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Vol. 30, Issue 2, 183-190, February 2002
State University of New York, Upstate Medical University,
Departments of Pediatrics (P.D.S., B.A.H., M.K.A., R.L.D., R.L.D.,
A.-K.S.) and Gynecologic Oncology (M.J.C.), Syracuse, New York; and
Syracuse University, Department of Chemistry (J.C.D., J.G.,
K.A.T.), Syracuse, New York
DNA platination by cisplatin (CDDP) was investigated in peripheral
blood mononuclear cells and ovarian cancer cells using atomic
absorption spectroscopy. Plots showing the amount of platinum (Pt)
bound to DNA versus the molar concentration of cisplatin in the
incubation medium ([CDDP]) were nonlinear. For [CDDP] < about 5 µM, the amount of Pt bound to DNA increased slowly with added drug.
However, for larger [CDDP], the slope of the plot increased
significantly. To study the role of thiols in affecting cisplatin
binding to DNA, cells were treated with
N-ethylmaleimide, which modifies thiol groups, rendering
them incapable of binding cisplatin. Analysis using high-pressure
liquid chromatography showed that ~99% of cellular glutathione was
modified by N-ethylmaleimide. A plot of the amount of Pt
bound to DNA versus [CDDP] for thiol-blocked cells is linear, with a
slope similar to that of unblocked cells at high [CDDP]. Neither
S-2-(3 aminopropylamino)ethanethiol (WR-1065) nor
mesna, when added at clinically achievable concentrations (i.e.,
<~300 µM), affected DNA platination. However, DNA platination was
totally abolished by millimolar concentrations of the drug thiols
(~1.25 mM WR-1065 or ~5 mM mesna). Thus, the data show that
endogenous thiols intercept cellular cisplatin, but this mechanism is
less important at high [CDDP]. Moreover, therapeutic concentrations
of drug thiols do not significantly affect DNA platination. A simple
model that reproduces the experimental results of the amount of
cisplatin binding to DNA as a function of [CDDP], time, and thiol
content is proposed. The model takes into account passage of cisplatin
and thiols through the cell membrane, binding of cisplatin to cellular
thiols, and platination of DNA.
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