Sequence-specific Changes in the Metal Site of Ferric Bleomycin Induced by the Binding of DNA

Sam, Joseph; Takahashi, Satoshi; Lippai, István; Peisach, Jack; Rousseau, Denis L.

doi:10.1074/jbc.273.26.16090

Cited by 30 publications

(42 citation statements)

References 41 publications

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“…Bleomycin sulfate is used clinically in combination chemotherapy for the treatment of head and neck cancer, certain lymphomas, and testicular cancer. [63] The cytotoxicity of BLM is believed to result from its ability to bind iron (20-Fe), [64] activate oxygen, and cleave DNA [63] and possibly RNA. [65] The ability of the Fe II ± BLM complex to bind to oxygen and produce oxygenated BLM species such as O 2 À -Fe III -BLM or O 2 -Fe II -BLM may be due to the presence of delocalized p electrons around iron and the strong iron ± pyrimidine p backbonding.…”

Section: Organic Drugs Targeted At Metalsmentioning

confidence: 99%

Metals in Medicine

Guo

Sadler

1999

Angew. Chem. Int. Ed.

838

504

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Not only the 24 or so essential elements, but also nonessential and even radioactive elements have enormous potential for applications in medicine. In the fight against cancer cisplatin, one of the world's best selling anticancer drugs, is being joined by other platinum, titanium, and ruthenium complexes. Gadolinium(III) complexes can be safely injected as magnetic resonance imaging contrast agents, and ligand design allows targeting of paramagnetic ions as well as radiodiagnostic (e.g. Tc) and radiotherapeutic isotopes (e.g. Re). Manganese superoxide dismutase mimics, vanadium insulin mimics, ruthenium nitric oxide scavengers, lanthanide-based photosensitizers, and metal-targeted organic agents show exciting clinical potential.

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Section: Organic Drugs Targeted At Metalsmentioning

confidence: 99%

Metals in Medicine

Guo

Sadler

1999

Angew. Chem. Int. Ed.

838

504

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“…Finally, recent studies indicate that both the metal and DNA domains of HO 2 -Co(III)Blm interact cooperatively with DNA oligomers containing the specific cleavage sites 59-GC-39 or 59-GT-39 [18,19,20]. Importantly, with both Co-and FeBlm species, binding to site-specific or nonspecific DNA 10-mers produces distinctly different properties at the metal-binding centers [21,22].…”

Section: Introductionmentioning

confidence: 97%

Interactions of iron bleomycin, phosphate or cyanide, and DNA: sequence-dependent conformations and reactions

Xia

Antholine

et al. 2001

JBIC

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The hypothesis was investigated that axial ligands bound to Fe(III)-bleomycin [Fe(III)Blm] are destabilized at specific 5'-guanine-pyrimidine-3' binding sites but are stable at nonselective dinucleotides. DNA oligomers and calf-thymus DNA were used in reactions with L-Fe(III)Blm, where phosphate and cyanide served as examples of large and small ligands (L). Both ligands underwent dissociation when L-Fe(III)Blm was bound to d(GGAAGCTTCC)2 (I) but not d(GGAAATTTCCC)2 (II) and at large ratios of calf-thymus DNA to drug. Fe(III)Blm is high spin in 20 mM phosphate buffer, signifying the presence of a phosphate adduct. In the titration of HPO4-Fe(III)Blm with calf-thymus DNA, a large excess of DNA was needed to reach the low-spin state, consistent with an equilibrium competition between phosphate and DNA for Fe(III)Blm. Equilibrium constants for binding Fe(III)Blm and CN-Fe(III)Blm to calf-thymus DNA (6.8x10(5) M(-1) and 5.9x10(4) M(-1), respectively, in HEPES buffer at 25 degrees C and pH 7.4) showed that the CN- ligand also reduced the affinity of DNA for the drug. The kinetics of dissociation of CN- from CN-Fe(III)Blm-DNA were slow and first order in bound drug. The reversible nature of these dissociation reactions was shown using 1H NMR spectroscopy of Fe(III)Blm-I in the absence and presence of large excesses of CN- or phosphate. The results are discussed in terms of a two-state hypothesis for the binding of L-Fe(III)Blm to specific and nonspecific dinucleotides. It is proposed that steric restrictions at specific sites inhibit binding of these ligands.

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“…There are significant decreases in the bandwidths of modes associated with G, A, and sugar modes, which may be due to restricted conformational movement within localized portions of the DNA structure resulting from the proximity of the drug. 46 At 19°C, a temperature more remote from physiological conditions, for the mixture of bleomycins A 2 ϩ B 2 with ct-DNA both G and C bases are consistently hypochromic but to a lesser extent than they are at 30°C in the spectral region 1160 -1290 cm Ϫ1 . Many of the other vibrational modes have become normochromic relative to ct-DNA.…”

Section: Discussionmentioning

confidence: 99%

“…While it is tempting to propose minor groove binding at lower temperatures, especially for Blm B2, there is no consistent Raman marker for this phenomenon other than decreases in the effects due to intercalation (i.e., decreased bandwidths and hypochromism). 16,35,46,47 The most persistent perturbation in the Raman spectrum of all the samples is the behavior of the bands in the spectral region 1215-1273 cm Ϫ1 . In this region, the relative hyperchromicity of the T mode at 1249 cm Ϫ1 is probably due to unstacking of T residues.…”

Section: Discussionmentioning

confidence: 99%

A systematic approach toward the analysis of drug–DNA interactions using Raman spectroscopy: The binding of metal‐free bleomycins A ₂ and B ₂ to calf thymus DNA

1999

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Sequence-specific Changes in the Metal Site of Ferric Bleomycin Induced by the Binding of DNA

Cited by 30 publications

References 41 publications

Metals in Medicine

Metals in Medicine

Interactions of iron bleomycin, phosphate or cyanide, and DNA: sequence-dependent conformations and reactions

A systematic approach toward the analysis of drug–DNA interactions using Raman spectroscopy: The binding of metal‐free bleomycins A ₂ and B ₂ to calf thymus DNA

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Sequence-specific Changes in the Metal Site of Ferric Bleomycin Induced by the Binding of DNA

Cited by 30 publications

References 41 publications

Metals in Medicine

Metals in Medicine

Interactions of iron bleomycin, phosphate or cyanide, and DNA: sequence-dependent conformations and reactions

A systematic approach toward the analysis of drug–DNA interactions using Raman spectroscopy: The binding of metal‐free bleomycins A 2 and B 2 to calf thymus DNA

Contact Info

Product

Resources

About

A systematic approach toward the analysis of drug–DNA interactions using Raman spectroscopy: The binding of metal‐free bleomycins A ₂ and B ₂ to calf thymus DNA