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PubMed1983

Alkylation by dehydroretronecine, a cytotoxic metabolite of some pyrrolizidine alkaloids: an in vitro test.

A method is described for detecting alkylation of nucleophiles by dehydroretronecine (DHR) in vitro: whereas DHR is rapidly polymerised by acid, alkylation products of DHR were relatively stable and could be detected using Ehrlich reagent. Using this test, nitrogen-containing compounds found to react with DHR included pyridine, adenine and guanine derivatives; NAD and NADP, but not NADH; cytidine; barbituric and parabanic acids; and azide, but not cyanide. Out of 19 amino acids tested, only histidine, tryptophan and citrulline showed evidence of reaction. Among sulphur compounds, thiols, thiosulphate and sulphite reacted strongly; thioethers and thiocyanate did not. Carbohydrate and phenolic hydroxyls were unreactive but resorcinol and pyrogallol, having activated benzene nuclei, did react. Enols, especially ascorbic acid, reacted with DHR. Sites of reaction have not yet all been identified. Some DHR alkylations, e.g. of nicotinamide, could be reversible, and such products could in effect extend the life of DHR in vivo.

Alkylating Agents↗

PubMed1989

Increased alkylation of liver DNA and cell turnover in young versus old rats exposed to vinyl chloride correlates with cancer susceptibility.

To investigate the factors responsible for the high sensitivity of the livers of young rats to the carcinogenic stimulus of vinyl chloride (VC) adult and 11-day-old Wistar rats were exposed to [1,2-14C] VC. Adult rats received either a single 6-h exposure, or 2 single 6-h exposures separated by a treatment-free time interval of 15 h. Eleven-day-old rats received 2 single 6-h exposures, according to the same treatment schedule. The animals were sacrificed 1 h after the end of the corresponding exposure period; liver DNA was isolated, enzymatically hydrolyzed and analyzed by column chromatography. Incorporation of [14C]VC-derived radioactivity into the physiological deoxyribonucleosides (presumably reflecting the activity of DNA replication) was observed for all three sets of experiments. Virtually no difference in 14C-incorporation was observed between adult rats sacrificed immediately after one single 6-h exposure to [14C]VC and those which received a second exposure on the following day. In contrast, an about 8-fold increase in 14C-incorporation into the physiological purines of DNA of young versus adult rats was detected. This difference is indicative of a significantly elevated DNA synthesis/cell replication in the liver of young (11-d) rats. Radioactivity associated with 7-(2-oxoethyl)guanine was taken as an indicator of DNA alkylation by [14C]VC. Analysis of 7-(2-oxoethyl)guanine revealed that in adult animals the amount of this alkylation product formed is increased by a second exposure to VC. About 5-fold of the amount of 7-(2-oxoethyl)guanine present in adults could be determined in liver DNA of young (11-d) animals exposed under the same exposure conditions. Our results suggest that the high sensitivity of young rats to VC-induced hepatocarcinogenesis can reasonably be explained by enhanced DNA-alkylation and by increased cellular proliferation at an early age.

Age Factors↗

PubMed1992

Increased sensitivity of a Chinese hamster ovary cell line to alkylating agents after overexpression of the human metallothionein II-A gene.

The elevation of intracellular levels of metallothionein has been associated with the development of resistance to the cytotoxic effects of some alkylating agents. In order to study the mechanisms underlying metallothionein associated drug resistance we transfected the alkylating agent sensitive CHO cell line MMC-1 (Robson et al., 1985) with an episomally replicating plasmid coding for the human metallothionein II-A gene. Two transfectants were isolated which carried about 10 copies of the plasmid. The basal expression of metallothionein was increased from undetectable levels in the recipient cell line MMC-1 to between 22 and 26 micrograms metallothionein per 10(7) cells in the transfectants. Treatment with cadmium salts increased metallothionein levels a further 1.7-fold. Cytotoxicity assays revealed that MTII-A transfection increased the sensitivity of the parental MMC-1 cells to N-methyl-N'-nitro-N-nitrosoguanidine and N-nitroso-N-methylurea. These results suggest that metallothionein does not act as a simple scavenger of alkylating agents, but interacts with unknown factor(s) in host cells.

Alkylating Agents↗

PubMed1995

Diverse capacities for the adaptive response to DNA alkylation in Bacillus species and strains.

Our previous studies of Bacillus subtilis showed that the genes responsible for the adaptive response to DNA alkylation were organized as a divergent regulon, in contrast to scattered operons in Escherichia coli ada regulon. To study the generality and diversity of gene organization, several species and strains of Bacillus were examined for the responsiveness to DNA alkylation. B. cereus cells exhibited the highest resistance to MNNG treatment. When the cells were grown in the presence of MNNG, 3-methyladenine DNA glycosylase and two species of DNA methyltransferase were induced as in B. subtilis 168 cells. B. licheniformis 749 and B. amyloliquefaciens H cells exhibited a partial response that manifested itself as the induction of one species of DNA methyltransferase. On the other hand, B. thuringiensis var. Tohokuensis, B. megaterium KMT, and B. subtilis W23 cells were totally deficient in this response, and were hypersensitive to alkylating agents. To determine the cause of this deficiency in strain W23, we examined the genomic structure of the corresponding region where three genes (alkA, adaA, and adaB) were located in 168. No homologues for the three genes were detected in W23 DNA by Southern hybridization. Two genes (glmS and ndhF) flanking the adaptive response regulon in 168 were also present in W23. A sequence of about 2750 bp that carried the entire regulon in 168 was replaced with a sequence of about 250 bp that was unique to W23. At the ends of the conserved segments, palindromic sequences corresponding to the transcriptional termination sites of the adaB and glmS genes were observed. The regulon in 168 could be artificially replaced by the W23 sequence, and be regained through DNA-mediated transformation.

Alkylation↗

PubMed1995

Enhanced host cell reactivation capacity and expression of DNA repair genes in human breast cancer cells resistant to bi-functional alkylating agents.

Human breast carcinoma (MCF7-MLNr) cells resistant to the bifunctional drugs L-phenylalanine mustard (L-PAM, 5-fold resistance), mechlorethamine (9-fold), cisplatin (3-fold), and BCNU (3-fold) were used to investigate the role of DNA repair in the development of resistance to alkylating agents. We have previously shown that neither L-PAM transport and metabolism nor glutathione-associated enzymes were altered in MCF7-MLNr cells, compared to the sensitive cells MCF7-WT. This study shows that treatment of pRSV-CAT plasmid with L-PAM at concentrations up to 1 microM proportionally inhibit the expression of chloramphenicol acetyl transferase (CAT) activity, while higher concentrations abolished CAT activity. pRSV-CAT reactivation was significantly increased when plasmid was transfected into MCF7-MLNr cells, compared to MCF7-WT cells. This indicates that resistant cells have more efficient capacity to recognize and repair L-PAM induced DNA damage. The mRNA expression of DNA nucleotide excision repair genes ERCC1, XPD (ERCC2), XPB (ERCC3), and polymerase beta was found to be similar in both the MCF7-WT and MCF7-MLNr cells. Western blot analysis also reveals no difference in the expression of ERCC1, AP endonuclease, poly (ADP-ribose) polymerase, and alkyl-N-purine-DNA glycosylase proteins. The lack of correlation between enhanced host cell reactivation capacity in resistant cells, and the expression of these specific DNA repair genes suggests that proteins encoded by these genes are not rate limiting steps for resistance to bi-functional alkylating drugs in human breast cancer cells.

Adenocarcinoma↗

PubMed1996

Thymidine kinase deficient cells with decreased TTP pools are hypersensitive to DNA alkylating agents.

The effect of mutational loss of thymidine kinase (TK) on the sensitivity to alkylating agents was investigated in promyelocytic, HL-60, and T-lymphoblastoid, Molt-3, human leukemia cell lines. Although both cell lines exhibited approx. 1% residual TK activity, only HL-60 TK deficient cells had a decreased intracellular TTP pool, i.e., 20% of that of the wild-type. When treated with N-methyl-N'-nitronitrosoguanidine or ethyl methanesulfonate, HL-60 TK deficient cells showed significantly increased killing and mutation frequencies at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus relative than did wild-type. Pretreatment of cells with O6-benzylguanine, an inhibitor of O6-alkylguanine-DNA alkyltransferase, partially abolished those differences. Molt-3 wild-type and TK deficient cells had similar cell survivals and HGPRT mutation frequencies following treatment with alkylating agents. These results indicate that TK deficiency, only when a concomitant decrease of TTP pool is detected, plays a pivotal role in the sensitivity to the cytotoxic and mutagenic effects of alkylating agents.

Antineoplastic Agents↗

PubMed1995

Selective recognition of the m5CpG dinucleotide sequence in DNA by mitomycin C for alkylation and cross-linking.

The clinically used natural antitumor agent mitomycin C (MC) is known to alkylate DNA monofunctionally and bifunctionally, resulting in the cross-linking of DNA. These reactions occur selectively with guanines at the CpG sequence. We show, confirming a previous report (Millard, J. T.; Beachy, T. M. Biochemistry 1993, 32, 12850) that cross-linking in oligonucleotides is further enhanced when the cytosines in CpG.CpG are 5-methylated to m5CpG.m5CpG. It is shown, furthermore, that guanines in m5CpG are monoalkylated two- to three-times faster than in CpG indicating that the m5C-induced rate enhancement occurs at the first, monoalkylation step of the two-step cross-linking process. The same MC-DNA adducts are formed in methylated as in non-methylated DNA. The basepaired but not the 5'-flanking, m5C residue is responsible for the enhanced alkylation of guanine. Enzymatically activated or Na2S2O4-activated MC shows identical rate-enhancement of alkylation at m5CpG. pBR322 DNA methylated by CpG-methylase was cross-linked two- to three-times more efficiently by MC than non-methylated DNA, indicating that the m5C effect is not an artifact of oligonucleotides. An electronic effect of the 5-methyl group of cytosine transmitted via G.C H-bonding to N2 of guanine is suggested as responsible for increased reactivity with MC. CpG is severely depleted in mammalian DNA and it is speculated that this factor attenuates MC cytotoxicity in human cells.

Alkylation↗

PubMed2006

5-Alkylated thiazolidinones as follicle-stimulating hormone (FSH) receptor agonists.

We prepared analogs of potent thiazolidinone-based follicle-stimulating hormone (FSH) agonists 1, that is, 3 that contained an additional 5-alkyl substituent. This extra substituent was added to reduce synthetic problems that arose during preparation of analogs of 1. These compounds (3) were evaluated in a Chinese hamster ovary (CHO) cell line that expressed recombinant human FSH receptor (FSHR) and a luciferase reporter gene regulated by a cAMP response element (CRE). Selected compounds were also tested on a CHO-cell line that over expressed the FSHR for the ability to induce cAMP production. When the 5-alkyl substituent was a methyl group as in analog 16a, similar FSH activity (i.e., EC(50) = 51 nM, 100% efficacy relative to hFSH) to the analogous 5-hydrogen series compound (e.g., 2) was observed; thus, proving that a small 5-alkyl substituent was well tolerated. New derivatives of 3, in which the potentially hydrolytically labile secondary amide function of 1 (-CONH-) was modified to other moieties (e.g., -CH(2)NH-, -CH(2)S-, and -CH(2)OCONH-), were also prepared and evaluated. These congeners (namely 21, 22, and 24) also displayed good potency in the CRE-luciferase assay.

Alkylation↗

PubMed2004

Preparation of alkylation agents for bulged DNA microenvironments.

A designed molecule with capacity to alkylate DNA bulges has been prepared from readily available starting materials. The spirocyclic template utilized was designed on the basis of established architectures, and equipped with a mustard alkylating group. Preliminary studies confirm alkylation of specific bulged sequences, paving the way for second generation substrates with higher affinity.

Alkylating Agents↗

PubMed2004

Influence of alkyl group on amide nitrogen atom on fluorescence quenching of tyrosine amide and N-acetyltyrosine amide.

The steady-state and time-resolved fluorescence spectroscopy was applied to determine the influence of an alkyl substituent(s) (methyl or ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, or t-butyl) on amide nitrogen atom on photophysical properties of tyrosine and N-acetyltyrosine amides in water. Generally, the amide group strongly quenches the fluorescence of tyrosine, however, the size and number of substituents on amide nitrogen atom modify the quenching process only in small degree. The fluorescence intensity decays of all amides studied are bi-exponential. The contribution of both components (alphai) to the fluorescence decay undergoes irregular change. An introduction of alkyl substituent on amide nitrogen atom causes an increase of the fluorescence lifetime of tyrosine derivative compared to the unsubstituted amide for both N-acetyltyrosine and tyrosine with the protonated amino group. Calculated, basing on the fluorescence quantum yield (QY) and average lifetime, the radiative rate constants (kf) are similar, which indicates that the substituent(s) does not have substantial influence on radiative process of the deactivation of the excited state of the phenol chromophore for all compounds studied regardless the amino group status as well as the number and type of substituent (linear or branched). The comparison of the ground-state rotamer populations of tyrosine amides and N-acetyltyrosine amides with different alkyl substituent on amide nitrogen atom obtained from 1H NMR with the value of pre-exponential factors indicates that not the rotamer populations, but specific hydration of a whole molecule of the amino acid including chromophore and amino acid moiety, seems to be the main reason of the heterogenous fluorescence intensity decay of tyrosine derivatives.

Alkylation↗

PubMed2006

Effects of N-alkyl and ammonium groups on the hydrolytic cleavage of DNA with a Cu(II)TACH (1,3,5-triaminocyclohexane) complex. Speciation, kinetic, and DNA-binding studies for reaction mechanism.

cis,cis-1,3,5-Triaminocyclohexane (c-TACH), its N-alkyl-derivatives (alkyl = methyl, ethyl), and trans,cis-1,3,5-triaminocyclohexane (t-TACH) were prepared, and speciation and DNA cleaving property of Cu(II) complexes of these ligands were investigated. All of the complexes efficiently promote the hydrolytic cleavage of supercoiled plasmid DNA under physiological conditions without further additives. The DNA cleavage rate (V(obs)) trend at pH values between 8 and 9 is N-Me(3) = N-Et(1) < t-TACH < c-TACH < N-Et(2) < N-Et(3). At pH 7, the trend is c-TACH < N-Et(3) = N-Et(2) < N-Et(1) < N-Me(3) << t-TACH. The cleavage rate constants at 35 degrees C, for the c-TACH complex are 3 x 10(-1) h(-1) at pH 8.1 and 2 x 10(-1) h(-1) at pH 7.0 ([DNA] = 7 microM, [Cu(II)-complex] = 105 microM). The hydrolytically active species at pH > 8 is CuL(H(2)O)(OH)(+) in which L coordinates to Cu(II) as a tridentate ligand for all complexes except for t-TACH. The hydrolytically active species at pH 7 is CuLH(H(2)O)(3)(3+) or CuLH(H(2)O)(4)(3+) in which LH coordinates as bidentate ligand. DNA-binding constants of c-TACH and t-TACH complexes are presented and the effects of N-alkyl and ammonium groups are discussed in light of the proposed reaction mechanism.

Alkylation↗

PubMed2006

Inhibition of RecBCD enzyme by antineoplastic DNA alkylating agents.

To understand how bulky adducts might perturb DNA helicase function, three distinct DNA-binding agents were used to determine the effects of DNA alkylation on a DNA helicase. Adozelesin, ecteinascidin 743 (Et743) and hedamycin each possess unique structures and sequence selectivity. They bind to double-stranded DNA and alkylate one strand of the duplex in cis, adding adducts that alter the structure of DNA significantly. The results show that Et743 was the most potent inhibitor of DNA unwinding, followed by adozelesin and hedamycin. Et743 significantly inhibited unwinding, enhanced degradation of DNA, and completely eliminated the ability of the translocating RecBCD enzyme to recognize and respond to the recombination hotspot chi. Unwinding of adozelesin-modified DNA was accompanied by the appearance of unwinding intermediates, consistent with enzyme entrapment or stalling. Further, adozelesin also induced "apparent" chi fragment formation. The combination of enzyme sequestering and pseudo-chi modification of RecBCD, results in biphasic time-courses of DNA unwinding. Hedamycin also reduced RecBCD activity, albeit at increased concentrations of drug relative to either adozelesin or Et743. Remarkably, the hedamycin modification resulted in constitutive activation of the bottom-strand nuclease activity of the enzyme, while leaving the ability of the translocating enzyme to recognize and respond to chi largely intact. Finally, the results show that DNA alkylation does not significantly perturb the allosteric interaction that activates the enzyme for ATP hydrolysis, as the efficiency of ATP utilization for DNA unwinding is affected only marginally. These results taken together present a unique response of RecBCD enzyme to bulky DNA adducts. We correlate these effects with the recently determined crystal structure of the RecBCD holoenzyme bound to DNA.

Adenosine Triphosphate↗

PubMed2005

Targeting of O6-MeG DNA methyltransferase (MGMT) to mitochondria protects against alkylation induced cell death.

Mitochondrial DNA (mtDNA) mutations are implicated in pathogenesis of human diseases including cancer. To prevent mutations cells have developed repair systems to counteract harmful genetic changes caused by DNA damaging agents. One such DNA repair protein is the O(6)-Methylguanine-DNA methyltransferase (MGMT) that prevents certain types of alkylation damage. Yet, the role of MGMT in preventing alkylation induced DNA damage in mtDNA is unclear. We explored the idea of increasing cell survival after alkylation damage by overexpressing MGMT in mitochondria. We show that overexpression of this repair protein in mitochondria increases cell survival after treatment with the DNA damaging agent MNNG.

Alkylation↗

PubMed2004

Separation of aromatic-carbon 13C NMR signals from di-oxygenated alkyl bands by a chemical-shift-anisotropy filter.

Selection of alkyl-carbon and suppression of aromatic-carbon 13C nuclear magnetic resonance (NMR) signals has been achieved by exploiting the symmetry-based, systematic difference in their 13C chemical-shift anisotropies (CSAs). Simple three- or five-pulse CSA-recoupling sequences with "gamma-integral" cleanly suppress the signals of all sp2- and sp-hybridized carbons. The chemical-shift-anisotropy-based dephasing is particularly useful for distinguishing the signals of di-oxygenated alkyl (O-C-O) carbons, found for instance as anomeric carbons in carbohydrates, from bands of aromatic carbons with similar 13C isotropic chemical shifts. The alkyl signals are detected with an efficiency of > 60%, with little differential dephasing. Combined with C-H dipolar dephasing, the CSA filter can identify ketal (unprotonated O-C-O) carbons unambiguously for the first time. Conversely, after short cross polarization and the CSA filter, O-CH-O (acetal) carbon signals are observed selectively. The methods are demonstrated on various model compounds and applied to a humic acid.

Algorithms↗

PubMed2004

Sensitivity of the FPG protein towards alkylation damage in the comet assay.

The comet assay (single cell gel electrophoresis) is widely used for the evaluation of DNA-damaging effects in genotoxicity testing and population monitoring. In its standard version at pH >13, DNA double strand breaks (DSB), DNA single strand breaks (SSB) and alkali-labile sites (ALS) lead to increased DNA migration. At reduced pH (12.5-12.1) the expression of ALS as SSB can be eliminated and the effect of SSB only can be identified. Specific endonucleases have been used to characterize specific classes of DNA damage. The formamido pyrimidine glycosylase (FPG) protein has been used to assess oxidative DNA base damage because it detects 8-OH guanine and other oxidatively damaged purines. Here, we show that the FPG protein also detects alkylation damage with high sensitivity in the comet assay. Human whole blood, isolated lymphocytes and V79 cells were treated with alkylating agents and post-incubated with FPG. FPG strongly enhanced MMS- and EMS-induced DNA damage but had no significant effect on ENU-induced DNA damage, indicating that the amount of N-7 guanine alkylation is responsible for the observed effect. Reducing the pH during alkali unwinding and electrophoresis to 12.5 to avoid the contribution of ALS to the comet assay effects, strongly decreased the sensitivity of the comet assay with and without FPG treatment and prevented DNA migration. We conclude that enhanced DNA effects in the comet assay by FPG after exposure to genotoxins with unknown mode of action should not directly be regarded as evidence for the presence of oxidative damage. Furthermore, reducing the pH leads to a considerable loss in sensitivity and should not be used in biomonitoring and other applications which require a sensitive protocol.

Alkylation↗

PubMed2006

In vivo effects of myeloablative alkylator therapy on survival and differentiation of MGMTP140K-transduced human G-CSF-mobilized peripheral blood cells.

High-intensity alkylator-based chemotherapy is required to eradicate tumors expressing high levels of O6-methylguanine DNA methyltransferase (MGMT). This treatment, however, can lead to life-threatening myelosuppression. We investigated a gene therapy strategy to protect human granulocyte colony-stimulating factor-mobilized peripheral blood CD34+ cells (MPB) from a high-intensity alkylator-based regimen. We transduced MPB with an oncoretroviral vector that coexpresses MGMT(P140K) and the enhanced green fluorescent protein (EGFP) (n = 5 donors). At 4 weeks posttransplantation into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, cohorts were not treated or were treated with low- or high-intensity alkylating chemotherapy. In the high-intensity-treated cohort, it was necessary to infuse NOD/SCID bone marrow (BM) to alleviate hematopoietic toxicity. At 8 weeks posttreatment, human CD45+ cells in the BM of mice treated with either regimen were EGFP+ and contained MGMT-specific DNA repair activity. In cohorts receiving low-intensity therapy, both primitive and mature hematopoietic cells were present in the BM. Although B-lymphoid and myeloid cells were resistant to in vivo drug treatment in cohorts that received high-intensity therapy, no human CD34+ cells or B-cell precursors were detected. These data suggest that improved strategies to optimize repair of DNA damage in primitive human hematopoietic cells are needed when using high-intensity anti-cancer therapy.

Animals↗

PubMed1998

The native molecular size of alkyl-dihydroxyacetonephosphate synthase and dihydroxyacetonephosphate acyltransferase.

Dihydroxyacetonephosphate acyltransferase (DHAP-acyltransferase) and alkyl-dihydroxyacetonephosphate synthase (alkyl-DHAP synthase) are the first two enzymes involved in the biosynthesis of ether phospholipids. Both peroxisomal enzymes have recently been purified to homogeneity and their molecular weights under denaturing conditions were reported. To determine the in situ functional size of both enzymes, radiation inactivation experiments were performed. Alkyl-DHAP synthase showed single exponential decays, both when enzymatic activity and when immunoreactive protein levels were measured, from which target sizes of 79+/-2 kDa and 78+/-4 kDa, respectively, were calculated. DHAP-acyltransferase activity increased at lower doses and decayed upon further irradiation with an apparent target size of 62+/-7 kDa. We conclude from these data that the functional unit sizes for both enzymes in situ are represented by their single polypeptide chains.

Activation Analysis↗

PubMed2001

Conjugative metabolism of 1,2-dibromoethane in mitochondria: disruption of oxidative phosphorylation and alkylation of mitochondrial DNA.

1,2-Dibromoethane (DBE) is an environmental contaminant that is metabolized by glutathione S-transferases to a haloethane-glutathione conjugate. Since haloethane-glutathione conjugates are known to alkylate nuclear DNA and cytoplasmic proteins, these effects were investigated in isolated rat liver mitochondria exposed to DBE by measuring guanine adducts and several aspects of oxidative phosphorylation including respiratory control ratios, respiratory enzyme activity, and ATP levels. Mitochondrial large-amplitude swelling and glutathione status were assessed to evaluate mitochondrial membrane integrity and function. When exposed to DBE, mitochondria became uncoupled rapidly, yet no large-amplitude swelling or extramitochondrial glutathione was observed. Mitochondrial GSH was depleted to 2-53% of controls after a 60-min exposure to micromolar quantities of DBE; however, no extramitochondrial GSH or GSSG was detected. The depletion of mitochondrial glutathione corresponded to an increase of an intramitochondrial GSH-conjugate which, based on HPLC elution profiles and retention times, appeared to be S,S'-(1,2-ethanediyl)bis(glutathione). Activities of the NADH oxidase and succinate oxidase respiratory enzyme systems were inhibited 10-74% at micromolar levels of DBE, with succinate oxidase inactivation occurring at lower doses. ATP concentrations in DBE-exposed mitochondria in the presence of succinate were 5-90% lower than in the controls. The DNA adduct S-[2-(N(7)-guanyl)ethyl]glutathione was detected by HPLC in mtDNA isolated from DBE-exposed mitochondria. The results suggest that respiratory enzyme inhibition, glutathione depletion, decreased ATP levels, and DNA alkylation in DBE-exposed mitochondria occur via the formation of an S-(2-bromoethyl)glutathione conjugate, the precursor of the episulfonium ion alkylating species of DBE.

Adenosine Triphosphate↗