Showing papers on "Polyamine binding published in 2009"

The polyamine analog PG11047 potentiates the antitumor activity of cisplatin and bevacizumab in preclinical models of lung and prostate cancer.

Abstract: PG11047 is a polyamine analog currently in Phase I trials for advanced cancer as a monotherapy and in combination with a number of approved anti-cancer agents The use of polyamines as a target for antiproliferative therapy is based on findings that cells synthesize polyamines excessively when induced to grow and that polyamine metabolism is frequently dysregulated in cancer A selective polyamine transport system provides access for PG11047 into rapidly dividing cells to inhibit polyamine biosynthetic enzymes, to induce the polyamine catabolic enzymes spermidine/spermine N 1-acetyltransferase (SSAT) and spermine oxidase (SMO) which could subsequently induce reactive oxygen species that contribute to tumor cell responses to PG11047, and to function as a polyamine with altered function when it binds to natural polyamine binding sites The objective of the present study was to assess the antitumor effects of PG11047 alone and in combination with approved anti-cancer agents The antitumor efficacy of PG11047 as a single agent, and in combination with cisplatin and bevacizumab, was tested in models of lung (A549) and prostate (DU-145) cancer, respectively PG11047 significantly inhibited tumor development in both lung and prostate cancer models when administered as a single agent In the lung cancer model, PG11047 potentiated the antitumor effect of cisplatin Although potent activity was observed with PG11047 and bevacizumab when administered as single agents in the prostate cancer model, the combination arm significantly enhanced antitumor activity compared with either agent alone In all experiments, PG11047 was well tolerated with no adverse effects on bodyweight gain The preclinical data support the rationale for the current Phase I trials which are assessing PG11047 as a monotherapy and in combination with a number of approved anti-cancer agents including cisplatin and bevacizumab

A conceptual model of the polyamine binding site of N1-acetylpolyamine oxidase developed from a study of polyamine derivatives.

Abstract: We used various polyamine derivatives to study the substrate binding site of N 1-acetylpolyamine oxidase (PAO) that was partially purified from rat liver. The substrate activities of acetylpolyamines indicated the presence of two anionic centers corresponding to the 1,3-diaminopropane (1,3-DAP) structure and a hydrophobic region in addition to the cleavage site of the acetamidopropyl group. Based on the results of the inhibitory activities of 1,3-DAP derivatives, we developed a conceptual model of the polyamine binding site of PAO. We used this model to identify a potent competitive inhibitor, N 1,N 7-dihexyl-1,7-diamino-4-azaheptane, and to develop an affinity column, 1,16-diamino4,13-diazahexadecane–linked Sepharose, which was useful for the purification of PAO.

Docking simulation of polyamines on a kissing-loop RNA dimer

Abstract: Polyamines, especially branched polyamines such as tetrakis(3-aminopropyl)ammonium (Taa), stabilize the tertiary structure of RNA molecules. In this study, we examined the polyamine binding site of the HIV-1 dimerization initiation site (DIS) in the kissing-loop dimer by the docking simulation. It was found that Taa binds predominantly to the kissing loop interaction site of DIS.

Macro-ions collapse leading to hybrid bio-nanomaterials.

Abstract: I used supramolecular self-assembling cyanine and the polyamine spermine binding to Escherichia coli genomic DNA as a model for DNA collapse during high throughput screening. Polyamine binding to DNA converts the normally right handed B-DNA into left handed Z-DNA conformation. Polyamine binding to DNA was inhibited by the supramolecular self-assembling cyanine. Self-assembly of cyanine upon DNA scaffold was likewise competitively inhibited by spermine as signaled by fluorescence quench from DNA-cyanine ensemble. Sequence of DNA exposure to cyanine or spermine was critical in determining the magnitude of fluorescence quench. Methanol potentiated spermine inhibition by >10-fold. The IC{sub 50} for spermine inhibition was 0.35 {+-} 0.03 {micro}M and the association constant Ka was 2.86 x 10{sup -6}M. Reversibility of the DNA-polyamine interactions was evident from quench mitigation at higher concentrations of cyanine. System flexibility was demonstrated by similar spermine interactions with {lambda}DNA. The choices and rationale regarding the polyamine, the cyanine dye as well as the remarkable effects of methanol are discussed in detail. Cyanine might be a safer alternative to the mutagenic toxin ethidium bromide for investigating DNA-drug interactions. The combined actions of polyamines and alcohols mediate DNA collapse producing hybrid bio-nanomaterials with novel signaling properties that might be useful in biosensor applications. Finally, this work will be submitted to Analytical Sciences (Japan) for publication. This journal published our earlier, related work on cyanine supramolecular self-assembly upon a variety of nucleic acid scaffolds.