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PubMed1979

Simultaneous production of Q and R bands after staining with chromomycin A3 or olivomycin.

Human and mouse chromosomes, stained with either chromomycin A3 or olivomycin, which bind preferentially to G - C-rich DNA (where G is guanosine and C is cytosine), exhibit a Q or a reverse banding pattern, depending on the wavelength used for excitation. The two complementary banding patterns can be observed in the same metaphase simply by changing the combination of excitation filters. These data suggest, therefore, that in addition to base composition, other factors are involved in the production of chromosome banding by chromomycin A3 and olivomycin.

Animals↗
PubMed1977

Chromomycin A3 as a fluorescent probe for flow cytometry of human gynecologic samples.

Chemical, physical and optical properties of chromomycin A3 are examined so as to ascertain appropriate staining and analysis procedures for flow cytometry of human gynecologic samples. Fluorescence excitation and emission spectra of chromomycin A3-stained cervical cells are compared with those of chromomycin A3-stained deoxyribonucleic acid. Conditions for deoxyribonucleic acid-specific staining of cervical cells are presented, and staining specificity of cervical cells with chromomycin A3 is compared to that obtained with ethidium bromide, propidium iodide and Hoechst 33258. Also presented is a brief review of two parameter flow cytometry as a prescreening procedure for detection of cervical neoplasia. Results of flow cytometry and cell sorting are interpreted based on the deoxyribonucleic acid-specificity of chromomycin A3 staining.

Cell Nucleus↗
PubMed1993

The sugars in chromomycin A3 stabilize the Mg(2+)-dimer complex.

Chromomycin A3 (CRA3) is a glycosylated antitumor antibiotic that binds as a dimer to the minor groove of DNA, with a Mg2+ cation (or another divalent cation with a radius less than 0.85 A) forming the center of the dimer. It has been shown that the chromose sugars are necessary for DNA binding [Kaziro & Kamiyama (1967) J. Biochem. (Tokyo) 62, 424-429; Kamiyama (1968) J. Biochem. (Tokyo) 63, 566-572], although the reason for this has not been addressed. We have investigated the role that the chromose sugars play in metal complexation in solution (methanol) by comparing the optical behavior of CRA3 and its aglycon, CRN, in the presence of various divalent metals (Mg2+, Ni2+, and Ca2+). The results show that CRA3 forms a dimeric complex [i.e., (CRA3)2M, where M is a metal ion] in the presence of 1 mol equiv of either Ni2+ or Mg2+ but a 1:1 complex in the presence of the much larger Ca2+. In contrast, CRN forms a 1:1 complex (CRN.M)+ with all three metals under identical conditions (1:1 mole ratio of drug to metal). Thus, for the smaller metal ions the sugars stabilize the 2:1 CRA3-metal complex in solution. NMR data on the 2:1 CRA3-Mg2+ complex show that the trisaccharide of one CRA3 molecule lies in close proximity to the chromophore of the other CRA3 molecule. This interaction, which is also present in the Mg(2+)-CRA3-DNA complex [Gao & Patel (1989) Biochemistry 28, 751-762], appears to be related to the stability of the dimer in solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Anthracenes↗
PubMed1978

Chromomycin A3 for advanced breast cancer: a Southwest Oncology Group study.

Chromomycin A3 was administered iv to 26 patients in a phase I trial. The maximum tolerated dose established in this study was 0.75 mg/m2/day iv X 5 days. The drug was then given to 48 evaluable patients with far-advanced disseminated breast cancer. Two short partial remissions and one clinical improvement were seen. Toxic manifestations consisted of frequent and usually reversible renal toxicity, nausea and vomiting, occasional thrombocytopenia, hypocalcemia, and two instances of semicoma. Drug toxicity may have contributed to the death of two patients.

Breast Neoplasms↗
PubMed1993

Selective accumulation of diamidino yellow and chromomycin A3 by retinal glial cells.

We applied the fluorescent DNA stains diamidino yellow (DY) and chromomycin A3 to rat and rabbit retinas in vivo and in vitro. They accumulated in the nuclei of a subpopulation of cells of the inner nuclear layer. The number and distribution of the fluorochrome-accumulating cells were similar to those of the Müller glia, and double-labeling experiments showed that the cells accumulating DY or chromomycin A3 contained oriented filaments of vimentin. The fluorochromes also accumulated in the sparse astrocytes and oligodendrocytes located among the myelinated fibers of the rabbit central retina. Specific accumulation in retinal glia occurred only when the fluorochromes were applied to living retinas. If the plasma membranes were disrupted by fixation or exposure to detergent, most retinal cells were stained. This indicates that the locus of specificity is the entry of the molecules into the cells. When applied to living retinas, other DNA stains selectively accumulate in subclasses of retinal neurons. Why DNA-binding molecules should selectively cross the membranes of either retinal neurons or retinal glia remains an unsolved problem.

Amidines↗
PubMed2006

Deoxysugar transfer during chromomycin A3 biosynthesis in Streptomyces griseus subsp. griseus: new derivatives with antitumor activity.

Chromomycin A3 is an antitumor drug produced by Streptomyces griseus subsp. griseus. It consists of a tricyclic aglycone with two aliphatic side chains and two O-glycosidically linked saccharide chains, a disaccharide of 4-O-acetyl-D-oliose (sugar A) and 4-O-methyl-D-oliose (sugar B), and a trisaccharide of D-olivose (sugar C), D-olivose (sugar D), and 4-O-acetyl-L-chromose B (sugar E). The chromomycin gene cluster contains four glycosyltransferase genes (cmmGI, cmmGII, cmmGIII, and cmmGIV), which were independently inactivated through gene replacement, generating mutants C60GI, C10GII, C10GIII, and C10GIV. Mutants C10GIV and C10GIII produced the known compounds premithramycinone and premithramycin A1, respectively, indicating the involvement of CmmGIV and CmmGIII in the sequential transfer of sugars C and D and possibly also of sugar E of the trisaccharide chain, to the 12a position of the tetracyclic intermediate premithramycinone. Mutant C10GII produced two new tetracyclic compounds lacking the disaccharide chain at the 8 position, named prechromomycin A3 and prechromomycin A2. All three compounds accumulated by mutant C60GI were tricyclic and lacked sugar B of the disaccharide chain, and they were named prechromomycin A4, 4A-O-deacetyl-3A-O-acetyl-prechromomycin A4, and 3A-O-acetyl-prechromomycin A4. CmmGII and CmmGI are therefore responsible for the formation of the disaccharide chain by incorporating, in a sequential manner, two D-oliosyl residues to the 8 position of the biosynthetic intermediate prechromomycin A3. A biosynthetic pathway is proposed for the glycosylation events in chromomycin A3 biosynthesis.

Antibiotics, Antineoplastic↗
PubMed1997

Differential interactions of the Mg2+ complexes of chromomycin A3 and mithramycin with poly(dG-dC) x poly(dC-dG) and poly(dG) x poly(dC).

The interaction of the two anticancer antibiotics, chromomycin A3 and mithramycin, with the polynucleotides poly(dG-dC) x poly(dC-dG), representative of B-DNA, and poly(dG) x poly(dC), representative of A-DNA, in the presence of Mg2+ is studied by spectroscopic techniques such as absorbance, fluorescence, and dircular dichroism (CD). The studies were done with both drug x Mg2+ complexes, I and II, having 1:1 and 2:1 stoichiometries with respect to drug and Mg2+, respectively [Aich, P., Sen, R., & Dasgupta, D. (1992) Biochemistry 31, 2988-2997]. The objective of the present work is 2-fold. First, an attempt is made to understand the structural basis of the ligand-DNA interaction, particularly the role of DNA backbone conformation with its groove size and the accessibility of the 2-amino group in the minor groove of guanosine. Second, the role of the antibiotic saccharide moieties in the association with DNA was studied. For this purpose, the spectroscopic characterization of the binding was done followed by the evaluation of binding parameters and associated thermodynamics. Analysis of the observed thermodynamics for the ligand-DNA interactions in terms of the different structures of the polynucleotides was done. The salient results are as follows. Complex I does not discriminate significantly among the A- and B-forms of DNA when it binds to them in an entropy-driven process. On the other hand, complex II for both drugs recognizes B- and A-forms of DNA in different ways. This observation implies that the sequence specificity shown by this complex is a sequel to the difference in the parameters such as groove size and accessibility of the guanosine amino group. Another important finding is that binding with the same polynucleotide is not comparable for the complex II of the two drugs. It emphasizes the involvement of the sugar moieties, when the drug x Mg2+ complex binds to DNA. The presence of an acetoxy group in the sugars of chromomycin A3 imparts some distinctive specific features of the association of the chromomycin dimer x Mg2+ complex with DNA. Finally, the results are compared with those available from NMR studies of different drug-oligonucleotide complexes under conditions where complex II is the ligand.

Chromomycin A3↗
PubMed1985

Development of enzyme immunoassay for chromomycin A3 and olivomycin using beta-D-galactosidase as a label.

An antibody specific for chromomycin A3 (CHM; byname, toyomycin) was produced in sufficiently high titer in rabbits by immunization with a CHM-bovine serum albumin conjugate, prepared using diazotized p-aminobenzoic acid as a coupling agent. CHM was also coupled with beta-D-galactosidase (EC 3.2.1.23) using diazotized m-aminobenzoic acid and was used as a tracer. With these reagents, a double-antibody enzyme immunoassay for CHM and for the CHM homologue olivomycin was developed which was highly sensitive and accurate enough to measure as little as 10 and 50 pg of each drug per assay tube, respectively. The enzyme immunoassay did not cross-react with mithramycin and drugs commonly used with CHM in combination chemotherapy for cancer treatment. Using this assay, drug levels were easily determined in blood and urine of rats following administration of CHM in a single dose of 2.0 mg/kg i.v. The sensitivity and specificity of the enzyme immunoassay for CHM and olivomycin should provide a valuable new tool for use in pharmacokinetic and toxicity studies of these drugs.

Animals↗
PubMed2002

Chromomycin A3 inhibits influenza a virus multiplication in chick embryo fibroblast cells.

The multiplication of Ulster 73 virus, an avian strain of type A influenza virus, was blocked in chick embryo fibroblast cells, CEF, by treatment with 0.5 microg/ml of chromomycin A3 whereas in LLC-MK2 cells no inhibition of replication was observed. Virus-induced polypeptide synthesis in chick embryo fibroblast cells was confined to the synthesis of PB2, PB1 and PA subunits of the RNA dependent-RNA polymerase, the nucleoprotein NP, the non-structural protein NS1, the haemagglutinin HA, the non-structural protein NS2; only the membrane M1 polypeptide synthesis was greatly inhibited. Viral unpolyadenylated cRNAs synthesis was studied at a late time of the infection, 8 hours p.i.: chromomycin A3 was able to inhibit the "novo" synthesis of complementary RNA poly(A)- and segment 7 of virion RNA. The mode of action of the drug in chick embryo fibroblast cells is discussed.

Animals↗
PubMed1975

Effect of the antitumor antibiotic chromomycin A3 on the humoral immune response in rats.

Chromomycin A3 (250 mug/kg) suppressed the humoral immune response in rats against sheep erythrocytes when administered 48 h or later after antigenic stimulus. The antibiotic at this dose enhanced immunity when given along with or before antigen administration. The natural heterohemagglutinin levels in rabbits and guinea pigs were not affected by the antibiotic (10 mug/kg per day x 7).

Animals↗
PubMed2005

DNA structural similarity in the 2:1 complexes of the antitumor drugs trabectedin (Yondelis) and chromomycin A3 with an oligonucleotide sequence containing two adjacent TGG binding sites on opposing strands.

Yondelis (trabectedin) is an antitumor ecteinascidin that binds covalently to the 2-amino group of the central guanine in the minor groove of selected DNA pyrimidine-G-G and purine-G-C triplets. Chromomycin A3 is an aureolic acid derivative that binds noncovalently to the DNA minor groove in G/C-rich triplet sites as a metal-chelated dimer. Despite their different binding modes, the cytotoxicity profiles of these two drugs, as assessed in the COMPARE analysis carried out by the National Cancer Institute on data from 60 human tumor cell lines, are highly correlated (Pearson's correlation coefficient of 0.96). We now report that in an oligonucleotide containing the "natural bending element" TGGCCA, the structural distortions inflicted by the tail-to-tail bonding of two trabectedin molecules to adjacent target sites on opposing strands are strikingly similar to those observed in a crystal containing d(TTGGCCAA)2 and two bound chromomycin A3 molecules arranged in a head-to-tail orientation in the minor groove. In both complexes, the double helix is characterized by being considerably unwound and possessing a notably widened minor groove. Binding of the drugs to this sequence could be favored by the distinct bends at each of the TpG steps that are already present in the free oligonucleotide. Simultaneous drug binding to the two strands in the manner described here is proposed to stabilize the helical structure of duplex DNA to prevent or hamper strand separation and stall replication and transcription forks.

Antineoplastic Agents↗
PubMed1988

Improved resolution of flow cytometric measurements of Hoechst- and chromomycin-A3-stained human chromosomes after addition of citrate and sulfite.

The resolution of bivariate flow karyotypes of human chromosomes stained with Hoechst 33258 and chromomycin A3 can be increased by adding sodium citrate and sodium sulfite to the chromosomes shortly before measurement. A flow karyotype of a patient with chronic myelocytic leukemia is shown to illustrate that the addition of these compounds allows high-resolution measurements to be made and evaluated reliably from clinical samples.

Benzimidazoles↗
PubMedDate not supplied

Interactions of chromomycin A3 and mithramycin with the sequence d(TAGCTAGCTA)2.

Anti-cancer antibiotics, chromomycin A3 (CHR) and mithramycin (MTR) inhibit DNA directed RNA synthesis in vivo by binding reversibly to template DNA in the minor groove with GC base specificity, in the presence of divalent cations like Mg2+. Under physiological conditions, (drug)2Mg2+ complexes formed by the antibiotics are the potential DNA binding ligands. Structures of CHR and MTR differ in their saccharide residues. Scrutiny of the DNA binding properties reveal significant differences in their sequence selectivity, orientation and stoichiometry of binding. Here, we have analyzed binding and thermodynamic parameters for the interaction of the antibiotics with a model oligonucleotide sequence, d(TAGCTAGCTA)2 to understand the role of sugars. The oligomer contains two potential binding sites (GpC) for the ligands. The study illustrates that the drugs bind differently to the sequence. (MTR)2Mg2+ binds to both sites whereas (CHR)2Mg2+ binds to a single site. UV melting profiles for the decanucleotide saturated with the ligands show that MTR bound oligomer is highly stabilized and melts symmetrically. In contrast, with CHR, loss of symmetry in the oligomer following its association with a single (CHR)2Mg2+ complex molecule leads to a biphasic melting curve. Results have been interpreted in the light of saccharide dependent differences in ligand flexibility between the two antibiotics.

Binding Sites↗
PubMed1990

NMR studies of the interaction of chromomycin A3 with small DNA duplexes. Binding to GC-containing sequences.

The interaction of chromomycin A3 with the oligodeoxyribonucleotides 1, d(ATGCAT), 2, d(ATCGAT), 3, d(TATGCATA), and 4, d(ATAGCTAT), has been investigated by 1H and 31P NMR. In the presence of Mg2+, chromomycin binds strongly to the three GC-containing oligomers 1, 3, and 4 but not to the CG-containing oligomer 2. The proton chemical shift changes for 1 and 3 are similar, and these DNA duplexes appear to bind with a stoichiometry of 2 drugs:1 Mg2+:1 duplex. The same stoichiometry of 2 drugs:1 duplex is confirmed with 4; however, proton chemical shift changes differ. An overall C2 symmetry is exhibited by the drug complex with 1, 3, and 4. At a molar ratio of 2.0 (drugs:duplex), no free DNA proton NMR signals remain. Two-dimensional nuclear Overhauser exchange spectroscopy (NOESY) of the saturated chromomycin complex with 1 and 3 positions both chromomycinone hydroxyls and the E carbohydrates in the minor groove and provides evidence suggesting that the B carbohydrates lie on the major-groove side. This is supported by several dipolar coupling cross-peaks between the drug and the DNA duplex. Drug-induced conformational changes in duplex 1 are evaluated over a range of NOESY mixing times and found to possess some characteristics of both B-DNA and A-DNA, where the minor groove is wider and shallower. A widening of the minor groove is essential for the DNA duplex to accommodate two drug molecules. This current minor-groove model is a substantial revision of our earlier major-groove model [Keniry, M.A., Brown, S.C., Berman, E., & Shafer, R.H. (1987) Biochemistry 26, 1058-1067] and is in agreement with the model recently proposed by Gao and Patel [Gao, X., & Patel, D. J. (1989a) Biochemistry 28, 751-762].

Base Composition↗
PubMed1973

Potentiation of 5-fluorouracil, chromomycin A3, and bleomycin by amphotericin B or polymyxin B in transformed fibroblastic cells.

By using cultured, transformed fibroblastic cells, antitumor agents including cytosine arabinoside, thio-tepa, nitrogen mustard N-oxide, mitomycin C, chromomycin A3, 5-fluorouracil, daunomycin, vinblastine, vincristine, and bleomycin A2 were screened for the potentiation of their activity by amphotericin B or polymyxin B. Among them, the action of 5-fluorouracil and chromomycin A3 on ribonucleic acid synthesis was potentiated in their action by amphotericin B, not by polymyxin B. Bleomycin A2 was potentiated in its action on deoxyribonucleic acid and ribonucleic acid synthesis only by polymyxin B.

Amphotericin B↗
PubMed1979

Flow cytometry of human gynecologic specimens using log chromomycin A3 fluorescence and log 90 degrees light scatter.

Flow cytometry and electronic cell sorting are being investigated to screen gynecologic specimens for cervical neoplasia. Cellular DNA content is quantitated by Chromomycin A3 fluorescence and cell size is quantitated by 90 degrees light scatter; the logarithms of the measured intensities are used to produce a two parameter histogram. To determine the cell types responsible for signals in various histogram regions, systematic electronic cell sorting is performed. The sorted fractions are sedimented into microscope slides and stained by the Papanicolaou technique. The cells in each fraction are identified by conventional cytomorphologic criteria. Morphologic analysis of sorted cells reveals histogram regions corresponding to specific cell types. One very important region contains the highest concentration of signals from abnormal cells and is therefore the best region to analyze for specimen abnormality. However, because a significant number of signals in this region are from normal cells, specimens cannot be diagnosed by their analysis. Another important histogram region is composed primarily of signals from endocervical columnar and metaplastic cells. The presence of such cells is a good criterion for specimen adequacy, therefore analysis of signals in this region is essential to assess specimen adequacy for automatic screening.

Cervix Uteri↗