Chemotherapy of Testicular Germinal Tumors

2012

IJMS

176

Circular dichroism (CD) spectroscopy is an optical technique that measures the difference in the absorption of left and right circularly polarized light. This technique has been widely employed in the studies of nucleic acids structures and the use of it to monitor conformational polymorphism of DNA has grown tremendously in the past few decades. DNA may undergo conformational changes to B-form, A-form, Z-form, quadruplexes, triplexes and other structures as a result of the binding process to different compounds. Here we review the recent CD spectroscopic studies of the induction of DNA conformational changes by different ligands, which includes metal derivative complex of aureolic family drugs, actinomycin D, neomycin, cisplatin, and polyamine. It is clear that CD spectroscopy is extremely sensitive and relatively inexpensive, as compared with other techniques. These studies show that CD spectroscopy is a powerful technique to monitor DNA conformational changes resulting from drug binding and also shows its potential to be a drug-screening platform in the future.

Section: Conformational Polymorphism Of Dna and Dna-drug Complexesmentioning

confidence: 99%

Conformational Changes in DNA upon Ligand Binding Monitored by Circular Dichroism

Chang

Chen

2012

IJMS

176

“…Mithramycin (plicamycin, Mith) is a member of the aureolic family of drugs isolated from Streptomyces plicatus and contains A-B disaccharide and C-D-E trisaccharide moieties that are connected to a chromophore aglycon via opposing O-glycosidic bonds (Figure ). This drug has been used clinically to treat several types of cancer including testicular carcinoma, chronic myeloid leukemia (CML), and acute myeloid leukemia (AML) , . Structural analysis revealed that Mith binds to the minor groove of DNA duplexes around GC-rich sequences and that this binding is mediated by divalent metal ions such as Mg(II), Co(II), and Fe(II) − .…”

mentioning

confidence: 99%

Effects of Polyamines on the DNA-Reactive Properties of Dimeric Mithramycin Complexed with Cobalt(II): Implications for Anticancer Therapy

Huang

et al. 2009

Biochemistry

Few studies have examined the effects of polyamines on the action of DNA-binding anticancer drugs. Here, a Co(II)-mediated dimeric mithramycin (Mith) complex, (Mith)(2)-Co(II), was shown to be resistant to polyamine competition toward the divalent metal ion when compared to the Fe(II)-mediated drug complexes. Surface plasmon resonance experiments demonstrated that polyamines interfered with the binding capacity and association rates of (Mith)(2)-Co(II) binding to DNA duplexes, while the dissociation rates were not affected. Although (Mith)(2)-Co(II) exhibited the highest oxidative activity under physiological conditions (pH 7.3 and 37 degrees C), polyamines (spermine in particular) inhibited the DNA cleavage activity of the (Mith)(2)-Co(II) in a concentration-dependent manner. Depletion of intracellular polyamines by methylglyoxal bis(guanylhydrazone) (MGBG) enhanced the sensitivity of A549 lung cancer cells to (Mith)(2)-Co(II), most likely due to the decreased intracellular effect of polyamines on the action of (Mith)(2)-Co(II). Our study suggests a novel method for enhancing the anticancer activity of DNA-binding metalloantibiotics through polyamine depletion.

“…Both anticancer antibiotics, chromomycin A 3 (Chro) and mithramycin (Mith), are members of the aureolic family isolated from Streptomyces griseus and Streptomyces argillaceus, respectively – . These drugs contain di- and trisaccharide moieties connected to an aglycon chromophore via opposite O-glycosidic bonds, with the A−B disaccharide being on one side, while the C−D−E trisaccharide on the other side (Figure A).…”

mentioning

confidence: 99%

Studies of Sequence-Specific DNA Binding, DNA Cleavage, and Topoisomerase I Inhibition by the Dimeric Chromomycin A₃ Complexed with Fe^II

Lin

et al. 2008

Biochemistry

Chromomycin A3 (Chro) has been evidenced to exhibit much higher binding affinity toward Fe(II) by forming a highly stable 2:1 drug/metal complex, compared to its structural analogue, mithramycin (Mith). Different properties of the [(Chro)2-Fe(II)] complex acting on DNA, such as sequence specificity, DNA cleavage, and topoisomerase I (TopI) inhibition were studied. Kinetic analyses of surface plasmon resonance showed that the affinity of the [(Chro)2-Fe(II)] complex upon binding to hairpin DNA duplexes containing various tetranucleotide sequences follows the order: GGCC > CGCG > CCGG approximately GCGC > AGCT > ACGT > TGCA > TCGA. According to circular dichroism (CD) studies, most hairpin DNA duplexes appeared to retain their B-type conformations in the presence of the [(Chro)2-Fe(II)] complex, except the duplex containing the GGCC sequence, which exhibited the features of both A- and B-type DNA. In DNA-cleavage assays, the [(Chro) 2-Fe(II)] complex was shown to cause single-stranded cleavage of plasmid DNA because of a Fenton-type reaction. DNA cleavage activity of the [(Chro) 2-Fe(II)] complex was increased at low pH. Moreover, the complex was capable of inhibiting TopI activity. The [(Chro)2-Fe(II)] complex exhibited higher cytotoxicity than the [(Mith) 2-Fe(II)] complex in several cancer cell lines, most likely owing to its more stable dimeric structure and higher DNA-binding affinity. Our results provide significant evidence that the [(Chro)2-Fe(II)] complex could be promising in terms of its biological applications in the future.