A Molecular Mechanism of Mitomycin Action: Linking of Complementary Dna Strands

Iyer, V. N.; Szybalski, Waclaw

doi:10.1073/pnas.50.2.355

Cited by 464 publications

(195 citation statements)

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“…Mitomycin C acts as an alkylating agent and causes prophage induction by direct DNA damage (Iyer and Syzbalski, 1963) and activation of the recA repair system. As a result of this toxicity, a decrease in viral production is often observed in treated samples when prophage induction is not present.…”

Section: Discussionmentioning

confidence: 99%

Comparison of lysogeny (prophage induction) in heterotrophic bacterial and Synechococcus populations in the Gulf of Mexico and Mississippi river plume

et al. 2007

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Lysogeny has been documented as a fundamental process occurring in natural marine communities of heterotrophic and autotrophic bacteria. Prophage induction has been observed to be prevalent during conditions of low host abundance, but factors controlling the process are poorly understood. A research cruise was undertaken to the Gulf of Mexico during July 2005 to explore environmental factors associated with lysogeny. Ambient physical and microbial parameters were measured and prophage induction experiments were performed in contrasting oligotrophic Gulf and eutrophic Mississippi plume areas. Three of 11 prophage induction experiments in heterotrophic bacteria (27%) demonstrated significant induction in response to Mitomycin C. In contrast, there was significant Synechococcus cyanophage induction in seven of nine experiments (77.8%). A strong negative correlation was observed between lysogeny and log-transformed activity measurements for both heterotrophic and autotrophic populations (r ¼ À0.876, P ¼ 0.002 and r ¼ À0.815, P ¼ 0.025, respectively), indicating that bacterioplankton with low host growth favor lysogeny. Multivariate statistical analyses indicated that ambient level of viral abundance and productivity were inversely related to heterotrophic prophage induction and both factors combined were most predictive of lysogeny (q ¼ 0.899, P ¼ 0.001). For Synechococcus, low ambient cyanophage abundance was most predictive of lysogeny (q ¼ 0.862, P ¼ 0.005). Abundance and productivity of heterotrophic bacteria was strongly inversely correlated with salinity, while Synechococcus was not. This indicated that heterotrophic bacterial populations were well adapted to the river plume environments, thus providing a possible explanation for differences in prevalence of lysogeny observed between the two populations.

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Section: Discussionmentioning

confidence: 99%

Comparison of lysogeny (prophage induction) in heterotrophic bacterial and Synechococcus populations in the Gulf of Mexico and Mississippi river plume

et al. 2007

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“…S1; 6 ref. 21). ICLs represent a major threat to cell viability, insofar as they are highly effective in blocking replication and transcription forks (5).…”

Section: Introductionmentioning

confidence: 99%

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin

Casado

Rı́o

Marco³

et al. 2008

Molecular Cancer Therapeutics

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Trabectedin (Yondelis; ET-743) is a potent anticancer drug that binds to DNA by forming a covalent bond with a guanine in one strand and one or more hydrogen bonds with the opposite strand. Using a fluorescence-based melting assay, we show that one single trabectedin-DNA adduct increases the thermal stability of the double helix by >20°C. As deduced from the analysis of phosphorylated H2AX and Rad51 foci, we observed that clinically relevant doses of trabectedin induce the formation of DNA double-strand breaks in human cells and activate homologous recombination repair in a manner similar to that evoked by the DNA interstrand cross-linking agent mitomycin C (MMC). Because one important characteristic of this drug is its marked cytotoxicity on cells lacking a functional Fanconi anemia (FA) pathway, we compared the response of different subtypes of FA cells to MMC and trabectedin. Our data clearly show that human cells with mutations in FANCA, FANCC, FANCF, FANCG, or FANCD1 genes are highly sensitive to both MMC and trabectedin. However, in marked contrast to MMC, trabectedin does not induce any significant accumulation of FA cells in G 2 -M. The critical relevance of FA proteins in the response of human cells to trabectedin reported herein, together with observations showing the role of the FA pathway in cancer suppression, strongly suggest that screening for mutations in FA genes may facilitate the identification of tumors displaying enhanced sensitivity to this novel anticancer drug.

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“…Such a prediction was realized in studies with CHO cells transfected with a cDNA encoding rat NBR, in that nuclear localization of the enzyme resulted in greater cell kill and increased numbers of MC-DNA adducts over those occurring with overexpressed NBR localized predominantly in its normal mitochondrial and endoplasmic recticulum locations (29). Since NQO1, being a two-electron reducing system that directly generates MCH 2 (4,7,10,15,22,(31)(32)(33)(34)(35), is considered to be a more important bioactivator of MC than the one-electron activating system, NBR, we have measured the cytotoxicity of MC and the number of MC-DNA adducts formed from this agent in CHO cells overexpressing NQO1 activity in the cytosolic and nuclear compartments under aerobic and hypoxic conditions.…”

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confidence: 99%

Nuclear Overexpression of NAD(P)H:Quinone Oxidoreductase 1 in Chinese Hamster Ovary Cells Increases the Cytotoxicity of Mitomycin C under Aerobic and Hypoxic Conditions

Seow¹,

Penketh²,

Belcourt³

et al. 2004

Journal of Biological Chemistry

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The effects of the subcellular localization of overexpressed bioreductive enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) on the activity of the antineoplastic agent mitomycin C (MC) under aerobic and hypoxic conditions were examined. Chinese hamster ovary (CHO-K1/ dhfr ؊ ) cells were transfected with NQO1 cDNA to produce cells that overexpressed NQO1 activity in the nucleus (148-fold) or the cytosol (163-fold) over the constitutive level of the enzyme in parental cells. Subcellular localization of the enzyme was confirmed using antibody-assisted immunofluorescence. Nuclear localization of transfected NQO1 activity increased the cytotoxicity of MC over that produced by overexpression in the cytosol under both aerobic and hypoxic conditions, with greater cytotoxicity being produced under hypoxia. The greater cytotoxicity of nuclear localized NQO1 was not attributable to greater metabolic activation of MC but instead was the result of activation of the drug in close proximity to its target, nuclear DNA. A positive relationship existed between the degree of MC-induced cytotoxicity and the number of MC-DNA adducts produced. The findings indicate that activation of MC proximal to nuclear DNA by the nuclear localization of transfected NQO1 increases the cytotoxic effects of MC regardless of the degree of oxygenation and support the concept that the mechanism of action of MC involves alkylation of DNA.Mitomycin C (MC) 1 is a naturally occurring antibiotic that was isolated originally from the microorganism Streptomyces caspitosus (1). MC exhibits a broad spectrum of antitumor activity and is an important component in the combination chemotherapy of malignancies such as early stage head and neck cancer, early stage cervical cancer, and intravesicle therapy of superficial bladder cancer. Specific MC-DNA lesions associated with the action of MC consist of both monofunctional and bifunctional alkylations (2-9). Monoalkylations initially occur through the linkage of the C-1 position of MC to the amino function in the 2-position of guanine bases in DNA and may proceed to a DNA cross-link through the C-10 position of MC to an amino entity in the 2-position of an adjacent DNA guanine (6). Although monoalkylations are potentially cytotoxic, compelling evidence in both bacterial and mammalian systems implicates MC-induced cross-links as the primary event responsible for cell death (10 -12).A salient feature of the molecular mechanism of action of MC is that this agent exists as a prodrug, and both its DNA crosslinking and monoalkylating activities require the reduction of the quinone ring to a hydroquinone, which transforms MC into a highly reactive alkylating species (11). Enzymes known to activate MC to intermediates capable of alkylating DNA do so either by a one-or a two-electron reduction mechanism. Oneelectron reducing enzymes include NADPH:cytochrome P450 oxidoreductase (NPR; EC 1.6.2.4) (13-16); NADH:cytochrome b 5 oxidoreductase (NBR; EC 1.6.2.2) (17, 18); xanthine:oxygen oxidoreductase (EC 1.1.3.23) (16); nitric-oxide s...

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A Molecular Mechanism of Mitomycin Action: Linking of Complementary Dna Strands

Abstract: in preparation. 19 By "temperature-sensitive," we mean responding differently to temperature than growth rate. The use of the differential plot automatically normalizes to the growth rate.

Cited by 464 publications

References 20 publications

Comparison of lysogeny (prophage induction) in heterotrophic bacterial and Synechococcus populations in the Gulf of Mexico and Mississippi river plume

Comparison of lysogeny (prophage induction) in heterotrophic bacterial and Synechococcus populations in the Gulf of Mexico and Mississippi river plume

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin

Nuclear Overexpression of NAD(P)H:Quinone Oxidoreductase 1 in Chinese Hamster Ovary Cells Increases the Cytotoxicity of Mitomycin C under Aerobic and Hypoxic Conditions

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