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Co-Investigators
Clinton J. Grubbs,
Ph.D.
Donald L. Hill, Ph.D.
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Overview
Of all cancers affecting
women in the U.S., 5% are ovarian. Most of these are diagnosed
in advanced stages, and survival rates are low. At present,
there is no verified, established animal model for this disease.
For screening potential chemopreventive agents, animal models
are important in that they allow determination of organ specificity,
collection of dose-response data, observation of long-term toxic
effects, and accumulation of pharmacological data. The overall
goals of this developmental project are to establish and validate
an in vivo model for ovarian cancer and to use this model
to evaluate potential chemopreventive agents. An ovarian cancer
model that involves dosing of pregnant Wistar rats with N-nitrosobis-(2-oxopropyl)amine(BOP)
has been reported. Our laboratory is currently validating this
model. Because the model requires over a year for development
of a significant number of ovarian tumors in the offspring,
we plan to improve it to allow a more rapid evaluation of chemopreventive
agents. We propose, therefore, to evaluate the effect of BOP
in the induction of ovarian cancer in Lewis (inbred) and Wistar
Furth (inbred) rats in Swiss Webster (outbred), BALB/c (inbred),
and B6D2F1 (hybrid) mice. Since we anticipated that the ovarian
model will be validated in our laboratory before the end of
the first year, we will, at that time, initiate the evaluation
of atleast one potential chemopreventive agent (medroxyprogesterone).
Two additional agents, levonorgestrel and N-(4-hydroxyphenyl)retinamide
(4-HPR), will be evaluated once we have established the best
ovarian model. Tissues will be collected for biomarker evaluations
in Core A, "Tissue Resources and Immunopathology." The studies
described should establish a useful, short-term in vivo
model, similar to those currently used by the NCI for breast,
urinary bladder, lung, and skin cancers, that will allow screening
of new chemopreventive compounds against ovarian cancers.
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