The anticancer drug 7,10-dihydroxy-2-[2-[(2-hydroxyethyl)amino]- ethyl]-5-[[2-(methylamino)ethyl]amino]anthra[1,9-c,d]pyrazole- 6(2H)-one dihydrochloride (CI-937) is 1 of 3 anthrapyrazole derivatives chosen for phase I and phase II clinical trials. Although the chemical structure of CI-937 signals a contribution of redox reactions in the pharmacology of the drug, a study concerning the biotransformation of CI-937 is still missing. Incubations of primary cultures of rat hepatocytes with CI-937 result in the formation of three glutathione conjugates and a glucuronic acid conjugate. The structures of the glutathione conjugates have been established by reference synthesis with activated horseradish peroxidase and HPLC-MS-MS and two-dimensional NMR measurements. The glucuronic acid derivative of CI-937 has been identified by MS. The formation of the glutathione conjugates in cells establishes the ability of the drug to form covalent bonding to intracellular nucleophilic targets. The conjugation with glutathione has been rationalized by oxidative activation of CI-937, yielding an electrophilic intermediate that finally reacts with glutathione.

01 Oct 1994·Journal of Pharmaceutical and Biomedical AnalysisQ3 · MEDICINE

Stabilization of an anthrapyrazole antitumour agent, DuP 937, on complexation with heptakis(2,6-di-O-methyl)-β-cyclodextrin in aqueous solution

Q3 · MEDICINE

Article

Author: Krishnaswamy Raghavan ; Munir A. Hussain ; Gregory Nemeth ; David Gray

DuP 937, an anthrapyrazole antitumour agent that is chemically unstable in aqueous solution, was shown, by absorption spectroscopy, to form an inclusion complex with heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM beta CD) in aqueous solution. Proton nuclear magnetic resonance spectroscopy was used to determine the stoichiometry and association constant of the complex. The 1:1 stoichiometry of the complex was established by the continuous variation method by following changes in the chemical shifts of aromatic protons of DuP 937. The complex association constants determined by different techniques used in this study were in the same order of magnitude. The kinetics of degradation of DuP 937 in aqueous solution were investigated as a function of DM beta CD concentration at pH 5.5 and 60 degrees C. The results indicated about a seven-fold increase in the stability of DuP 937 in the presence of DM beta CD in aqueous solution.

17 Aug 1994·JNCI Journal of the National Cancer InstituteQ1 · MEDICINE

Topoisomerase II Inhibition and Cytotoxicity of the Anthrapyrazoles DuP 937 and DuP 941 (Losoxantrone) in the National Cancer Institute Preclinical Antitumor Drug Discovery Screen

Q1 · MEDICINE

Article

Author: Kenneth D. Paull ; François Leteurtre ; Yves Pommier ; Glenda Kohlhagen

BACKGROUNDThe cumulative cardiotoxicity of anthracyclines is thought to result from the generation of free radicals. New DNA topoisomerase II inhibitors less prone to redox reactions, such as mitoxantrone and more recently the anthrapyrazoles, were developed to circumvent this toxicity.PURPOSETwo anthrapyrazoles currently in clinical evaluation, DuP 941 (Losoxantrone) and DuP 937, were compared to other topoisomerase II inhibitors with respect to their cytotoxic potency and selectivity and with respect to topoisomerase II inhibition.METHODSCytotoxicity was tested in the 60 cell lines of the National Cancer Institute preclinical antitumor drug discovery screen (NCI screen). The potency of anthrapyrazoles to inhibit purified topoisomerase II was determined. The specificity of drug-induced topoisomerase II pattern of cleavage, one of the cellular determinants of cytotoxicity, was investigated in human c-myc DNA.RESULTSUsing the COMPARE analysis, we found that the most closely related cytotoxic profiles in the NCI screen were between the anthrapyrazoles and mitoxantrone. Among topoisomerase II inhibitors, the cytostatic potency was by decreasing order: mitoxantrone; doxorubicin, which was slightly greater than DuP 941, azatoxin; DuP 937; and amsacrine, which was much greater than VP-16. The potency of mitoxantrone and anthrapyrazoles to generate DNA double-strand breaks, by induction of the topoisomerase II cleavable complexes in nuclear extracts, was in agreement with cytotoxicity. Sequencing of drug-induced topoisomerase II cleavages in c-myc DNA showed a common cleavage pattern for anthrapyrazoles and mitoxantrone. This pattern was different from the patterns obtained with other topoisomerase II inhibitors.CONCLUSIONAt the molecular and cellular levels, anthrapyrazoles are potent topoisomerase II inhibitors closely related to mitoxantrone.IMPLICATIONSThese results validate the COMPARE analysis using the NCI screen to predict molecular mechanisms of drug action. Anthrapyrazoles, which are unlikely to produce free radicals, might be useful in the same indications as mitoxantrone, especially for patients with cardiac risks, for pediatric patients, and for patients treated with intensified protocols.

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