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A large intrinsic magnetoresistance has been found near the ferromagnetic transition of metallic manganese oxides with perovskite-type crystal structure. The magnetic and transport properties were measured on bulk and thin-film La1−xAxMnO3+δ with A=Ca,Sr,Ba. Assuming the double-exchange model proposed by Zener [Phys. Rev. 81, 440 (1951); 82, 403 (1951)], the strong dependence of the transport properties on the magnetic field and also on the chemical composition is attributed to the mixed Mn3+/Mn4+ valence.

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In the present study, we conducted a retrospective analysis of 343 in vitro experiments to ascertain whether observed (experimentally determined) values of Ki for reversible cytochrome P450 (P450) inhibition could be reliably predicted by dividing the corresponding IC₅₀ values by two, based on the relationship (for competitive inhibition) in which Ki = IC₅₀/2 when [S] (substrate concentration) = Km (Michaelis-Menten constant). Values of Ki and IC₅₀ were determined under the following conditions: 1) the concentration of P450 marker substrate, [S], was equal to Km (for IC₅₀ determinations) and spanned Km (for Ki determinations); 2) the substrate incubation time was short (5 minutes) to minimize metabolism-dependent inhibition and inhibitor depletion; and 3) the concentration of human liver microsomes was low (0.1 mg/ml or less) to maximize the unbound fraction of inhibitor. Under these conditions, predicted Ki values, based on IC₅₀/2, correlated strongly with experimentally observed Ki determinations [r = 0.940; average fold error (AFE) = 1.10]. Of the 343 predicted Ki values, 316 (92%) were within a factor of 2 of the experimentally determined Ki values, and only one value fell outside a 3-fold range. In the case of noncompetitive inhibitors, Ki values predicted from IC₅₀/2 values were overestimated by a factor of nearly 2 (AFE = 1.85; n = 13), which is to be expected because, for noncompetitive inhibition, Ki = IC₅₀ (not IC₅₀/2). The results suggest that, under appropriate experimental conditions with the substrate concentration equal to Km, values of Ki for direct, reversible inhibition can be reliably estimated from values of IC₅₀/2.

Laromustine [VNP40101M, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine, also known as Cloretazine] is an active member of a relatively new class of sulfonylhydrazine prodrugs under development as antineoplastic alkylating agents (Penketh et al., 2004;Baumann et al., 2005). As shown in Fig. 1, laromustine generates two distinct types of reactive intermediates: 90CE and methylisocyanate. 90CE and other hard chloroethylating (DNA-reactive) species alkylate DNA at the O 6 -position of guanine residues that progress to G-C interstrand cross-links (Penketh et al., 2000(Penketh et al., , 2004. Methylisocyanate, a soft electrophilic carbamoylating agent, binds preferentially and stoichiometrically to sulfhydryl groups and inhibits a number of enzymes, including O 6 -alkylguanine-DNAalkyltransferase (AGT), a DNA repair enzyme. The release of methylisocyanate and its inhibition of DNA repair by AGT is thought to augment the antineoplastic effect of 90CE and related chloroethylating species. This process probably accounts for the considerably greater antineoplastic activity of laromustine relative to that of other sulfonylhydrazine alkylating agents, many of which generate 90CE like laromustine, but in contrast to laromustine do not generate methylisocyanate (Baumann et al., 2005). Laromustine displays anticancer activity against a broad spectrum of transplanted tumors (Finch et al., 2001) and exhibited antileukemic activity in initial clinical trials (Giles et al., 2004). Laromustine is being evaluated in clinical trials for the treatment of acute myelogenous leukemia and bone marrow transplant in patients with cancer.Drug interactions in patients receiving multiple drug treatments are an important cause of adverse events, as evidenced by the recent withdrawal of newly marketed drugs with unacceptable drug-interacThis work was supported by Vion Pharmaceuticals, Inc., New Haven, CT. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.doi:10.1124/dmd.109.027516.ABBREVIATIONS: VNP40101M, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine, laromustine, also known as Cloretazine; 90CE, a pharmacologically active degradation product of laromustine (as VNP4090CE and, in this study, C-8); AGT, O 6 -alkylguanine-DNAalkyltransferase; FDA, Food and Drug Administration; P450, cytochrome P450; FMO, flavin-containing monooxygenase; DMSO, dimethyl sulfoxide; HPLC, high-performance liquid chromatography; r, recombinant; C-7, VNP40107 (a metabolite of laromustine); ANOVA, analysis of variance.

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The Seebeck effect and the thermal diffusivity of La0.67Ca0.33MnO3−δ were investigated in the temperature range 35<T<300 K and in particular in the regime of the high magnetoresistance and maximum resistivity ρmax. We find a sign change of the thermoelectric power S(T) and a step in heat conductivity near ρmax which we attribute to a temperature-induced metal–insulator transition at about 80 K, suggesting that the large giant magnetoresistance found in these substances is due to a field-induced metal–insulator transition.

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