The effects of pretreatment with nitrogen mustard n-oxide and strain-specific tumor tissue on the development of spontaneous mammary tumors.
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Animals↗
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Results for “MECHLORETHAMINE OXIDE”
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Xeroderma pigmentosum group E binding factor recognizes a broad spectrum of DNA damage.
Xeroderma pigmentosum complementation group E binding factor (XPE-BF) is a damaged DNA binding protein that is deficient in a subset of patients from complementation group E of xeroderma pigmentosum. The protein recognizes various forms of DNA damage including some cyclobutane pyrimidine dimers, 6-4 photoproducts, cis-diamminedichloroplatinum(II) adducts, and single-stranded DNA. We now show that it also recognizes damage induced by nitrogen mustard; N-methyl-N'-nitro-N-nitrosoguanidine, and depurination, but has no detectable affinity for DNA adducts generated by trans-diamminedichloroplatinum(II), 4-nitroquinoline-N-oxide, 8-methoxypsoralen, or enzymatically methylated cytosine and adenine. The failure to recognize 4-nitroquinoline-N-oxide and 8-methoxypsoralen adducts is consistent with previous reports that XPE cells carry out wild-type levels of repair synthesis after DNA damage by those drugs. These results demonstrate that XPE-BF is a versatile damage recognition protein, but suggest that other proteins must contribute to the recognition of DNA lesions for the human excision repair pathway.
4-Nitroquinoline-1-oxide↗
[On the N1 latency prolongation in guinea pigs treated with nitrogen mustard-N-oxide with special reference to narrow-band analysis].
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Animals↗
The mutagenic activity of 61 agents as determined by the micronucleus, Salmonella, and sperm abnormality assays.
A comparison of two rapid and inexpensive in vivo mammalian assays and the Ames Salmonella assay is presented for 61 agents; Acetylsalicylic acid; Acriflavine; Actinomycin D; 2(2-furyl)-3-(5-nitro-2-furyl)acrylamide (AF-2); Aflatoxin B1; 2-aminofluorene; Aminopterin; Aroclor 1254; Ascorbic acid; Azathioprine; Benzo(a)pyrene; 5-Bromo-2'-deoxyuridine; Busulphan, Butylated hydroxytoluene; Cadmium chloride; Caffeine; Calcium cyclamate; Chloral hydrate; Chloromycetin succinate; Codeine phosphate, Colchicine; Cycloheximide; Cyclophosphamide; DDT; 2,4-Diaminoanisole; Dibutylnitrosamine; 9, 10 Dimethyl-1,2-benzanthracene; 1,1-Dimethylhydrazine; Dimethylnitrosamine; Epinephrine; Ethyl methane sulphonate (EMS); 2-formylamino-4-(5-nitro-2-furyl)thiazole (FANFT); 2-(2-formylhydrazino)-4-(5-nitro-2-furyl)thiazole (FNT); Glucose, Griseofulvin; Hycanthone methane sulphonate; Hydroxyurea; 5-Iodo-2'-deoxyuridine; Lead acetate; Mechlorethamine; 3-Methylcholanthrene; Methyl mercury acetate; Methyl methane sulfonate (MMS); N-methyl-N-nitro-N'-nitrosoguanidine; Mitomycin C; Monosodium glutamate; 1-Naphthalamine; 2-Naphthalamine; Nitrofurazone; 4-Nitro-O-phenylene diamine; 4-Nitro-quinoline-1-oxide (4-NQO); Phenobarbitone; Procarbazine; Quinacrine dihydrochloride; Radiation (gamma-rays); Sodium chloride; Triethylene thiophosphoramide; Trimethyl phosphate; Tris(2-methyl-1-arizidinyl) phosphine oxide; Urethan; Vinblastine. The results support the concept of multiple assays for mutagenicity and show that some combinations of assays are superior to others.
Animals↗
Genetic damage by bifunctional agents in repair-active pre-meiotic stages of Drosophila males.
Most of our understanding of germline mutagenesis in Drosophila is based on the DNA repair-inactive, haploid post-meiotic stages. The diploid, repair-active pre-meiotic stages are more relevant to the situation encountered in somatic cells. DNA mono-adducts induced by agents like methyl methanesulphonate (MMS) and ethylene oxide (EO) are well repaired in the pre-meiotic cell stages, and these agents show therefore, no or considerable lower mutagenic activity in these stages. In contrast, in this study the two bifunctional nitrogen mustards chlorambucil (CAB) and mechlorethamine (MEC) show significantly elevated mutant frequencies of both post- and pre-meiotic germ cells. Results were similar for the X-chromosomal and the autosomal (2nd) recessive lethal (RL) test. CAB and MEC were also active in stem cells, but in comparison with post-stem cell stages they seem to be better protected. The germ cell specific response in post- and pre-meiotic cell stages was for both nitrogen mustards comparable to mutagenic activity patterns observed in the specific locus test in the mouse. It was reported that for diepoxybutane (DEB), another cross-linking agent, the ratio of the RL frequency for the 2nd- and the X-chromosome was increased from 2.1 for post-meiotic stages to 9.5 for pre-meiotic stages. In own experiments aiming to confirm this observation, a high ratio was indeed found. The induction of large deletions by DEB could be the reason for this difference, since such lesions might include both a sex-linked lethal and a vital gene required for the development of spermatocytes into mature sperm. Similar differences were expected for CAB and MEC since they are also inducers of large deletions. But unexpectedly, no differences in 2nd/X RL ratio between post- and pre-meiotic cell stages were found for the nitrogen mustards. Possible causes such as distinct proportions of multi-locus deletions (MLDs), mitotic recombination and the formation of persistent lesions, are discussed.
Animals↗
Reductive activation of N-oxides to cause DNA strand breakage in cell lines in vitro.
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Aerobiosis↗
Comparison of mutagenicity and inducibility of DNA single-strand breaks and chromosome aberrations in cultured mouse cells by potent mutagens.
Induction of 8-azaguanine-resistant mutation, DNA single-strand breaks, and chromosome aberrations by treatment with ethyl methanesulfonate (EMS), N-methyl-N'nitro-N-nitrosoguanidine (MNNG), nitrogen mustard hydrochloride (HN2), or 4-nitroquinoline 1-oxide (4-NQO) was compared under similar experimental conditions using cultured FM3A cells from a C3H mouse mammary carcinoma. All the chemicals induced 8-azaguanine-resistant mutations and chromosome aberrations in a dose-dependent manner; a good correlation between the two activities was demonstrated. An alkaline sucrose gradient method demonstrated that DNA single-strand breaks were induced only in a high dose range by 1- and 24-hr treatment with the chemicals. One exception was that a 1-hr treatment with HN2 produced an anomalous sedimentation pattern. These data suggest that caution is necessary for the interpretation of results obtained by the alkaline sucrose gradient analysis, and that examination of mutagenicity and chromosome aberrations is more feasible as screening procedures for potential mutagens than analysis of DNA single-strand breaks.
4-Nitroquinoline-1-oxide↗
A novel role for DNA photolyase: binding to DNA damaged by drugs is associated with enhanced cytotoxicity in Saccharomyces cerevisiae.
DNA photolyase binds to and repairs cyclobutane pyrimidine dimers induced by UV radiation. Here we demonstrate that in the yeast Saccharomyces cerevisiae, photolyase also binds to DNA damaged by the anticancer drugs cis-diamminedichloroplatinum (cis-DDP) and nitrogen mustard (HN2) and by the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Surprisingly, mutations in photolyase were associated with resistance of yeast cells to cis-DDP, MNNG, 4-nitroquinoline oxide (4NQO), and HN2. Transformation of yeast photolyase mutants with the photolyase gene increased sensitivity to these agents. Thus, while the binding of photolyase to DNA damaged by UV radiation aids survival of the cell, binding to DNA damaged by other agents may interfere with cell survival, perhaps by making the lesions inaccessible to the nucleotide excision repair system.
4-Nitroquinoline-1-oxide↗
Repair of DNA alkylation damage.
Alkylation damage of DNA is one of the major types of insults which cells must repair to remain viable. One way alkylation damaged ring nitrogens are repaired is via the Base Excision Repair (BER) pathway. Examination of mutants in both BER and Nucleotide Excision Repair show that there is actually an overlap of repair by these two pathways for the removal of cytotoxic lesions in Escherichia coli. The enzymes removing damaged bases in the first step in the BER pathway are DNA glycosylases. The coding sequences for a number of methylpurine-DNA glycosylases (MPG proteins) were cloned, and a comparison of the amino-acid sequences shows that there are some similarities between these proteins, but nonetheless, compared to other DNA glycosylases, MPG proteins are more divergent. MPG proteins have been purified to homogeneity and used to identify their substrates ranging from methylating agents to deamination products to oxidatively damaged bases. The ligation-mediated polymerase chain reaction has been used to study the formation of alkylation damage, and its repair in mammalian cells. We have studied DNA damage in the PGK1 gene for a series of DNA alkylating agents including N-methyl-N'-nitro-N-nitrosoguanidine, Mechlorethamine, and Chlorambucil and shown that the damage observed in the PGK1 (phosphoglycerate kinase 1) gene depends on the alkylating agent used. This report reviews the literature on the MPG proteins, DNA glycosylases removing 3-methyladenine, and the use of these enzymes to detect DNA damage at the nucleotide level.
Alkylation↗
Phenotypes of Drosophila homologs of human XPF and XPG to chemically-induced DNA modifications.
DmXPF (mei9) and DmXPG (mus201) mutants are Drosophila homologs of the mammalian XPF and XPG genes, respectively. For Drosophila germ cells, causal correlations exist between the magnitude of a potentiating effect of a deficiency in these functions, measured as the M(NER-)/M(NER+) mutability ratio, and the type of DNA modification. M(NER-)/M(NER+) mutability ratios may vary with time interval between DNA adduct formation and repair, mutagen dose and depend also on the genetic endpoint measured. For forward mutations, there is no indication of any differential response of DmXPF compared to DmXPG. Subtle features appeared from a class-by-class comparison: (i) Methylating agents always produce higher M(NER-)/M(NER+) ratios than their ethylating analogs; (ii) M(NER-)/M(NER+) mutability ratios are significantly enhanced for cross-linking N-mustards, aziridine and di-epoxide compounds, but not for cross-linking nitrosoureas. The low hypermutability effects with bifunctional nitrogen mustards, aziridine and epoxide compounds are attributed to unrepaired mono-alkyl adducts; (iii) The efficient repair of mono-alkyl-adducts at ring nitrogens in wild-type germ cells is evident from the absence of a dose-response relationship for ethylene oxide, propylene imine and methyl methanesulfonate (MMS). These chemicals become powerful germline mutagens when the NER system is disrupted. Systematic studies of the type performed on germ cells are not available for somatic cells of Drosophila. The sparse data available show large differences in the response of germ cells and somatic cells. The bifunctional agent mechlorethamine (MEC) but not the monofunctional MMS or 2-chloroethylamine cause in NER(-) XXfemale symbol the highest potentiating effect on mitotic recombination. The causes of the discrepancy between the extraordinarily high activity of MEC in mus201 somatic cells and its low potentiating effect in germ cells is unknown at present.
Animals↗
A glutathione depletion selectively imposed on mu glutathione S-transferase overproducing cells increases nitrogen mustard toxicity.
Glutathione (GSH) contributes to the detoxification of anticancer drugs through the operation of specific glutathione S-transferases (GST) and innate, or acquired, overexpression of this enzyme family has been frequently observed in tumor cell lines. In the GMA32 line of Chinese hamster fibroblasts, we showed that GSH starvation produced by exposing cells to buthionine sulfoximine (BSO) increased the toxicity of chlorambucil and melphalan, but not that of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), cisplatine and doxorubicin. This indicates that efficient mechanisms of detoxification using GSH operate for chlorambucil and melphalan, but not for the other drugs in these cells. We then showed that GSH depletion could be selectively and transiently induced in the mu GST overexpressing cell line derived from GMA32, HC474, by exposing cells to substrates specific to the overexpressed isozyme. Exposing cells to such a substrate, trans-stilbene oxide, does not alter the sensibility of GMA32 cells to melphalan and chlorambucil, but increases that of HC474 cells to these drugs, to an extent comparable to that obtained with BSO. This observation highlights the possibility of exploiting GST overexpression, a frequent feature of tumor cells, to selectively sensitize these undesirable cells to anticancer drugs.
Animals↗
Studies on cyclophosphamide metabolites and their related compounds. 2. Preparation of an active species of cyclophosphamide and related compounds.
A synthetic study was made on the active metabolite of cyclophosphamide. Ozonolysis of O-(3 butenyl)-N,N-bis(2-chloroethyl)phosphorodiamidate, prepared by reaction of POC13 with 3-buten-1-ol followed by treatment with N,N-bis(2-chloroethyl)amine (nor mustard) and NH3, afforded 2-[bis(2-chloroethyl)amino]-4-hydroperoxytetrahydro-2H-1, 3,2-oxazaphosphorine 2-oxide (4-hydroperoxycyclophosphamide). Deoxygenation of 4-hydroperoxycyclophosphamide by triphenylphosphine yielded 4-hydroxycyclophosphamide in a pure crystalline state. These products exhibited high cytostatic activity in both in vitro and in vivo experiments. The results give confirmatory evidence for the hypothesis that C4-hydroxylation on the 1,3,2-oxazaphosphorinane ring of cyclophosphamide is necessary for its activation.
Acetals↗
[Four cases of Hodgkin's disease treated with MOPP/ABV hybrid regimen using nitrogen mustard-N-oxide hydrochloride].
Four patients with fresh Hodgkin's disease were treated with MOPP/ABV hybrid regimen using nitrogen mustard-N-oxide hydrochloride (NH2-O). All patients responded well to this therapy and achieved complete remission. Toxicity was minimum except for an older patient. He was 70 years old and developed arrhythmia after MOPP therapy but recovered without any treatment. The continuation of therapy was possible by dose reduction in this case. We conclude MOPP/ABV regimen using NH2-O is valuable for the treatment of Hodgkin's disease.
Adult↗
Assays for phosphotriester formation in the reaction of bacteriophage R17 with a group of alkylating agents.
The interaction of bacteriophage R17 with 8 compounds has been studied, comparing the contribution of degradation of ribonucleic acid to the total toxicity. Breaks in the RNA chain result from the hydrolysis of phosphotriesters and thus are a measure of the extent of O-alkylation and of the SN1-type mechanism of the reaction. With many alkylating agents mutagenicity and carcinogenicity increase with increasing SN1 character of the reaction. In experiments with methyl methanesulphonate no evidence of degradation was observed at up to 19 times the mean lethal dose (620 methylations/RNA molecule). Breaks in the RNA chain accounted for 1 in 10 of the lethal lesions with beta-hydroxyethyl methanesulphonate, 1 in 60 with bis-(2-chloromethyl)methylamine (nitrogen mustard, HN2), less than 1 in 125 with 2,2-dichlorvinyl dimethyl phosphate (dichlorovos, DDVP), and 1 in 200 with propylene oxide. The hydrolysis rate of bis-(2 chloroethyl)ether was too slow for any reaction to be detected. In reactions with the carcinogen bis-(2-chloromethyl)ether the toxicity observed could be accounted for by the formaldehyde produced on hydrolysis. Cross-linking of the bacteriophage components by formaldehyde reduced the survival range over which the physical state of the RNA could be studied. No evidence of RNA degradation was observed. Reaction of the formaldehyde led to a progressive loss of biological activity over 24 h, a loss which was partially reversed by dialysis.
Alkylating Agents↗
[Role of glutathione antiperoxide system in the mechanism of cytotoxic action of embichin].
Dynamics of changes in the peroxide level, contents of reduced and oxidized glutathione, activity of glutathione peroxidase and glutathione reductase in different organs of a rat under the influence of a single injection of embiquine in the dose of 1/2 DL50 was studied. Alkylating antitumor preparation was shown to cause the decrease of glutathione peroxidase and glutathione reductase activity. Activation glutathione antiperoxide system decreased cytotoxic effects of embiquine by prevention of lipoperoxid accumulation in the liver in the nearest periods of investigation after injection of the preparation, and in the kidney and spleen--during the whole period of investigation.
Animals↗
Hypoxia-selective antitumor agents. 16. Nitroarylmethyl quaternary salts as bioreductive prodrugs of the alkylating agent mechlorethamine.
Nitrobenzyl quaternary salts of nitrogen mustards have been previously reported as hypoxia-selective cytotoxins. In this paper we describe the synthesis and evaluation of a series of heterocyclic analogues, including pyrrole, imidazole, thiophene, and pyrazole examples, chosen to cover a range of one-electron reduction potentials (from -277 to -511 mV) and substitution patterns. All quaternary salt compounds were less toxic in vitro than mechlorethamine, and all were more toxic under hypoxic than aerobic conditions, although the differentials were highly variable within the series. The most promising analogue, imidazole 2, demonstrated DNA cross-linking selectively in hypoxic RIF-1 cells, and was active in vivo in combination with radiation or cisplatin. However, 2 also produced unpredictable toxicity in vivo, suggestive of nonspecific nitrogen mustard release, and this has restricted further development of these compounds as hypoxia-selective cytotoxins.
Animals↗
N1 latency prolongation in the guinea pig cochlea treated with nitrogen mustard-N-oxide studied by narrow band analysis.
The effect of nitrogen mustard-N-oxide (NMO) upon the click and tone burst-evoked N1 latency was examined in 14 albino guinea pigs. In all animals except one, the pseudothresholds of action potentials were elevated, especially in the high tone area. In addition to the amplitude reduction, the N1 latency was prolonged in 12 animals. The narrow band analysis of N1 revealed that the latency was equally prolonged in all frequency areas, although the amount of the amplitude reduction was much larger in the high frequency area. It was concluded that the prolongation of the N1 latency in NMO-treated animals was due to dysfunction of outer hair cells along the entire cochlear partition.
Acoustic Stimulation↗
Lack of chemically induced mutation in repair-deficient mutants of yeast.
Two genes, rad6 and rad9, that confer radiation sensitivity in the yeast Saccharomyces cerevisiae also greatly reduce the frequency of chemically-induced reversions of a tester mutant cyc1-131, which is a chain initiation mutant in the structural gene determining iso-1-cytochrome c. Mutations induced by ethyl methanesulfonate (EMS), diethyl sulfate (DES), methyl methanesulfonate (MMS), dimethyl sulfate (DMS), nitroquinoline oxide (NQO), nitrosoguanidine (NTG), nitrogen mustard (HN2), beta-propiolactone, and tritiated uridine, as well as mutations induced by ultraviolet light (UV) and ionizing radiation were greatly diminished in strains homozygous for either the rad6 or rad9 gene. Nitrous acid and nitrosoimidazolidone (NIL), on the other hand, were highly mutagenic in these repair-deficient mutants, and at low doses, these mutagens acted with about the same efficiency as in the normal RAD strain. At high doses of either nitrous acid or NIL, however, reversion frequencies were significantly reduced in the two rad mutants compared to normal strains. Although both rad mutants are immutable to about the same extent, the rad9 strains tend to be less sensitive to the lethal effect of chemical mutagens than rad6 strains. It is concluded that yeast requires a functional repair system for mutation induction by chemical agents.
Cytochrome c Group↗