In 5-day incubation of an
estrogen receptor-negative human
ovarian cancer cell line (KF) with N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (
DPPE), the concentration of
DPPE required for 50% inhibition of KF cell proliferation (IC50) was 1.7 microM. The IC50 of
DPPE for inhibition of
protein kinase C (PKC) activity was 3.0 microM, a similar value to those of other
antiestrogens such as
tamoxifen and
clomiphene.
DPPE also inhibited phosphorylation of
mitogen-activated protein kinase in KF cells. When treatment with
DPPE was started 7 days after inoculation of KF cells into nude mice, 50 mg/kg
DPPE alone resulted in a significant growth retardation in the early stage of
tumor growth. Although 25 mg/kg
DPPE showed a similar effect to 2 mg/kg
cisplatin (CDDP), the combination had the most marked
tumor growth-inhibitory effect. Nude mice treated with combinations of CDDP and
DPPE survived significantly longer than not only untreated, but also CDDP-alone-treated mice, while 50 mg/kg but not 25 mg/kg
DPPE alone had an effect comparable to that of 2 mg/kg CDDP alone. If treatment with
DPPE was begun from the day after
tumor inoculation, the inhibitory effect of
DPPE was further enhanced, especially when combined with CDDP. If treatment with
DPPE was started in nude mice with a lower
tumor burden, 25 mg/kg as well as 50 mg/kg
DPPE had a similar effect to 2 mg/kg CDDP, in terms of survival. When
DPPE was combined with CDDP, the effect was significantly enhanced, compared to that of either alone. These treatments could be done without any adverse side effect. Thus, we conclude that
DPPE has an
antiestrogen action and its
tumor growth-inhibiting activity is enhanced on administration in combination with CDDP.