CHEMOPREVENTION OF MAMMARY CANCER BY ORGANOSELENIUM

Project: Research project

Project Details

Description

We have consistently shown that synthetic organoselenium compounds (OSC)
are superior cancer chemopreventative agents with less toxicity than
selenite, naturally-occurring selenoamino acids, or their sulfur analogs.
The proposed research focuses on our lead compound [1, 4-
phenylenebis(methylene)selenocyanate, p-XSC] and will verify whether p-XSC
or one of its metabolites is responsible for the chemoprevention of
cancer; moreover it will seek to establish (a) plausible mechanism(s) for
such an effect, especially during the post-initiation phase of
carcinogenesis in the 7, 12-dimethylbenz(a)anthracene (DMBA) mammary tumor
model in rats. Comparisons of our preliminary results with those obtained
previously with benzyl selenocyanate (BSC), lead us to believe that
glutathione conjugate (BSe-SG), a putative metabolite of BSC, has a higher
chemopreventative index than the parent compound (BSC) in this DMBA
mammary tumor model. In addition, BSe-SG is stable at pH ranges between 2
and 7.4 at 37 degrees Celsius. The efficacy of this conjugate in vivo
indicates systemic absorption. However, it remains to be determined
whether the intact conjugate or one of its metabolites is delivered to
extrahepatic tissues. Our future studies, however, will focus on p-XSC,
because we hypothesize that the glutathione conjugate (p-XSe-SG) is a
primary metabolite of p-XSC, that will lead to the formation of an aryl
selenol intermediate as the active chemopreventative principle. Support
for the formation of an aryl selenol intermediate is based on the
identification of tetraselenocyclophane (TSC) as a metabolite derived from
p-XSC or p-XSe-SG. Thus, to test our hypothesis and to achieve the goals
of this Project, in Aim 1, we will synthesize ample materials of p-XSC, p-
XSe-SG, and TSC. To unequivocally confirm the presence of p-XSe-SG as a
primary metabolite of p-XSC in vivo, we will conduct the synthesis and
additional metabolism studies with the dual-labelled version of p-XSe-SG.
In Aim 2, following determination of maximally tolerated doses, we will
compare the efficacy of p-XSC, p-XSe-SG, and TSC in the initiation and
post-initiation phases of carcinogenesis in the DMBA mammary tumor model
in rats. The most effective compound will be further examined following
its delayed administration (13 weeks after DMBA administration). Our
results to date, together with literature data, appear to favor the
hypothesis that p-XSC and/or one of its metabolites could inhibit
oxidative damage, down-regulate cyclooxygenase (COX-2) expression, induce
apoptosis and, consequently, inhibit carcinogenesis. Therefore, in Aim 3,
we will examine the effect of those OSC that will emerge with significant
chemopreventative activity from Aim 2 on markers that are especially
important in the post-initiation phase of carcinogenesis, namely levels of
lipid peroxidation (isoprostane), COX-2 expression, and apoptosis and on
levels of 8-hydroxydeoxy-guanosine (8-OHdG). The results of this Project
will provide insights into the feasibility of using p-XSC and/or one of
its metabolites in future clinical trials on breast cancer chemoprevention
and into the underlying mechanism(s) of action.
StatusFinished
Effective start/end date10/1/977/31/99

Funding

  • National Cancer Institute

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