A Critical Appraisal of the Evolution of<i>N</i>-Nitrosoureas as Anticancer Drugs

Gnewuch, C. T.; Sosnovsky, George

doi:10.1021/cr941192h

Cited by 168 publications

(73 citation statements)

References 580 publications

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“…offer an explanation as to why it is O-alkylation or N-alkylation of DNA that occurs (Gnewuch and Sosnovsky, 1997). Thus, it is possible, as previously described for busulfan, that nitrososulfamide analogs, especially compound 4, do not produce enough O 6 lesions to have a significant impact on the sensitivity of melanoma cells (Westerhof et al, 2001).…”

Section: Fotemustine Analogs Activity According To Mgmt Expressionmentioning

confidence: 83%

“…More than 14 different types of DNA alkylations were described, leading essentially to the formation of N 1 -, N 3 -, and N 7 -alkyladenines or to N 3 -and N 7 -O 6 -alkylguanines (Gnewuch and Sosnovsky, 1997). However, O 6 -alkylguanine is considered to be the most mutagenic and cytotoxic lesion.…”

Section: Discussionmentioning

confidence: 99%

“…DNA damage and the resulting cytotoxicity of CENUs is based on their ability to form chloroethyl adducts on nucleic acids. Despite the fact that more than 14 DNA alkylation sites have been described, O 6 -chloroethylation of guanine is considered to be the most cytotoxic lesion through the secondary formation of a DNA-interstrand cross-link (Gnewuch and Sosnovsky, 1997).…”

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confidence: 99%

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Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Passagne¹,

Evrard²,

Winum³

et al. 2003

J Pharmacol Exp Ther

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Fotemustine is a third generation chloroethylnitrosourea that has demonstrated significant antitumoral effects in malignant melanoma. However, its use is somewhat limited by its toxic side effects and chemoresistance caused by direct repair of O 6 -alkyl groups by the enzyme O 6 -methylguanine DNA-methyltransferase (MGMT). The aim of this work was to determine to what extent the expression of MGMT influences cytotoxicity, DNA damage, and apoptosis induced by new nitrososulfamide analogs of fotemustine (compounds 4 and 8), which have previously demonstrated interesting antiproliferative properties. We carried out complementary strategies that consisted of MGMT cDNA transfection in CAL77 MerϪ melanoma cells and of MGMT inhibition with O 6 -benzylguanine (BG) in A375 Merϩ melanoma cells. MGMT-transfected cells were 7 to 9 times less sensitive to fotemustine than parent cells, whereas no difference between the transfected and parent cells was observed for nitrososulfamide analogs. The cytotoxicity of these analogs vis à vis a MGMT-proficient A375 melanoma cell line was approximately 3 times greater than that of fotemustine. Coincubation of these cells with O 6 -benzylguanine significantly increased the cytotoxicity of fotemustine and compound 8, whereas BG had little effect on the cytotoxicity of compound 4. Furthermore, DNA fragmentation determined by a comet assay was greater with nitrososulfamide analogs than with fotemustine. O 6 -benzylguanine increased DNA fragmentation for fotemustine and compound 8, but not for compound 4, which induced comets with a typical apoptotic appearance. The ability of this compound to induce apoptosis in the absence of BG was confirmed by a specific enzyme-linked immunosorbent assay apoptotic assay using a single-stranded DNA monoclonal antibody.

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Section: Fotemustine Analogs Activity According To Mgmt Expressionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Passagne¹,

Evrard²,

Winum³

et al. 2003

J Pharmacol Exp Ther

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“…Reduced toxicity and increased antineoplastic properties were achieved when nitroxyl (aminoxyl) groups, such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TMPO), were introduced in chemical structure of certain antitumour drugs [9] [10]. Following this finding, we have synthesised a number of spin-labelled analogues of the anticancer drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU).…”

Section: Introductionmentioning

confidence: 99%

Spin-Labelled 1-Ethyl-1-Nitrosourea Prevents Doxorubicin and Bleomycin-Induced Oxidative Stress in Lungs, Hearts and Kidneys of Tumour-Bearing Mice

Gadjeva¹,

Nikolova²,

Grigorov³

et al. 2014

ABC

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This study was carried out to determine the possible protective effect of 1-ethyl-3-[4-(2, 2, 6, 6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (SLENU), recently synthesised in our laboratory on doxorubicin and bleomycin-induced oxidative toxicity in C57 black tumour-bearing mice. Specifically, alterations in some biomarkers of oxidative stress, such as lipid peroxidation products measured as malondialdehyde (MDA) levels and activities of the antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), were studied in lung, heart and kidney homogenates isolated from C57 black tumor-bearing mice after i.p. treatment with solutions of DOX (60 mg/kg) and BLM (60 mg/kg). The same biomarkers were also measured after i.p. pretreatment of mice with SLENU (100 mg/kg). After treatment with doxorubicin, heart and kidney homogenates of mice had significantly higher productions of lipid peroxidation compared to lung homogenates. It was accompanied by increased activity of the antioxidant defence enzyme superoxide dismutase and decreased activity of catalase. Bleomycin-induced oxidative stress was confirmed by significantly higher production of lipid peroxidation in lungs compared to heart homogenates, elevation of the antioxidant activity of superoxide dismutase and decreased activity of catalase enzymes. After pretreatment of the mice with SLENU, the levels of all studied oxidative stress biomarkers were significantly improved

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“…However, numerous compounds possessing significant biological activity have been found among them. Nitrosoureas exhibiting anticarcinogenic activity [2] have been obtained by using ureas as skeletal fragments (Scheme 1). Antiarrhythmic properties are among a range of biological activities characteristic of ureas 1a, obtained by reaction of the corresponding amines with alkyl-and arylisocyanates [3].…”

Section: Introductionmentioning

confidence: 99%

Azabrendanes V. Synthesis and reactions of stereoisomeric exo- and endo-5-aminomethylbicyclo[2.2.1]hept-2-ene-based ureas

Kas’yan

Kas’yan²,

Tarabara

et al. 2008

Open Chemistry

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A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

Cited by 168 publications

References 580 publications

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Spin-Labelled 1-Ethyl-1-Nitrosourea Prevents Doxorubicin and Bleomycin-Induced Oxidative Stress in Lungs, Hearts and Kidneys of Tumour-Bearing Mice

Azabrendanes V. Synthesis and reactions of stereoisomeric exo- and endo-5-aminomethylbicyclo[2.2.1]hept-2-ene-based ureas

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A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

Cited by 168 publications

References 580 publications

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O6-Methylguanine DNA-Methyltransferase Expression

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O6-Methylguanine DNA-Methyltransferase Expression

Spin-Labelled 1-Ethyl-1-Nitrosourea Prevents Doxorubicin and Bleomycin-Induced Oxidative Stress in Lungs, Hearts and Kidneys of Tumour-Bearing Mice

Azabrendanes V. Synthesis and reactions of stereoisomeric exo- and endo-5-aminomethylbicyclo[2.2.1]hept-2-ene-based ureas

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Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression

Cytotoxicity, DNA Damage, and Apoptosis Induced by New Fotemustine Analogs on Human Melanoma Cells in Relation to O⁶-Methylguanine DNA-Methyltransferase Expression