Ribonuclease-Activated
Cancer Prodrug
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Abstract
Cancer chemotherapeutic agents often have a narrow therapeutic
index that challenges the maintenance of a safe and effective dose.
Consistent plasma concentrations of a drug can be obtained by using
a timed-release prodrug strategy. We reasoned that a ribonucleoside
3′-phosphate could serve as a pro-moiety that also increases
the hydrophilicity of a cancer chemotherapeutic agent. Herein, we
report an efficient route for the synthesis of the prodrug uridine
3′-(4-hydroxytamoxifen phosphate) (UpHT). UpHT demonstrates
timed-released activation kinetics with a half-life of approximately
4 h at the approximate plasma concentration of human pancreatic ribonuclease
(RNase 1). MCF-7 breast cancer cells treated with UpHT showed decreased
proliferation upon coincubation with RNase 1, consistent with the
release of the active drug4-hydroxytamoxifen. These data demonstrate
the utility of a human plasma enzyme as a useful activator of a prodrug