tirapazamine has been researched along with 2-4-5-trihydroxypentanoic-acid-gamma-lactone* in 2 studies
2 other study(ies) available for tirapazamine and 2-4-5-trihydroxypentanoic-acid-gamma-lactone
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DNA strand damage product analysis provides evidence that the tumor cell-specific cytotoxin tirapazamine produces hydroxyl radical and acts as a surrogate for O(2).
The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ) is a clinically promising anticancer agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. It has long been known that, under hypoxic conditions, TPZ causes DNA strand damage that is initiated by the abstraction of hydrogen atoms from the deoxyribose phosphate backbone of duplex DNA, but exact chemical mechanisms underlying this process remain unclear. Here we describe detailed characterization of sugar-derived products arising from TPZ-mediated strand damage. We find that the action of TPZ on duplex DNA under hypoxic conditions generates 5-methylene-2-furanone (6), oligonucleotide 3'-phosphoglycolates (7), malondialdehyde equivalents (8 or 9), and furfural (10). These results provide evidence that TPZ-mediated strand damage arises via hydrogen atom abstraction from both the most hindered (C1') and least hindered (C4' and C5') positions of the deoxyribose sugars in the double helix. The products observed are identical to those produced by hydroxyl radical. Additional experiments were conducted to better understand the chemical pathways by which TPZ generates the observed DNA-damage products. Consistent with previous work showing that TPZ can substitute for molecular oxygen in DNA damage reactions, it is found that, under anaerobic conditions, reaction of TPZ with a discrete, photogenerated C1'-radical in a DNA 2'-oligodeoxynucleotide cleanly generates the 2-deoxyribonolactone lesion (5) that serves as the precursor to 5-methylene-2-furanone (6). Overall, the results provide insight regarding the chemical structure of the DNA lesions that confront cellular repair, transcription, and replication machinery following exposure to TPZ and offer new information relevant to the chemical mechanisms underlying TPZ-mediated strand cleavage. Topics: Antineoplastic Agents; Chromatography, High Pressure Liquid; Cytotoxins; DNA Damage; Furaldehyde; Hydrogen; Hydroxyl Radical; Malondialdehyde; Models, Chemical; Neoplasms; Oligonucleotides; Sugar Acids; Time Factors; Tirapazamine; Transcription, Genetic; Triazines | 2007 |
Reaction of the hypoxia-selective antitumor agent tirapazamine with a C1'-radical in single-stranded and double-stranded DNA: the drug and its metabolites can serve as surrogates for molecular oxygen in radical-mediated DNA damage reactions.
The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (1, tirapazamine; also known as SR4233, WIN 59075, and tirazone) is a clinically promising anticancer agent that selectively kills the oxygen-poor (hypoxic) cells found in tumors. When activated by one-electron enzymatic reduction, tirapazamine induces radical-mediated oxidative DNA strand cleavage. Using the ability to generate a single deoxyribose radical at a defined site in an oligonucleotide, we recently provided direct evidence that, in addition to initiating the formation of DNA radicals, tirapazamine can react with these radicals and convert them into base-labile lesions [Daniels et al. (1998) Chem. Res. Toxicol. 11, 1254-1257]. The rate constant for trapping of a C1'-radical in single-stranded DNA by tirapazamine was shown to be approximately 2 x 10(8) M(-1) s(-1), demonstrating that tirapazamine can substitute for molecular oxygen in radical-mediated DNA strand damage reactions. Because reactions of tirapazamine with DNA radicals may play an important role in its ability to damage DNA, we have further characterized the ability of the drug and its metabolites to convert a C1'-DNA radical into a base-labile lesion. We find that tirapazamine reacts with a C1'-radical in double-stranded DNA with a rate constant of 4.6 x 10(6) M(-1) s(-1). The mono-N-oxide (3) stemming from bioreductive metabolism of tirapazamine converts the C1'-radical to an alkaline-labile lesion more effectively than the parent drug. Compound 3 traps a C1'-radical in single-stranded DNA with a rate constant of 4.6 x 10(8) M(-1) s(-1) and in double-stranded DNA with a rate constant of 1.4 x 10(7) M(-)(1) s(-)(1). We have also examined the rate and mechanism of reactions between the C1'-radical and representatives from two known classes of "oxygen mimetic" agents: the nitroxyl radical 2,2,6, 6-tetramethylpiperidin-N-oxyl (4, TEMPO) and the nitroimidazole misonidazole (5). TEMPO traps the C1'-radical in single-stranded DNA (7.2 x 10(7) M(-1) s(-1)) approximately 3 times less effectively than tirapazamine, but 2 times as fast in double-stranded DNA (9.1 x 10(6) M(-1) s(-1)). Misonidazole traps the radical in single- (6. 9 x 10(8) M(-1) s(-1)) and double-stranded DNA (2.9 x 10(7) M(-1) s(-1)) with rate constants that are roughly comparable to those measured for the mono-N-oxide metabolite of tirapazamine. Finally, information regarding the chemical mechanism by which these compounds oxidize a monomeric C1'-nucleoside radical has bee Topics: Antineoplastic Agents; Antioxidants; Cell Hypoxia; Cyclic N-Oxides; DNA; DNA Damage; DNA, Single-Stranded; Free Radicals; Misonidazole; Reactive Oxygen Species; Sugar Acids; Tirapazamine; Triazines | 1999 |