Oxidative degradation of cardiotoxic anticancer anthracyclines to phthalic acids: novel function for ferrylmyoglobin.

We show that the pseudoperoxidase activity of ferrylmyoglobin(MbIV) promotes oxidative degradation ofdoxorubicin (DOX), an anticancer anthracycline knownto induce severe cardiotoxicity. MbIV, formed in vitro byreacting horse heart MbIII with H2O2, caused disappearanceof the spectrum of DOX at 477 nm and appearanceof UV-absorbing chromophores that indicated openingand degradation of its tetracyclic ring. Electron sprayionization mass spectrometry analyses of DOX/MbIV ultrafiltratesshowed that DOX degradation resulted information of 3-methoxyphthalic acid, the product of oxidativemodifications of its methoxy-substituted ring D.Other methoxy-substituted anthracyclines similarly released3-methoxyphthalic acid after oxidation by MbIV,whereas demethoxy analogs released simple phthalicacid. Kinetic and stoichiometric analyses of reactionsbetween DOX and MbIII/H2O2 or hemin/H2O2 showedthat the porphyrin radical of MbIV-compound I and theiron-oxo moiety of MbIV-compound II were sequentiallyinvolved in oxidizing DOX; however, oxidation by compoundI formed more 3-methoxyphthalic acid than oxidationby compound II. Sizeable amounts of 3-methoxyphthalicacid were formed in the heart of micetreated with DOX, in human myocardial biopsies exposedto DOX in vitro, and in human cardiac cytosol thatoxidized DOX after activation of its endogenous myoglobinby H2O2. Importantly, H9c2 cardiomyocytes weredamaged by low concentrations of DOX but could tolerateconcentrations of 3-methoxyphthalic acid higherthan those measured in murine or human myocardium.These results unravel a novel function for MbIV in theoxidative degradation of anthracyclines to phthalic acidsand suggest that this may serve a salvage pathwayagainst cardiotoxicity

Oxidative Degradation of Cardiotoxic Anticancer Anthracyclines to Phthalic Acids

We show that the pseudoperoxidase activity of ferrylmyoglobin (MbIV) promotes oxidative degradation of doxorubicin (DOX), an anticancer anthracycline known to induce severe cardiotoxicity. MbIV, formed in vitro by reacting horse heart MbIII with H2O2, caused disappearance of the spectrum of DOX at 477 nm and appearance of UV-absorbing chromophores that indicated opening and degradation of its tetracyclic ring. Electron spray ionization mass spectrometry analyses of DOX/MbIV ultrafiltrates showed that DOX degradation resulted in formation of 3-methoxyphthalic acid, the product of oxidative modifications of its methoxy-substituted ring D. Other methoxy-substituted anthracyclines similarly released 3-methoxyphthalic acid after oxidation by MbIV, whereas demethoxy analogs released simple phthalic acid. Kinetic and stoichiometric analyses of reactions between DOX and MbIII/H2O2 or hemin/H2O2 showed that the porphyrin radical of MbIV-compound I and the iron-oxo moiety of MbIV-compound II were sequentially involved in oxidizing DOX; however, oxidation by compound I formed more 3-methoxyphthalic acid than oxidation by compound II. Sizeable amounts of 3-methoxyphthalic acid were formed in the heart of mice treated with DOX, in human myocardial biopsies exposed to DOX in vitro, and in human cardiac cytosol that oxidized DOX after activation of its endogenous myoglobin by H2O2. Importantly, H9c2 cardiomyocytes were damaged by low concentrations of DOX but could tolerate concentrations of 3-methoxyphthalic acid higher than those measured in murine or human myocardium. These results unravel a novel function for MbIV in the oxidative degradation of anthracyclines to phthalic acids and suggest that this may serve a salvage pathway against cardiotoxicity

Clinical and Pharmacologic Study of the Novel Prodrug Delimotecan (MEN 4901/T-0128) in Patients with Solid Tumors

Purpose: To investigate i.v. administration of delimotecan (MEN 4901/T-0128), a carboxymethyldextran polymer prodrug of the active camptothecin derivative T-2513, and to assess the maximum tolerated dose, safety profile, clinical pharmacology, and antitumor activity of delimotecan and metabolites. Experimental Design: Patients with solid tumors refractory to standard therapy received i.v. delimotecan as 3-hour infusion once every 6 weeks. The starting dose was 150 mg/m(2), followed by an accelerated dose escalation with at least one patient per dose level. The pharmacokinetics of delimotecan, T-2513, and its metabolites, SN-38, SN-38G, T-1335, T-0055, and T-3921, were assessed in plasma and urine, and their pharmacodynamics were determined by measuring the effect of the treatment on hematologic and nonhematologic toxicity. Results: Twenty-two patients received 35 courses. Dose-limiting toxicities were observed at 5,400 mg/m(2) (n = 1), 3,600 mg/m(2) (n = 1), and 2,400 mg/m(2) (n = 2). The dose level of 1,800 mg/m(2) was determined as maximum tolerated dose. Two partial responses were observed in patients with anal cancer (1800 mg/m(2)) and head and neck cancer (2400 mg/m(2)). Delimotecan had a long terminal half-life of 109 h, and relatively high exposures to T-2513 and SN-38 were obtained. The percentage decrease in WBC and absolute neutrophil count significantly correlated with the dose of delimotecan. Conclusions: Based on its preliminary antitumor activity, safety profile, and pharmacokinetic profile, we recommend to evaluate delimotecan given as 3-hour infusion once every 6 weeks at a dose level of 1,800 mg/m(2) in a phase II study

Total Synthesis, Stereochemical Assignment, and Biological Activity of All Known (−)-Trigonoliimines

A full account of our concise and enantioselective total syntheses of all known (−)-trigonoliimine alkaloids is described. Our retrobiosynthetic analysis of these natural products enabled identification of a single bistryptamine precursor as a precursor to all known trigonoliimines through a sequence of transformations involving asymmetric oxidation and reorganization. Our enantioselective syntheses of these alkaloids enabled the revision of the absolute stereochemistry of (−)-trigonoliimines A, B, and C. We report that trigonoliimines A, B, C and structurally related compounds showed weak anticancer activities against HeLa and U-937 cells.National Institute of General Medical Sciences (U.S.) (GM074825)EMD Serono, Inc. (Graduate Fellowship)Kenneth Gordon Summer Fellowshi