and cell division of both
estrogen receptor positive (MCF-7) and estrogen receptor negative (BT
-20) breast cancer cells in culture in a dose-dependent manner. Maxima
l inhibition in MCF-7 and BT-20 cells was obtained with 100 mu M AA-et
herA after four days of treatment, with an GI(50) of 58 and 37 mu M, r
espectively, AA-etherA is stable in the cytoplasm. Treated cells accum
ulate within the late G(1)/early S phase of the cell cycle and then pr
ogress only very slowly through S phase. AA-etherA does not activate R
Nase L, as do 2-5A and other 2-5A derivatives, nor does it increase p6
8 kinase (PKR) content of the cells. High resolution, two-dimensional
protein gel electrophoresis reveals twofold or greater inhibition of s
ynthesis of 92 proteins out of 682 proteins that were reproducibly det
ected as high quality spots with average rates of synthesis of greater
than or equal to 20 p.p.m. in untreated cells. The specificity of the
effects of AA-etherA on select proteins and its failure to activate R
Nase L indicate that AA-etherA does not act through a general effect o
n mRNA translation or stability, but rather inhibits cell proliferatio
n through a block to DNA replication, with a concommitant reduction in
the synthesis of specific proteins, some of which may be required for
cell cycle transit. Two likely targets to account for the AA-etherA i
nhibition of DNA replication are DNA topoisomerase I, which is inhibit
ed by AA-etherA in other cell lines, and thymidine kinase, which could
be inhibited in a manner similar to the effect of acyclovir. These da
ta indicate that 2-5A analogs, particularly bifunctional 2-5A analogs
like AA-etherA, will be useful for controlling cancer cell growth. Fur
ther development of such 2-5A analogs may provide highly specific comp
ounds for chemotherapy and chemoprevention.