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At least 19 recordsLinked to original sources

PubMed1989

Sequence-specific intercalating agents: intercalation at specific sequences on duplex DNA via major groove recognition by oligonucleotide-intercalator conjugates.

An acridine derivative was covalently linked to the 5' end of a homopyrimidine oligonucleotide. Specific binding to a homopurine-homopyrimidine sequence of duplex DNA was demonstrated by spectroscopic studies (absorption and fluorescence) and by "footprinting" experiments with a copper phenanthroline chelate used as an artificial nuclease. A hypochromism and a red shift of the acridine absorption were observed. Triple-helix formation was also accompanied by a hypochromism in the ultraviolet range. The fluorescence of the acridine ring was quenched by a stacking interaction with a G.C base pair adjacent to the homopurine-homopyrimidine target sequence. The intercalating agent strongly stabilized the complex formed by the oligopyrimidine with its target duplex sequence. Cytosine methylation further increased the stability of the complexes. Footprinting studies revealed that the oligopyrimidine binds in a parallel orientation with respect to the homopurine-containing strand of the duplex. The intercalated acridine extended by 2 base pairs the region of the duplex protected by the oligopyrimidine against degradation by the nuclease activity of the copper phenanthroline chelate. Random intercalation of the acridine ring was lost due to the repulsive effect of the negatively charged oligonucleotide tail. Intercalation occurred only at those double-stranded sequences where the homopyrimidine oligonucleotide recognized the major groove of duplex DNA.

Base Sequence↗

PubMed1980

Inhibition of hepatitis B virus specific DNA polymerase by intercalating agents.

Intercalating agents, some of them in clinical use, were tested for their ability to inhibit the hepatitis B virus specific DNA polymerase reaction. Ethidium bromide was shown to be the strongest inhibitor among the compounds tested. Compounds in clinical use inhibited the DNA polymerase test only at high concentrations. The inhibitory activity of all compounds tested was increased when the MgCl2 content in the reaction mixture was lowered. UV absorption studies presented no evidence that this effect was due to complex formation of magnesium and the individual compounds. The therapeutic significance of these findings is not certain and needs further work.

Carrier State↗

PubMed1978

Mechanisms of selectivity of intercalating agents.

Intercalation, insertion of a conjugated polycyclic aromatic ligand between stacked bases of helical DNA, is a common means of binding for a number of agents. This mode of binding generally accounts directly for a number of effects which are broadly uniform for most cells under appropriate conditions. Intercalating agents bind to plasma and intracellular membranes and interact with phospholipids to varying degrees. Biotransformation and activation may also occur at the membrane sites. Besides effects attributable to DNA binding, many of the therapeutic and cytotoxic effects that are characteristic of these agents may be a function of binding and activation in membranes, appearing to be independent of intercalation in some cases but also enhancing DNA-related actions in others. The range of differential effects of intercalating drugs stemming from binding at DNA and membranal sites seems sufficiently diverse to explain selectivity which is expressed in cell- and organ-specific changes, individual and species variability, and numerous drug actions apparently unrelated to intercalation alone.

Animals↗

PubMed1983

On the fidelity of DNA replication. Specificity of nucleotide substitution by intercalating agents.

The effects of intercalating agents on the fidelity of DNA synthesis in vitro have been investigated. The accuracy of DNA synthesis with Escherichia coli DNA polymerase I with both the poly[d(A-T)] and poly[d(G-C)] templates is decreased in the presence of the intercalating agents proflavin, ethidium bromide, acridine orange, ICR-170, and ICR-191. Nearest neighbor analyses of the product of the reaction indicate that two different types of misincorporations occur in the presence of intercalating agents, frameshifts, and single-base substitutions. With alternating polynucleotide templates, frameshifts involving pyrimidines are the most frequent change in sequence observed. Overall, frameshift misincorporations occur with frequencies of one complementary pyrimidine for each intercalated site and one noncomplementary pyrimidine for each 150 sites. From analysis of nearest neighbor frequencies in the product, it is inferred that the intercalating agents interact specifically with pyrimidine (3' leads to 5') purine sequences. An analysis of ratios of correct nucleotide incorporations as a function of intercalator concentration indicates that frameshifts are predominantly additions; however, one cannot rule out infrequent deletions. Base substitutions in the presence of intercalators occur less frequently than frameshifts. From the results of reaction kinetics and nearest neighbor frequencies, it is concluded that the noncomplementary nucleotides are incorporated in phosphodiester linkage and are present as single-base substitutions. Taken together, the results of these studies suggest at least two different modes of action for intercalating agents on the accuracy of DNA synthesis: one leading to frameshift misincorporations and the other leading to single-base substitutions.

DNA Polymerase I↗

PubMed1989

Control of gene expression by oligonucleotides covalently linked to intercalating agents.

Oligodeoxynucleotides covalently linked to intercalating agents selectively recognize the complementary sequence of the oligonucleotide. The intercalating agent provides an additional binding energy which stabilizes the complex. These substances can be used in vitro to block mRNA translation. In cell cultures they are able to inhibit the cytopathic effect of viruses, such as influenza virus and the oncogenic virus SV40. They kill trypanosomes in culture as a result of protein synthesis inhibition. A reactive group can be attached to an oligodeoxynucleotide in order to achieve site-directed modifications of the target sequence. Metal complexes of EDTA, phenanthroline or porphyrins induce cleavage reactions of the phosphodiester backbone in both DNA and RNA. Photoactive groups can be used to modify bases in the complementary sequence. The double helix can be recognized and modified by oligonucleotides that bind to the major groove, forming a local triple helix. These site-directed modifications may inhibit biological processes. The oligonucleotide can be made resistant to nuclease digestion by substituting the synthetic alpha-anomers of nucleosides to the natural beta-nucleosides. These results provide the basis for the design of gene-specific inhibitors that can be used as tools in molecular and cellular biology. They also suggest new approaches for the rational development of selective anti-viral, anti-parasitic, and anti-tumoral agents.

Antineoplastic Agents↗

PubMed1984

Effect of intercalating agents on RNA polymerase I promoter selection in Xenopus laevis.

We have analyzed the effect of DNA intercalating agents on the transcription signals from two different Xenopus laevis RNA polymerase I promoters. The transcription signal from the promoter for the 7.5-kilobase rRNA precursor (the gene promoter) is unaffected over a large range of intercalating agent concentrations regardless of whether the template is injected plasmid DNA in oocytes, the amplified endogenous nucleoli of oocytes, or the endogenous chromosomes of cultured Xenopus kidney cells. The transcription signal from a closely related promoter located in the spacer DNA between genes (the spacer promoter) ranges between undetectable to equivalent to the gene promoter signal on different templates. The transcription signal from the spacer promoter is also differentially affected by intercalating agents relative to the gene promoter. Depending on the template, these agents can either increase or decrease the transcription signal from the spacer promoter. Fusions between the gene and spacer promoters demonstrate that intercalating agents affect transcription initiation. One explanation for these results is that the degree of supercoiling of the template DNA can differentially inhibit transcription from the spacer promoters. The different effects of intercalating agents on transcription from the spacer promoters of various templates could then be explained as differences in the degree of supercoiling present on these templates initially.

Animals↗

PubMed1983

[New substances with high specific activity for nucleic acid sequences: oligodeoxynucleotides covalently linked to an intercalating agent].

New molecules are described in which an intercalating agent is covalently linked through a polymethylene chain to an oligodeoxynucleotide. Using an oligodT sequence covalently linked to an acridine dye, it is shown that these molecules bind in a specific way to their complementary sequence (poly (A] and that the stability is strongly enhanced by the intercalating agent as compared with the unmodified oligodT. Substitution of a phosphate group by a positively charged group strengthens complex formation and protects the neighboring phosphodiester bond against nuclease cleavage.

Intercalating Agents↗

PubMed1988

Nuclear topoisomerase II levels correlate with the sensitivity of mammalian cells to intercalating agents and epipodophyllotoxins.

We have investigated the biochemical basis for the hypersensitivity to intercalating agents and epipodophyllotoxins of a Chinese hamster cell mutant, ADR-1. More topoisomerase II-induced DNA strand breaks are accumulated by ADR-1 than by parental CHO-K1 cells following exposure to the intercalating agent amsacrine. Levels of induced DNA strand breaks correlate with cell killing. Topoisomerase II activity is elevated in ADR-1 cells as a consequence of an increased cellular level of topoisomerase II protein. We have studied the phenotype of cell hybrids generated by fusing parental and mutant cells. The hybrid ADR-1/CHO-K1 exhibits normal levels of resistance to amsacrine and expresses the lower, parental level of topoisomerase II. These results provide additional evidence that topoisomerase II mediates the cytotoxic action of intercalating agents and epipodophyllotoxins and suggest that the intracellular level of topoisomerase II is an important determinant of cellular sensitivity to these drugs. This has implications for antitumor therapy. ADR-1 cells provide a model system for studying the effects of topoisomerase II overproduction on cell proliferation and chromosome organization.

Amsacrine↗

PubMed2006

The apoptotic effect of intercalating agents on HPV-negative cervical cancer C-33A cells.

Cervical cancer is one of the leading causes of female cancer death worldwide with about 500,000 deaths per year. Both mitomycin C and cisplatin are alkylating agents, which bind and intercalate DNA, and thus used as anti-cancer drugs. In these studies, we focused on investigating the apoptotic effects of intercalating agents on HPV-negative cervical cancer C-33A cells. Accordingly, C-33A cells were treated with carboplatin, mitomycin C or cisplatin. Cell cycle analysis revealed that treatment with mitomycin C and cisplatin but not with carboplatin resulted in apoptosis. Both mitomycin C and cisplatin induced apoptosis in C-33A cells via caspase-8 and -3 processing in a Fas/FasL-dependent manner and also suppressed IL-18 expression, while they down-regulated IkappaB expression and up-regulated p65 expression. These results suggest that both mitomycin C and cisplatin induce apoptosis, not only via the caspase-8 and -3 dependent Fas/FasL pathway, but also via the regulation of NF-kappaB activity and IL-18 expression in HPV-negative cervical cancer C-33A cells.

Apoptosis↗

PubMed1990

Potential antitumor agents. 59. Structure-activity relationships for 2-phenylbenzimidazole-4-carboxamides, a new class of "minimal" DNA-intercalating agents which may not act via topoisomerase II.

A series of substituted 2-phenylbenzimidazole-4-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. These compounds represent the logical conclusion to our search for "minimal" DNA-intercalating agents with the lowest possible DNA-binding constants. Such "2-1" tricyclic chromophores, of lower aromaticity than the structurally similar 2-phenylquinolines, have the lowest DNA binding affinity yet seen in the broad series of tricyclic carboxamide intercalating agents. Despite very low in vitro cytotoxicities, several of the compounds had moderate levels of in vivo antileukemic effects. However, the most interesting aspect of their biological activity was the lack of cross-resistance shown to an amsacrine-resistant P388 cell line, suggesting that these compounds may not express their cytotoxicity via interaction with topoisomerase II.

Animals↗

PubMed1984

Nucleic acid-binding molecules with high affinity and base sequence specificity: intercalating agents covalently linked to oligodeoxynucleotides.

Oligodeoxyribonucleotides covalently linked to an intercalating agent via a polymethylene linker were synthesized. Oligothymidylates attached to an acridine dye (Acr) through the 3'-phosphate group [(Tp)n(CH2) mAcr ] specifically interact with the complementary sequence. The interaction is strongly stabilized by the intercalating agent. By using absorption and fluorescence spectroscopies, it is shown that complex formation between (Tp)n(CH2) mAcr and poly(rA) involves the formation of n A X T base pairs, where n is the number of thymines in the oligonucleotide. The acridine ring intercalates between A X T base pairs. Fluorescence excitation spectra reveal the existence of two environments for the acridine ring, whose relative contributions depend on the linker length (m). The binding of (Tp)4(CH2) mAcr to poly(rA) is analyzed in terms of site binding and cooperative interactions between oligonucleotides along the polynucleotide lattice. Thermodynamic parameters show that the covalent attachment of the acridine ring strongly stabilizes the binding of the oligonucleotide to its complementary sequence. The stabilization depends on the linker length; the compound with m = 5 gives a more stable complex than that with m = 3. These results open the way to the synthesis of a family of molecules exhibiting both high-affinity and high-specificity for a nucleic acid base sequence.

Acridines↗

PubMed1982

Comparative mutagenicity of 4 DNA-intercalating agents in L5178Y mouse lymphoma cells.

The mutagenicity of 4 known intercalating agents acridine orange (AO), quinacrine mustard (QM), proflavin (PF) and ethidium bromide (EB) has been investigated in L5178Y mouse lymphoma cells. Methyl methanesulfonate (MMS) was used as a positive control in these studies. AO, QM and PF induced mutation in the excess thymidine- and thioguanine-selective systems. These 3 compounds were negative in the ouabain- and cytosine-arabinoside-selective systems while EB was positive only in the cytosine arabinoside system. It would appear that the EB-induced mutagenesis is different from that of AO, QM and PF though all are intercalating agents. Since the molecular origin of cytosine arabinoside mutants is unknown, further interpretation of the EB results is not possible.

Acridine Orange↗

PubMed1983

On the fidelity of DNA replication. Mechanisms of misincorporation by intercalating agents.

Two distinct mechanisms of action for intercalating agents have been delineated: one leading to the production of frameshift misincorporations and the other leading to the production of single-base substitutions. Addition misincorporations are competitive with respect to DNA template (a measure of classical intercalation) but are not competitive with respect to deoxynucleotide substrates. Single-base substitutions are not competitive with template, polymerase, or deoxynucleotide as tested individually, but are proportional to the absolute drug concentration, indicating a ternary complex involving intercalator, polymerase, and template. Increased frequencies of single-base substitutions have not been considered as a general property of intercalators. Using a mutant phi X174 DNA, we demonstrate that intercalators also induce single-base substitutions with natural DNA templates. Reversion of am3 phi X174 DNA occurs only by single-base substitutions at position 587; this is increased 8-fold when the DNA is copied in vitro in the presence of intercalators.

Animals↗

PubMed1987

Enzymatic amplification of translation inhibition of rabbit beta-globin mRNA mediated by anti-messenger oligodeoxynucleotides covalently linked to intercalating agents.

The effects of anti-messenger oligodeoxynucleotides, covalently linked to an intercalating agent, on translation of rabbit beta-globin mRNA, were investigated both in wheat germ extract and in microinjected Xenopus oocytes. A specific inhibition of beta-globin synthesis was observed in both expression systems with a modified 11-mer covalently linked to an acridine derivative. In injected oocytes a more efficient block was observed with this modified oligonucleotide than with its unsubstituted homolog. This was ascribed to stacking interactions of the intercalating agent with base pairs which provide an additional stabilization of the [mRNA/DNA] hybrid. We demonstrated that in wheat germ extract, the modified and unmodified oligonucleotides behaved similarly due to the presence of a high RNaseH activity. RNaseH was also present, although to a lesser extent, in the oocyte cytoplasm. This anti-messenger DNA-induced degradation of target mRNA resulted in amplified efficiency of hybrid-arrested translation. This additional mechanism might provide anti-sense DNAs with an advantage over anti-sense RNAs.

Aminacrine↗

PubMed1984

Changes in deoxyribonucleic acid linking number due to treatment of mammalian cells with the intercalating agent 4'-(9-acridinylamino)methanesulfon-m-anisidide.

Treatment of mammalian cells with DNA intercalating agents produces protein-associated DNA strand breaks. These breaks have been proposed to represent the action of a topoisomerase, which would alter the DNA linking number. Changes in DNA linking number in cells treated with the intercalating agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) were studied by ethidium titration of nucleoid sedimentation. m-AMSA treatment was found to produce an increase in DNA linking number. Previously, we had proposed that intercalator-induced protein-associated DNA breaks act to reduce DNA torsional strain that results from the intercalator-induced decrease in DNA twist. In such a model, linking number would be expected to decrease. The finding that the DNA linking number increased following m-AMSA treatment suggests that intercalators may block enzymes that normally decrease linking number. Such enzymes would have DNA gyrase like properties. Consistent with this possibility, a DNA gyrase inhibitor, novobiocin, inhibited the restoration of normal linking number and, to a lesser degree, the reversal of protein-associated strand breaks after removal of intercalator.

Aminoacridines↗

PubMed1988

A new combination of two intercalating agents (mitoxantrone + daunomycin) in adult refractory acute leukemia: the DON protocol.

A combination of two intercalating agents, mitoxantrone and daunorubicin with vincristine (the DON regimen) was studied in 16 patients with refractory acute leukemia, including three patients with myeloblastic transformation of refractory anemia with excess of myeloblasts after the failure of first-line chemotherapy and one additional patient with AML relapsing while off therapy. All patients had been heavily pretreated prior to receiving the DON regimen, and all but two had previously received high-dose anthracyclines. Of the 17 patients, nine (53%) who achieved complete remissions (CR) had myeloblastic leukemia. The three patients with acute lymphocytic leukemia did not achieve CR. Cardiac toxicity occurred in two patients and contributed to death in one. These results in very poor risk leukemia suggest a possible synergism in the action of the two intercalating agents and absence of increased cardiotoxicity.

Adolescent↗

PubMed1987

Double helices with parallel strands are formed by nuclease-resistant oligo-[alpha]-deoxynucleotides and oligo-[alpha]-deoxynucleotides covalently linked to an intercalating agent with complementary oligo-[beta]-deoxynucleotides.

Oligo-[alpha]-thymidylates have been synthesized and covalently linked to an intercalating agent (an acridine derivative) and/or to a p-azidophenacyl group. These molecules bind to a complementary oligo-[beta]-deoxynucleotide. A strong stabilization is obtained by covalent attachment of the acridine derivative at the 5' end of the oligo-[alpha]-deoxynucleotide. Upon excitation of the p-azidophenacyl group with ultraviolet light, the oligo-[alpha]-thymidylate is crosslinked to its target sequence. These crosslinks are converted to chain breaks under alkaline conditions. This allows an unambiguous assignment of the orientation of the two oligonucleotide chains. As expected, beta-beta hybrids have an antiparallel orientation, whereas the two chains of alpha-beta hybrids are parallel independently of whether an intercalating agent is covalently linked to the alpha-oligo-nucleotide. Oligo-[alpha]-thymidylates covalently linked to an acridine derivative are highly resistant to endo- and exonucleases. Therefore, they could be used as anti-messengers to block mRNA translation in vivo under conditions where oligo-[beta]-deoxynucleotides are usually hydrolysed.

Exonucleases↗

PubMed1981

Acridine dyes and other DNA-intercalating agents induce the luminescence system of luminous bacteria and their dark variants.

Acridine dyes and other DNA-intercalating agents such as ethidium bromide, theophylline, and caffeine induce luminescence in dark variants (K variants) different luminous species of bacteria, as well as in their wild-type luminous cells, prior to induction. The increase in luminescence appears 10-20 min after addition of these agents and is inhibited by chloramphenicol or rifampicin. Addition of these agents affects the synthesis of both luciferase and aldehyde-synthesizing enzymes. It is hypothesized that these agents, through their intercalation into DNA, cause configurational changes resulting in derepressed transcription of the luminescence operon.

Acridines↗