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PubMed1992

The in vivo and in vitro genotoxicity of aromatic amines in relationship to the genotoxicity of benzidine.

Benzidine and 12 related aromatic amines have been studied for the effects of substituent groups and pi orbital conjugation on their genotoxicity as measured by their mutagenicity in vitro with Salmonella and by chromosomal aberrations (CA) in vivo in the bone-marrow cells of mice. The in vitro studies indicated increases in mutagenicity with increases in the electron withdrawing ability of para' substituents. Mutagenicity also increases with increased conjugation as shown by the degree of planarity of the biphenyl compounds and by comparing the mutagenicities of biphenyl amines to stilbenes as well as to ethylene bridged diphenyl compounds. The relative in vitro mutagenicity results were not predictive of relative in vivo CA results. The 3 most genotoxic compounds in vivo were the conjugated amines without substituents in the para' position. The CA values for 4-aminostilbene were exceptionally high. These in vivo results indicate increased genotoxicity for benzidine analogs without substitution in the para' position.

Aminobiphenyl Compounds↗

PubMedDate not supplied

Quantifying genotoxicity and non-genotoxicity.

Since the ability to induce genotoxicity is often equated with the potential for initiating the carcinogenic process, a method for quantitating genotoxicity would provide a useful measure for this potential. It is demonstrated herein that CPBS, the Carcinogenicity Prediction and Battery Selection method, provides a useful quantitative measure of genotoxicity as well as allowing for the detailed evaluation of the performance of batteries of short-term tests in order to select those predictive of carcinogenic potential.

Animals↗

PubMed1992

D and C Red No. 9: genotoxic or non-genotoxic carcinogen?

The azo-compound, D and C Red No. 9 was assayed for genotoxicity in vivo using the rat micronucleus test and the rat ex vivo liver UDS assay. Uniformly negative results were obtained in both assays, even though large oral doses were used (2 g/kg). These results suggest that the tumorigenic effects of this compound in rats are mediated through non-genotoxic rather than a genotoxic mechanism. Further experiments using additional end-points such as 32P-post-labelling would further substantiate this conclusion.

Administration, Oral↗

PubMed2005

Genotoxicity and anti-genotoxicity of some traditional medicinal herbs.

Six herbal infusions used worldwide (Matricaria chamomilla, Tilia cordata, Mentha piperita, Mentha pulegium, Uncaria tomentosa and Valeriana officinalis) were assayed for anti-genotoxicity using the Somatic Mutation And Recombination Test (SMART) in Drosophila melanogaster. All these infusions are traditionally used for various medical purposes, including anti-inflammatory processes. Hydrogen peroxide was used as an oxidative genotoxicant to test the anti-genotoxic potency of the medicinal infusions. None of these infusions showed a significant genotoxicity, quite the reverse they were able to behave as desmutagens, detoxifying the mutagen hydrogen peroxide. The phenolic content of such herbal infusions is argued to be the possible scavenger of reactive oxygen radicals produced by the hydrogen peroxide.

Animals↗

PubMed2002

Genotoxic and anti-genotoxic properties of Calendula officinalis extracts in rat liver cell cultures treated with diethylnitrosamine.

Calendula officinalis flower extracts are used to cure inflammatory and infectious diseases, for wound healing and even cancer with partial objective evidence of its therapeutic properties or toxic effects, many of which can be attributed to the presence of flavonols. We studied whether C. officinalis extracts induce unscheduled DNA synthesis (UDS) in rat liver cell cultures, and if these extracts can reverse diethylnitrosamine (DEN)-induced UDS. Four different flower extracts were prepared: aqueous (AE), aqueous-ethanol (AEE), ethanol (EE) and chloroform (CE). AE and AEE were evaporated to 6.72 and 4.54 mg of solid material per ml, respectively and final ethanol concentration in AEE was 0.8%. EE and CE were dried and resuspended in dimethyl sulfoxide (DMSO) to 19.2 and 10 mg of solid material per ml. Ethanol residue of EE was 0.34%. In the UDS assay in liver cell cultures, DEN at 1.25 microM produced a maximal increase of 40% (3)H-thymidine ((3)HdTT) incorporation, and both, AE and AEE showed complete reversion of the DEN effect at around 50 ng/ml and between 0.4 to 16 ng/ml, respectively. In the absence of DEN, these two polar extracts induced UDS at concentrations of 25 microg for AE and 3.7 microg/ml for AEE to 100 microg/ml in rat liver cell cultures. Concentrations producing genotoxic damage were three orders of magnitude above concentrations that conferred total protection against the DEN effect. Thus, at the lower end, ng/ml concentrations of the two polar extracts AE and AEE conferred total protection against the DEN effect and at the higher end, g/ml concentrations produced genotoxic effects. These results justify the study of C. officinalis flower extracts to obtain products with biological activity and to define their genotoxic or chemopreventive properties.

Animals↗

PubMed1993

Genotoxicity studies in semiconductor industry. 1. In vitro mutagenicity and genotoxicity studies of waste samples resulting from plasma etching.

Solid waste samples taken from the etching reactor, the turbo pump, and the waste air system of a plasma etching technology line in semiconductor production were studied as to their genotoxic properties in a bacterial repair test, in the Ames/Salmonella microsome assay, in the SOS chromotest, in primary mouse hepatocytes, and in Chinese hamster V79 cell cultures. All three waste samples were found to be active by inducing of unscheduled DNA-synthesis in mouse hepatocytes in vitro. In the bacterial rec-type repair test with Proteus mirabilis, waste samples taken from the turbo pump and the vacuum pipe system were not genotoxic. The waste sample taken from the chlorine-mediated plasma reactor was clearly positive in the bacterial repair assay and in the SOS chromotest wit Escherichia coli. Mutagenic activity was demonstrated for all samples in the presence and absence of S9 mix made from mouse liver homogenate. Again, highest mutagenic activity was recorded for the waste sample taken from the plasma reactor, while samples collected from the turbo pump and from the waste air system before dilution and liberation of the air were less mutagenic. For all samples chromosomal damage in V79 cells was not detected, indicating absence of clastogenic activity in vitro. Altogether, these results indicate generation of genotoxic and mutagenic products as a consequence of chlorine-mediated plasma etching in the microelectronics industry and the presence of genotoxins even in places distant from the plasma reactor. Occupational exposure can be expected both from the precipitated wastes and from chemicals reaching the environment with the air stream.

Animals↗

PubMed1989

Genotoxicity of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): formation of 2-hydroxamino-PhIP, a directly acting genotoxic metabolite.

Hepatocytes isolated from Aroclor 1254 (PCB) pretreated rats metabolized 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to a reactive metabolite that induced DNA damage measured by alkaline elution or as increased unscheduled DNA synthesis. PhIP induced mutations in Salmonella typhimurium TA98 and DNA strand breaks and sister chromatid exchange(s) in Chinese hamster V79 cells co-incubated with PCB-hepatocytes. No, or only minor genotoxic, effects were observed when hepatocytes from non-induced rats were used. The bacterial mutagenicity could be inhibited by alpha-naphthoflavone, indicating a role of P-450 in the activation of PhIP. At least eight different metabolites could be separated on HPLC after PhIP had been incubated with PCB-hepatocytes. All of the directly acting mutagenicity towards S.typhimurium TA98 co-eluted with one of the metabolites. The identity of this metabolite was concluded to be 2-hydroxamino-PhIP based on the following evidence: (i) it reduced ferric ion to ferrous ion as hydroxylamines do, (ii) it had an identical UV spectrum and chromatographic properties as a species formed upon reduction of 2-nitro-PhIP by NADPH P-450 reductase. This product displayed a major peak at m/z 241 during thermospray mass spectrometry in the positive-ion mode as would be expected from 2-hydroxamino-PhIP. 2-Hydroxamino-PhIP was directly genotoxic both to TA98 and V79 cells. The genotoxic activity of the medium after removing the hepatocytes remained stable for several hours. Compared to 2-amino-3,4-dimethylimidazo[4,5-f]quinolone (MeIQ), PhIP caused a much larger increase in DNA damage in V79 cells (with hepatocyte activation), whereas MeIQ was more potent with respect to DNA damage induced in hepatocytes and bacteria.

Animals↗

PubMed1998

A new approach to identifying genotoxic carcinogens: p53 induction as an indicator of genotoxic damage.

The tumor suppressor gene p53 encodes a nuclear phosphoprotein which is critical for cell cycle control and prevention of uncontrolled cell proliferation that can lead to cancer. Previous studies have shown that cells respond to DNA damage by increasing their levels of p53, which then acts to prevent replication of damaged DNA. This study examined the effects on p53 protein levels of several different categories of chemical carcinogens. N-Methyl-N'-nitro-nitrosoguanidine and N-ethyl-N-nitrosourea, two direct-acting genotoxic (DNA-reactive) carcinogens, caused p53 induction as early as 2 h following treatment, with peak increases within 4-12 h. Aflatoxin B1 and 2-acetylaminofluorene, indirect-acting genotoxic carcinogens, caused a later induction of p53, with the peak increase appearing between 16 and 24 h following treatment. These observations demonstrate a correlation between p53 induction pattern and DNA damaging mechanism of genotoxins. Phenol, diethylstilbestrol and ethylacrylate also induced increases in cellular p53. The half-life of p53 protein was increased in cells treated with genotoxic agents. On the other hand, the epigenetic (non-DNA-reactive) carcinogens azathioprine and saccharin, as well as two substances generally considered to be non-carcinogens, dimethylsulfoxide and benzethonium chloride, had no effect on p53 protein levels of treated cells. Measurement of the cytotoxic effects of each of these chemicals led to the conclusion that p53 protein induction is not a general, non-specific consequence of the cytotoxic effect of these genotoxins. These results suggest that measurement of p53 protein induction may be an effective tool to identify environmental genotoxins.

Acrylates↗

PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. Cyclosporine A: review of genotoxicity and potential for adverse human reproductive and developmental effects. Report of a Working Group on the genotoxicity of cyclosporine A, August 18, 1993.

Cyclosporine is an important therapeutic agent for transplant recipients and for a growing number of autoimmune diseases. Experimental animal and human data has indicated that cyclosporine is unlikely to be genotoxic. In contrast, azathioprine, an agent often given with cyclosporine, is considered to be genotoxic making the assessment of the independent effects of cyclosporine difficult. Cyclosporine does appear to be related to the development of tumors, primarily lymphomas, in animals and humans, but the basis of its potential carcinogenicity is not completely understood. In terms of reproductive and developmental toxicity, cyclosporine produces some adverse effects in both experimental animals and humans. In animals, the effects are seen at high doses sufficient to cause maternal toxicity. In humans, outcomes such as growth retardation have been noted, but the confounding effects of renal toxicity and resultant pregnancy complications cloud the interpretation. An increase in congenital anomalies and genetic disease have not been found reported in human studies that are limited in sample size. Given that the present data indicate the lack of genotoxicity, a mutation epidemiology study of cyclosporine is not recommended. As indicated above, such a study is probably impractical for many genetic endpoints of interest. However, well-conducted, large multicenter studies of transplant patients and their offspring would allow for routine monitoring of an increased risk for some reproductive and developmental (possibly non-genetic) endpoints that are of public health importance.

Animals↗

PubMed1991

Lack of genotoxicity of cross-linked acrylate polymers in four short-term genotoxicity assays.

Three cross-linked polyacrylate polymers containing either methylenebis-acrylamide (MBA), trimethylolpropane triacrylate (TMPTA), or triallylamine (TAA) cross-linkers were tested for genotoxicity with the Salmonella mammalian microsome assay, the L5178Y mouse lymphoma TK +/- assay, the unscheduled DNA synthesis assay in primary cultures of rat hepatocytes, and the in vivo bone marrow cytogenetic assay. The results indicate that none of the three polymers was genotoxic in these assays.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1993

Perspective on the usefulness of the mouse lymphoma assay as an indicator of a genotoxic carcinogen: ten compounds which are positive in the mouse lymphoma assay but are not genotoxic carcinogens.

The mouse lymphoma assay is commonly included in batteries of tests for the mutagenic and carcinogenic potential of chemicals. Unlike other bacterial and mammalian cell tests, it has an unacceptably high incidence of false positive results. This paper reviews data on ten chemicals, all of which are positive in the mouse lymphoma assay but negative in all other genotoxicity tests. Three are non-genotoxic rodent carcinogens acting through a variety of secondary mechanisms, while seven are not carcinogenic. It is concluded that a positive mouse lymphoma assay alone cannot be a barrier to the human use of drugs and other chemicals.

Allylbenzene Derivatives↗

PubMed1985

Genotoxicity studies with mineral oils; effects of oils on the microbial mutagenicity of precursor mutagens and genotoxic metabolites.

In vitro genotoxicity assays are extensively used to predict carcinogenic activity in vivo. The standard microbial mutagenicity assays however often fail to yield positive results with mineral oils which are carcinogenic to mice in long-term skin-cancer studies. A comprehensive programme of studies has therefore investigated the basis of this apparently anomalous behaviour. This investigation has addressed the possible effects of oils on the bioactivation of precursor mutagens and the disposition of mutagenic metabolites by studying the microbial mutagenicity of selected precursor mutagens (benzo[a]pyrene, benzo[a]anthracene, 2-aminoanthracene and 2-naphthylamine) and intrinsically reactive mutagens [+/- )-benzo[a]pyrene-4,5-oxide and (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene) in the presence and absence of mineral oils. Notably the mutagenicity associated with the deliberate additions of these mutagens or precursor mutagens to oils was readily detected by the microbial assays. The mutagenicity of only one of the precursor mutagens, benzo[a]pyrene, was significantly reduced by the oils, and then only in the standard plate-incorporation assay. Interestingly the degree of suppression appeared to be related to the polycyclic aromatic hydrocarbon content of the oils. In the case of 2-aminoanthracene large enhancements in its mutagenicity were observed in the presence of oils. These latter findings appear to be due to effects of oils on the bioactivation of precursor mutagens rather than on the disposition of their bioactivation products. The mutagenicity of intrinsically reactive mutagens, of a type generated by bioactivation of polycyclic aromatic hydrocarbons, was not significantly reduced in the presence of mineral oils. This indicates that it is unlikely that components in oils trap or facilitate the deactivation of ultimate mutagens whether these pre-exist in the oil or are formed from precursors by bioactivation in the in vitro test system. Viewed overall these results suggest that mineral oils judged to be carcinogenic on the basis of in vivo studies in mouse skin may possess only very weak genotoxic potential. While this potential is likely to be a prerequisite for carcinogenic action, the current results cause attention to be focussed on other factors, e.g. promotion, as potentially important determinants of the carcinogenic potencies of mineral oils in mouse skin.

2-Naphthylamine↗

PubMedDate not supplied

Hydroquinone: genotoxicity and prevention of genotoxicity following ingestion.

Plant-derived polyphenolics and other chemicals with antioxidant properties have been reported to inhibit the expression of genotoxic activity by pro-oxidant chemicals (Sai et al., 1992, 1994; Teel and Castonguay, 1992). In vitro and in vivo studies with ionizing radiation suggest that hydroquinone (HQ) may have similar protective effects (Babaev et al., 1994). The present study was conducted to determine whether HQ is capable of inhibiting the induction of micronuclei in the bone marrow of mice following exposure to an oxidant, potassium bromate or KBrO3 (Nakajima et al., 1989; Sai et al., 1992, 1994). To be able to interpret the results of this work, it was also necessary to determine whether HQ is itself genotoxic when fed in the diet. HQ diets (0.8%) fed to mice for 6 days reduced the background incidence of micronuclei compared with the basal diet. KBrO3 dosed ip (12.5-100 mg/kg) produced a dose-dependent increase in micronuclei as reported by others. Mice fed 0.8% HQ diets 6 days, and then dosed intraperitoneally with KBrO3, showed a 36% reduction in micronuclei across the range of KBrO3 dose levels. This effect was associated with a reduction in the background micronucleus response as well as a reduction in response to KBrO3. Statistical significance (P < or = 0.05), observed at a dose of 25 mg/kg KBrO3 in the mice fed the control diet, was abolished in the group fed 0.8% HQ. When mice were given 50 mg HQ/kg by oral gavage and then given 50 mg KBrO3/kg ip 20 min later, the micronucleus response induced by KBrO3, was lower in animals given HQ. The results of this study demonstrate that large doses of HQ may be given orally without induction of micronuclei or bone marrow depression, that HQ reduces the background micronucleus response in animals fed a basal diet, and that the HQ reduces the micronucleus response to KBrO3 as well as background incidence of micronuclei in KBrO3-dosed animals. The protective effect of HQ may be due to enzyme induction or a direct antioxidant effect of HQ against oxidants commonly present in the diet.

Administration, Oral↗

PubMed1992

Response of the ke test to NCI/NTP-screened chemicals. II. Genotoxic carcinogens and non-genotoxic non-carcinogens.

A physico-chemical carcinogen-screening test was used to measure the rate constants of electron attachment, kes, of 105 chemicals that had been screened in long-term rodent bioassays and short-term in vitro tests by the NCI/NTP. In the ke test, a pulse-conductivity technique is used to generate and monitor the decay of excess electrons that serve as nucleophilic surrogates for the target tissue of rodents. Of the 61 chemicals that had been found to be rodent carcinogens as well as Salmonella mutagens, 36 yield kes that are equal to or greater than the diffusion-controlled ke of carbon tetrachloride and are considered to be positive ke test responses. In contrast, 29 of the remaining 44 chemicals that are putative non-carcinogens and non-mutagens yield kes that are negative ke test responses. These results are combined with the ke responses of 46 non-mutagenic carcinogens and 20 mutagenic non-carcinogens that were reported earlier and are evaluated to determine the degree to which the measure of electron-accepting capacity that ke provides complements or overlaps the electrophilicity or DNA reactivity of chemicals that is indicated by positive mutagenicity responses in the Ames Salmonella tester strains or by positive structural alerts, S/As, of the chemicals. The combined ke test results indicate that the overall predictivity of the ke test is comparable to and complements the Ames Salmonella test and S/As in identifying rodent carcinogens. Moreover, the electrons serve as non-discriminate nucleophilic targets for both genotoxic and non-genotoxic electron-accepting molecules and appear to attach with equal efficiency to carcinogens that are active in various tissues of rodents. This property of excess electrons suggests that the predictivity of the ke test could be enhanced by combining the measured ke with an appropriate lipophilicity or pharmacokinetic parameter. A pre-chemical electron-transfer step that had been proposed to precede chemical interactions between the carcinogen and target tissue is discussed in light of recent developments in electron-donor/-acceptor chemistry and in the application of structure--activity relationships to identify carcinogens.

Animals↗

PubMed2004

Discrimination of genotoxic from non-genotoxic carcinogens by gene expression profiling.

Two general mechanisms are implicated in chemical carcinogenesis. The first involves direct damage to DNA, referred to as genotoxic (GTX), to which the cell responds by repair of the damages, arrest of the cell cycle or induction of apoptosis. The second is non-DNA damaging, non-genotoxic (NGTX), in which a wide variety of cellular processes may be involved. Therefore, it can be hypothesized that modulation of the underlying gene expression patterns is profoundly distinct between GTX and NGTX carcinogens, and thus that expression profiling is applicable for classification of chemical carcinogens as GTX or NGTX. We investigated this hypothesis by analysing modulation of gene expression profiles induced by 20 chemical carcinogens in HepG2 cells with application of cDNA microarrays that contain 597 toxicologically relevant genes. In total, 22 treatments were included, divided in two sets. The training set consisted of 16 treatments (nine genotoxins and seven non-genotoxins) and the validation set of six treatments (three and three). Class discrimination models based on Pearson correlation analyses for the 20 most discriminating genes were developed with data from the training set, where after the models were tested with all data. Using all data, the correctness for classification of the carcinogens from the training set was clearly better than that for the validation set, namely 81 and 33%, respectively. Exclusion of the treatments that had only marginal effects on the expression profiles, improved the discrimination for the training and validation sets to 92 and 100% correctness, respectively. Exclusion of the gene expression signals that were hardly altered also improved classification, namely to 94 and 80%. Therefore, our study proves the principle that gene expression profiling can discriminate carcinogens with major differences in their mode of actions, namely genotoxins versus non-genotoxins.

Carcinogens↗

PubMed2006

In vivo evaluation of the genotoxic effects of clomiphene citrate on rat reticulocytes: a micronucleus genotoxicity.

OBJECTIVE: To determine the genotoxic effects of clomiphene citrate (CC) on rat reticulocytesin vivo. METHODS: In this prospective, randomized, controlled study, rats were each assigned randomly to the CC 50, CC 100, CC 200, or control group and were given repeat doses of 0.16, 0.32 or 0.64 mg CC, or normal saline, respectively. Each study group received its CC dose in 2 ml of saline intraperitoneally for 5 days, while the control group received only 2 ml of saline. Each treatment cycle was repeated six times. Six months later, the rats were euthanized. Bone marrow tissues were removed, and pluripotent reticulocyte cells with micronuclei, nuclear buds, and binuclear abnormalities were analyzed using an in situmicronuclei assay under light microscopy. The proportion of micronucleated erythrocytes was measured. RESULTS: Fewer cells with nuclear buds and binuclear abnormalities were detected in the CC 50 group and controls. The CC 100 and 200 groups had significantly (p < 0.05) more nuclear buds and binuclear abnormalities compared with the CC 50 group and controls in the cytogenetic analysis of bone marrow stem cells. CONCLUSION: In rats, the micronucleus genotoxicity assay suggests a dose-dependent CC effect on genomic instability in bone marrow stem cells in vivo.

Animals↗

PubMed2002

Genotoxicity of naturally occurring indole compounds: correlation between covalent DNA binding and other genotoxicity tests.

3-Methylindole (3MI), melatonin (Mel), serotonin (Ser), and tryptamine (Tryp) were evaluated in vitro for their potential to induce DNA adducts, DNA strand breaks, chromosomal aberrations (Abs), inhibition of DNA synthesis, and mutations. All compounds produced DNA adducts in calf thymus DNA in the presence of rat liver S9. In cultured rat hepatocytes, all produced DNA adducts but none induced DNA strand breaks. In Chinese hamster ovary cells, 3MI and Mel produced DNA adducts, Abs, and inhibition of DNA synthesis with and without S9, except that Mel without S9 did not form adducts. Ser formed DNA adducts, was an equivocal Abs inducer, and suppressed DNA synthesis. Tryp induced neither adducts nor Abs, but did suppress DNA synthesis with S9. Ser and Tryp were less cytotoxic than 3MI and Mel. Mel, Ser, and Tryp failed to induce mutations in Salmonella and E. coli strains with or without S9. 3MI and Mel produced DNA adducts but not mutations in Salmonella TA100 with S9. 3MI and its metabolite indole 3-carbinol also did not induce mutations in a shuttle vector system in human cells. The lack of correlation between DNA adducts and other genotoxicity endpoints for these indole compounds may be due to the higher sensitivity of the (32)P-postlabeling adduct assay or it may indicate that the indole-DNA adducts per se are not mutagenic and are not able to induce strand breaks or alkali-labile lesions. The indole-induced Abs may result from cytotoxicity and suppression of DNA synthesis with minimal if any contribution from DNA adducts.

Animals↗

PubMed2001

Characterization of DNA fragmentation events caused by genotoxic and non-genotoxic agents.

Leukemic cells have been shown to generate several classes of DNA fragments after treatment with cytotoxic cancer chemotherapy agents. However, it is unclear which of these fragmentation events are a direct effect of DNA-damaging chemotherapy agents, and which fragmentation events are caused by downstream processes, such as apoptosis. We have performed a detailed analysis of DNA fragmentation events which occur following cytotoxic chemotherapy in four representative leukemic cell lines (HL-60, Jurkat, K562, and Molt-4). We used a DNA topoisomerase II inhibitor (etoposide), an alkylating agent (melphalan), a nucleoside analog (cytosine arabinoside), and a non-genotoxic agent (N-methylformamide) to induce cell death. We studied high molecular weight and low molecular weight DNA fragmentation events, as well as the specific cleavage of the MLL breakpoint cluster region (bcr). The DNA fragments produced at late time points were largely independent of the agents used, while those generated at earlier time points showed clear differences in terms of fragment size and relative abundance, depending on the agent used. In addition, there were clear differences between cell lines in terms of size, relative abundance, and rate at which DNA fragments were produced by treatment with the same agents. We think that this survey documents the importance of studying several different cell lines, time points, and assays before reaching conclusions about the types of DNA fragments produced during treatment with cytotoxic agents, and provides a useful framework for studying a wide range of DNA fragments produced by cytotoxic agents.

Antimetabolites, Antineoplastic↗