Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis
P. Norgaard et al., Treatment with farnesyl-protein transferase inhibitor induces regression of mammary tumors in transforming growth factor (TGF) alpha and TGF alpha/neu transgenic mice by inhibition of mitogenic activity and induction of apoptosis, CLIN CANC R, 5(1), 1999, pp. 35-42
Mouse mammary tumor virus-transforming growth factor alpha (MRTV-TGF alpha)
and MMTV-TGF alpha/neu transgenic mice develop mammary tumors after a long
latency and therefore provide useful model systems for breast cancer with
its recognized activation of receptor tyrosine kinase signaling. We used th
ese mice to study the antitumor effect of L-744,832 (FTI), a potent and sel
ective inhibitor of farnesyl-protein transferase, and hence of Ras function
. A total of 55 mice were assigned randomly to treatment with FTI or vehicl
e, and one-half of the mice were crossed over after initial treatment to th
e opposite group. L-744,832 induced reversible regression of mammary tumors
that was paralleled by a decrease in serum levels of TGF alpha secreted by
the tumor cells. There was no difference in response to treatment with FTI
between MMTV-TGF alpha mice, in which tumorigenesis was accelerated by mul
tiparity or the chemical carcinogen 7,12-dimethylbenzanthracene, and MMTV-T
GF alpha/neu mice. The tumor histological type had no impact on FTI sensiti
vity. For mechanistic analyses, tumor excision biopsies were obtained from
12 mice before and after treatment with L-744,832. In these samples, tumor
regression was paralleled biochemically by inhibition of mitogen-activated
protein kinase activity and biologically by an increase in G(1)-phase and d
ecrease in S-phase fractions, as well as induction of apoptosis, These resu
lts suggest that the potential clinical use of FTI could be expanded to inc
lude cancers harboring activated receptor tyrosine kinases as well as those
containing activated Ras.