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K Reszka

Publications and source records attributed to K Reszka.

34 records · Page 2Linked to original sources
PubMed1988

Photosensitization by antitumor agents. 5. Daunorubicin-photosensitized oxidation of NAD(P)H in aqueous and N,N-dimethylformamide/aqueous solutions--an electron paramagnetic resonance study.

An EPR spectrum of the semiquinone radical of daunorubicin (D) was recorded upon illumination (480 nm) of the drug and NAD(P)H in deaerated aqueous and DMF/aqueous solutions. In the latter solvent system, an EPR spectrum with hyperfine structure was recorded. The kinetics of the photoinduced generation and decrease of the EPR signal intensity in the dark were measured. Second order rate constants for the radical recombination were derived for the two solvent systems. Photosensitized production of the superoxide radical, upon illumination of daunorubicin and NAD(P)H, in aerated aqueous or DMF/aqueous solutions, is evidenced by employing a spin trap DMPO (5,5-dimethyl-1-pyrroline-N-oxide) and an SOD assay. 5-Iminodaunorubicin (5-ID), in contrast to the parent compound (D), does not possess photosensitizing properties.

Daunorubicin↗
PubMed1988

Enzymatic oxidative activation and transformation of the antitumor agent mitoxantrone.

Ambient temperature incubation of the anticancer agent mitoxantrone with horseradish peroxidase and hydrogen peroxide converts it into a hexahydronaphtho[2,3-f]quinoxaline-7,12-dione in which one side chain has cyclized to the chromophore. The structure of this cyclic metabolite was secured by independent synthesis. This peroxidative conversion of mitoxantrone, the progress of which can be followed spectrophotometrically, is accompanied by formation of a free radical species. The EPR characteristics, and dependence on pH of the latter, suggest it exists as a radical cation. The enzymatic oxidation of mitoxantrone is totally irreversible. The purified cyclic metabolite is a substrate for the peroxidase affording the unstable fully oxidized diimino compound and this reaction is fully reversible upon addition of ascorbate or other biological reductants. Admixture of the fully oxidized diimino product with the reduced cyclic metabolite generates the corresponding radical cation species by disproportionation-comproportionation processes. Independent kinetic studies confirm that reaction of the peroxidase with the cyclic metabolite proceeds more rapidly than with mitoxantrone itself. A derivative of mitoxantrone, in which the side-chain secondary amine functions are acylated, generates a radical cation upon treatment with the peroxidase-H2O2 system but does not cyclize subsequently. Derivatives without phenolic hydroxyls or those in which the phenolic hydroxyls are blocked also undergo peroxidative reaction. These observations suggest that initial peroxidative attack occurs at the aromatic nitrogens of mitoxantrone. The possible relevance of these results to the anticancer action of mitoxantrone and the implications for suppression of lipid peroxidation in vivo are discussed.

Biotransformation↗
PubMed1988

Photosensitization by antitumor agents, 4. Anthrapyrazole-photosensitized formation of single strand-breaks in DNA.

Single-strand breaks can be introduced into PM2 closed-circular DNA upon illumination with blue light, in the presence of the anthrapyrazole antitumor agent, compound 1. Damage is observed already after 1 min of blue light illumination, and is significantly enhanced by the presence of electron donors such as NADH, ascorbic acid or Fe(III)/EDTA complex. The photosensitizing properties were not observed for anthrapyrazole analogues with one or more hydroxyl substituents in the chromophore of the drug. The inhibitory effects of sodium azide, methanol, mannitol, SOD, and catalase suggest an oxygen-dependent mechanism of strand-break production, probably involving hydroxyl radicals. However, a second mechanism involving drug molecules bound to the DNA is also indicated under anoxic conditions in the presence of NADH.

Anthracyclines↗
PubMed1988

Characteristics of the interaction of anthrapyrazole anticancer agents with deoxyribonucleic acids: structural requirements for DNA binding, intercalation, and photosensitization.

The binding constants for interaction of several novel anthra[1,9-cd]pyrazol-6(2H)-ones (anthrapyrazoles) with DNA have been determined by an ethidium displacement method. The apparent binding constants range from less than 2 X 10(6) to 2.7 X 10(8) M-1. The binding is influenced not only by the nature of the side chains but also by the number and position of hydroxyl groups on the chromophore. Unwinding angles, determined by a topoisomerase I assay, ranged from 0 degrees to 29.2 degrees. The deshydroxy compound 1 gave the highest unwinding angle, and both substitution of hydroxyl groups in the chromophore and alterations in the side chains decrease the unwinding angle, consistent with a decreased or partial intercalation. Representative anthrapyrazoles cause an increase in sonicated DNA viscosity as expected for intercalators. Spectrophotometric examination of the binding of compound 1 to DNAs of different base composition show that the apparent binding to GC is approximately 3 times that of AT, a result which was paralleled by thermal denaturation studies. Certain of the anthrapyrazoles exhibit marked visible light photosensitization and induce DNA single-strand breakage upon illumination in the presence of NADH. The essential structural requirement for photosensitizing properties with these agents was the absence of hydroxyl groups in the chromophore. By employing 32P-labeled DNA of known sequence, it was possible to examine the anthrapyrazole 1-photosensitized cleavage of DNA at the individual base level employing denaturing polyacrylamide sequencing gels. Smooth sequence neutral photosensitized cleavage of DNA is observed analogous to hydroxyl radical "footprinting."

Anthraquinones↗
PubMed1986

Horseradish peroxidase-catalyzed oxidation of mitoxantrone: spectrophotometric and electron paramagnetic resonance studies.

The clinical anticancer agent mitoxantrone is subject to irreversible oxidation by hydrogen peroxide catalyzed by horseradish peroxidase (HRP). The characteristic absorption changes that result provide evidence for an initial metabolite which is further oxidized enzymatically. The formation of the metabolite is accompanied by the concomitant generation of a free radical species detected by EPR spectroscopy. The intensity of the latter is dependent on the ratio of mitoxantrone to oxidant as well as on the pH of the medium. The metabolite in its oxidized form is a strong electrophile and can be reduced by biologically and physiologically relevant electron donors including ascorbic acid, L-cysteine and reduced glutathione. The results establish a new facile metabolic conversion of this clinically useful anticancer agent that may be relevant to its mode of action.

Electron Spin Resonance Spectroscopy↗
PubMed1986

Photosensitization by the trypanocidal agent crystal violet. Type I versus type II reactions.

The photoreduction of crystal violet to a carbon-centered radical was detected directly by electron spin resonance (ESR) spectroscopy under anaerobic conditions. The linewidth (0.9 G) of this radical was less broad than the linewidth (11.0 G) of the free radical obtained in Trypanosoma cruzi incubations. No crystal violet radical could be detected under aerobic conditions. However, crystal violet was found to convert oxygen to superoxide anion and hydrogen peroxide in the presence of light. This superoxide anion and hydrogen peroxide formation was greatly enhanced by reducing agents such as NAD(P)H. In addition, irradiation of crystal violet did not generate detectable amounts of singlet oxygen.

Animals↗
PubMed1986

Photosensitization by antitumor agents 3: spectroscopic evidence for superoxide and hydroxyl radical production by anthrapyrazole-sensitized oxidation of NADH.

EPR and spin-trapping techniques were employed to study the oxidation of the dihydronicotinamide adenine dinucleotide (NADH) photosensitized by an anthrapyrazole-antitumor agent. The superoxide radical was detected as a DMPO adduct upon illumination of the system with visible light. Photoinduced generation of hydroxyl radicals is demonstrated by detection of DMPO adducts of OH scavengers, such as ethyl alcohol, sodium formate, and sodium azide. The dependence of the production of these spin adducts on the presence of catalase implies the involvement of hydrogen peroxide in that process. The production of hydrogen peroxide is demonstrated independently during oxygen consumption measurements with the Clark electrode technique.

Anthraquinones↗
PubMed1986

Photosensitization by antitumor agents 2: anthrapyrazole-photosensitized oxidation of ascorbic acid and 3,4-dihydroxyphenylalanine.

A novel anthrapyrazole anticancer agent has been examined for photosensitizing properties. Illumination of the anthrapyrazole and ascorbic acid with blue light in aerated aqueous solutions causes SOD and catalase-sensitive oxygen consumption, indicating involvement of both superoxide radical and hydrogen peroxide in this process. Electron paramagnetic resonance showed that the ascorbyl radical is also produced during the photooxidation. When 3,4-dihydroxyphenylalanine (Dopa) is used as a substrate, production of hydrogen peroxide is evidenced by catalase-sensitive oxygen consumption. Generation of hydroxyl radicals during illumination of the drug and ascorbic acid (or Dopa) in the presence of catalytic amounts of the Fe(III)/EDTA complex is demonstrated using EPR and spin-trapping techniques.

Anthraquinones↗
PubMed1986

Design, biochemical pharmacology, electrochemistry and tumour biology of anti-tumour anthrapyrazoles.

Chromophore modification of the anthracenediones related to mitoxantrone in an attempt to provide agents with diminished or no cardiotoxicity has resulted in a novel class of DNA binders, the anthrapyrazoles. Selected biochemistry, electrochemistry and tumour biology were carried out for a series of compounds possessing the same upper and lower side chains but with varying A-ring hydroxylation patterns. The anthrapyrazoles bind strongly to DNA, are selective and potent inhibitors of DNA synthesis and cause the formation of single-strand breaks in DNA. They also induced far less (20-200-fold) superoxide dismutase-sensitive oxygen consumption than doxorubicin in the rat liver microsomal system, a property that may be indicative of reduced cardiotoxicity. This result is in accord with their polarographic properties in which the anthrapyrazoles show a much greater resistance to reduction (E'1/2 = -0.983- -1.085 V) relative to daunorubicin (E'1/2 = -0.625 V) and mitoxantrone (E'1/2 = -0.775 V). The anthrapyrazoles demonstrate high levels of activity against a broad range of murine tumours in vivo including the P388 leukaemia and mammary adenocarcinoma 16c lines detailed in this study.

Animals↗