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Division of Medical Oncology, Department of Internal Medicine, University of Utah and Salt Lake City Veterans’ Administration Medical Centers, Salt Lake City, Utah 84148 [P. J. S., L. Y. W.]; Basic Research Program [J. E. S., B. A. D., G. S. B., M. L. C.] and Analytical Chemistry Laboratory [S. D. F.], Science Applications International Corporation-Frederick, National Cancer Institute at Frederick, Frederick, Maryland 21702; Department of Pharmacology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213 [S. V. S., Y. G.]; Macromolecular Crystallography Laboratory, National Cancer Institute at Frederick, Frederick, Maryland 21702 [Y. G., X. J.]; Department of Chemistry, George Mason University, Fairfax, Virginia 22030 [K. M. D.]; and Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland 21702 [C. L. B., D. J. W., L. K. K.]

² To whom requests for reprints should be addressed, at SLC VA Medical Center, Box 151M, 500 Foothill Boulevard, Salt Lake City, UT 84148. Phone: (801) 582-1565; Fax: (801) 583-9624; E-mail: p.shami{at}m.cc.utah.edu

We have previously shown that nitric oxide (NO) inhibits growth and induces differentiation and apoptosis in acute myeloid leukemia cells, with the HL-60 human myeloid leukemia line being particularly sensitive to NO-mediated cytolysis. With the goal of identifying a prodrug that can target NO to the leukemia cells without inducing NO-mediated systemic hypotension, we have screened a series of O²-aryl diazeniumdiolates designed to be stable at physiological pH but to release NO upon reaction with glutathione. O²-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) proved to be the most active antiproliferative agent among those tested in HL-60 cells, with an IC₅₀ of 0.2–0.5 µM. After 5 days of exposure to 0.5 µM JS-K, HL-60 cells had differentiated and acquired some of the phenotypic features of normal monocytes. One- to 2-day treatment with JS-K at concentrations of 0.5–1 µM resulted in apoptosis induction in a concentration- and caspase-dependent manner. JS-K also inhibited the growth of solid tumor cell lines but to a lesser extent than HL-60 cells. JS-K was administered i.v. to nonobese diabetic-severe combined immune deficient mice at doses of up to 4 µmol/kg without inducing significant hypotension. The growth of s.c. implanted HL-60 cells was reduced by 50% when the mice received i.v. injections three times/week with 4 µmol/kg boluses of JS-K. Histological examination of tumor explants from JS-K-treated animals revealed extensive necrosis. Similar results were seen with s.c. human prostate cancer (PPC-1) xenografts. Our data indicate that JS-K is a promising lead compound for the possible development of a novel class of antineoplastic agents.

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