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Purpose: This pilot trial was performed to evaluate the safety, pharmacokinetics and feasibility of incorporating BMS-275291, a matrix metalloproteinase inhibitor (MMPI), into adjuvant breast cancer therapy., Experimental Design: Patients with stage I (T1c)-IIIA breast cancer were eligible if planned adjuvant therapy consisted of either tamoxifen alone, doxorubicin + cyclophosphamide every 21 days for four cycles (AC), or AC followed by paclitaxel every 21 days for 4 cycles (AC>T). Patients were stratified by planned adjuvant therapy and randomized (2:1 ratio) to BMS-275291 (1200 mg/day) or matched placebo for 1 year., Results: Seventy-two patients were recruited from March 2001 to July 2002. Grade >or=2 musculoskeletal toxicity, generally reversible arthralgia, was reported by 36.2% of patients receiving BMS-275291 compared with 16.7% of patients receiving placebo; difference = 19.5% (95% confidence interval: -0.06, 0.44; P = NS). Two patients receiving BMS-275291 developed palpable nodules along tendons. Grade >or=3 rash was reported by 8.5% of patients receiving BMS-275291 compared with 4.2% of patients receiving placebo; difference = 4.3% (95% confidence interval: -0.18, 0.3; P = NS). Overall, 33% of BMS-275291 patients and 21% of placebo patients discontinued treatment due to adverse events. BMS-275291 trough levels tended to decrease over time; 9 of 47 (19%) had >or=50% of trough concentrations > 124 ng/ml (IC(90) for matrix metalloproteinase-9)., Conclusions: The pattern of arthralgia in BMS-275291-treated patients was consistent with matrix metalloproteinase inhibitor toxicity. Although the differential incidence of arthralgia did not reach statistical significance, the trial was terminated. An adjuvant trial in this patient population is not feasible.

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 O(2)-aryl diazeniumdiolates designed to be stable at physiological pH but to release NO upon reaction with glutathione. O(2)-(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 IC(50) of 0.2-0.5 microM. After 5 days of exposure to 0.5 micro M 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 microM 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 micromol/kg without inducing significant hypotension. The growth of s.c. implanted HL-60 cells was reduced by approximately 50% when the mice received i.v. injections three times/week with 4 micromol/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.

A sensitive, precise and accurate stable isotope dilution high-performance liquid chromatography-electrospray ionization mass spectrometry method has been developed for measuring endogenous 2- and 4-hydroxyestrones, the main catechol estrogens in human urine. Compared to the published methods using gas chromatography-mass spectrometry, this approach simplifies sample preparation and increases the throughput of analysis. The unique part of our method is the use of a simple and rapid derivatization step that forms a hydrazone at the C-17 carbonyl group of catechol estrogens. This derivatization step has greatly enhanced method sensitivity as well as HPLC separability of 2- and 4-hydroxyestrones. Standard curves were linear over a 100-fold calibration range with correlation coefficients for the linear regression curves typically greater than 0.996. The lower limit of quantitation for each catechol estrogen is 1 ng per 10-ml urine sample, with an accuracy of 97-99% and overall precision, including the hydrolysis, extraction and derivatization steps, of 1-3% for samples prepared concurrently and 2-11% for samples prepared in several batches. This method is adequate for measuring the low endogenous levels of catechol estrogens in urine from postmenopausal women., (Copyright 2002 Elsevier Science B.V.)

High-performance liquid (HPLC) and thin-layer (TLC) chromatographic methods for the detection and quantification of diazeniumdiolates are described. The HPLC determinations were made using a Rocket Platinum NH2 column (7 x 53 mm, 100-A pore size, 3-microm particle size), under isocratic conditions with mixtures of acetonitrile, methanol, and water containing 0.1% diethylamine (v/v), at a flow rate of 2.5 ml/min, a column temperature of 22 degrees C, and UV detection at 250 nm. The TLC determinations were similarly made using Merck NH2 F254S precoated glass plates (approximately 2 x 5 cm, 5-microm particle size, 0.2-mm layer thickness) with mixtures of acetonitrile, methanol, and water containing 0.1% diethylamine (v/v). Preexisting traces of carcinogenic nitrosamines were detected in some samples of diazeniumdiolates. The methods provide a more efficient means of characterizing the purity of diazeniumdiolate samples prepared for use in biomedical applications than older procedures which rely on differential absorbance measurements at 250 and 350 nm, respectively.