Antitumor activity, distribution, and metabolism of 13-cis-retinoic acid as a single agent or in combination with tamoxifen in established human MCF-7 xenografts in mice
Ba. Conley et al., Antitumor activity, distribution, and metabolism of 13-cis-retinoic acid as a single agent or in combination with tamoxifen in established human MCF-7 xenografts in mice, CANC CHEMOT, 43(3), 1998, pp. 183-197
Purpose: The efficacy of 13-cis-retinoic acid (13-CRA) given as a single ag
ent or in combination with tamaxifen (TAM) was determined in athymic nude m
ice bearing advanced s.c. MCF-7 human breast cancers. Methods: 13-CRA alone
was given by gavage at doses ranging from 26.4 to 200 mg/kg. TAM alone was
given by gavage at doses of 7.5, 15, 30, or 60 mg/kg. For combination stud
ies, each dose of TAM was followed 4 h later by 13-CRA at doses of 25, 50,
100, or 200 mg/kg. All treatments began on day 12 and were continued for 3
weeks. Results: The median time to two doublings recorded for the control a
nd for 13-CRA and TAM given as single agents at the highest dose were 22.2,
29.2, and 54.7 days, respectively. In combination, 100 and 200 mg/kg 13-CR
A with 7.5 mg/kg TAM resulted in a delay in tumor growth at least as high a
s that achieved with highest-dose TAM alone, but the effect was not synergi
stic. Pharmacokinetic analysis of 13-CRA was performed in plasma, liver, an
d tumor from mice bearing 0.5- to 2.0 g carcinomas following a single dose
of 100 mg/kg 13-CRA. Results showed that 13-CRA was metabolized differently
in various tissues, but concentrations of 13-CRA detected in tumor were in
the range reported to be active in vitro. all-trans-Retinoic acid (ATRA) c
oncentrations were about 5% of the 13-CRA concentrations detected in plasma
, 68% of those found in liver, and 20% of those found in tumor. 4-oxo-CRA r
epresented between 2% and 10% of 13-CRA concentrations detected in plasma a
nd liver but was not detected in tumor. Furthermore there was no difference
in peak plasma 13-CRA concentrations found in the same tissues at 30 min a
fter a single dose or after the eighth doss of 100 mg/kg 13-CRA or 13-CRA a
nd TAM. Mean 13-CRA concentrations detected in liver and tumor were 50-90%
and 16-30% of plasma peak concentrations, respectively. No difference in 4-
oxo-CRA concentration was observed between the treatment groups. Conclusion
s: These data suggest that 13-CRA is not effective against established huma
n breast tumor xenografts despite the stability of the pharmacokinetics of
Ij-CRA and the generation of ATRA as a metabolite. The addition of 13-CRA t
o TAM did not improve the efficacy of TAM against these estrogen-receptor-p
ositive xenografts.