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Biomedical subjects

A Rodger

Publications and source records attributed to A Rodger.

At least 19 recordsLinked to original sources
PubMed1998

Spectroscopic studies of 9-hydroxyellipticine binding to DNA.

The binding of 9-hydroxyellipticine to calf thymus DNA, poly[d(A-T)]2, and poly[d(G-C)]2 has been studied in detail by means of CD, linear dichroism, resonance light scattering, and molecular dynamics. The transition moment polarizations of 9-hydroxyellipticine were determined in polyvinyl alcohol stretched film. Spectroscopic solution studies of the DNA/drug complex are combined with theoretical CD calculations using the final 50 ps of a series of molecular dynamics simulations as input. The spectroscopic data shows 9-hydroxyellipticine to adopt two main binding modes, one intercalative and the other a stacked binding mode involving the formation of drug oligomers in the DNA major groove. Analysis of the intercalated binding mode in poly[d(A-T)]2 suggests the 9-hydroxyellipticine hydroxyl group lies in the minor groove and hydrogen bonds to water with the pyridine ring protruding into the major groove. The stacked binding mode was examined using resonance light scattering and it was concluded that the drug was forming small oligomer stacks rather than extended aggregates. Reduced linear dichroism measurements suggested a binding geometry that precluded a minor groove binding mode where the plane of the drug makes a 45 degrees angle with the plane of the bases. Thus it was concluded that the drug stacks in the major groove. No obvious differences in the mode of binding of 9-hydroxyellipticine were observed between different DNA sequences; however, the stacked binding mode appeared to be more favorable for calf thymus DNA and poly[d(G-C)]2 than for poly[d(A-T)]2, an observation that could be explained by the slightly greater steric hindrance of the poly[d(A-T)]2 major groove. A strong concentration dependence was observed for the two binding modes where intercalation is favored at very low drug load, with stacking interactions becoming more prominent as the drug concentration is increased. Even at DNA: drug mixing ratios of 70:1 the stacked binding mode was still important for GC-rich DNAs.

Animals↗
PubMed1997

DNA-binding studies of XSPTSPSZ, derivatives of the intercalating heptad repeat of RNA polymerase II.

The synthesis, solution conformation, and interaction with DNA of three 8-residue peptides structurally related to the heptad repeat unit found at the C-terminus of RNA polymerase II are reported. Peptides QQ, XQ, and PQ are derived from the parent sequence YSPTSPSY (peptide YY), which was reported to bind to DNA by bisintercalation [M. Suzuki (1990) Nature, Vol. 344, pp. 562-565], and contain either a 2-quinolyl (Q), 2-quinoxolyl (X), or 5-phenanthrolyl (P) group in place of the aromatic side chains of the N- and C-terminal tyrosine residues present in the parent sequence. The combined results of linear dichroism and induced CD measurements of peptides QQ, XQ, and PQ with calf thymus DNA are consistent with weak binding of the peptides to DNA in a preferred orientation in which the chromophores are intercalated. Small increases in the melting temperatures of poly[d(A-T)2] are also consistent with the peptides interacting with DNA. While enzymatic footprinting with DNase I showed no protection from cleavage by the enzyme, chemical footprinting with fotemustine showed that the peptides modify the reactivity of the major groove, presumably via minor groove binding. Peptide QQ inhibited fotemustine alkylation significantly more than either XQ or PQ, and slightly more than YY. In aqueous solution, nmr experiments on QQ, XQ, and PQ show a significant population of a conformation in which Ser2-Pro3-Thr4-Ser5 form both type I and type II beta-turn conformations in equilibrium with open chain conformations. Nuclear magnetic resonance titration experiments of PQ with (GCGTACGC)2 showed small changes in chemical shifts, consistent with the formation of a weak nonspecific complex. Analogous experiments, using peptides QQ and XQ with (GCGTACGC)2, and peptide YY with (CGTACG)2, showed no evidence for the interaction of the peptides with these oligonucleotides. These results show that peptides of general structure XSPTSPSZ are weak nonspecific DNA binders that differ significantly from previously characterized S(T)PXX DNA-binding motifs that are generally AT-selective minor groove binders.

Amino Acid Sequence↗
PubMed1997

Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules.

BACKGROUND: The optimum dose and fractionation schedule for the palliative irradiation of painful bone metastases is controversial. PURPOSE: To compare the efficacy, side-effects and effect on quality of life of two commonly used radiotherapy schedules in the management of painful bone metastases. MATERIALS AND METHODS: In a prospective trial, 280 patients were randomised to receive either a single 10 Gy treatment or a course of 22.5 Gy in five daily fractions for the relief of localised metastatic bone pain. RESULTS: Response rates have been calculated from 240 assessable treated sites of pain. The overall response rates were 83.7% (single treatment) and 89.2% (five fractions). The complete response rates were 38.8% (single treatment) and 42.3% (five fractions). The median duration of pain control was 13.5 weeks (single treatment) and 14.0 weeks (five fractions). None of these differences was statistically significant. There were no differences between the groups in the effect of treatment on a variety of quality of life parameters. CONCLUSIONS: It is concluded that a single 10 Gy treatment is as effective as a course of 22.5 Gy in five fractions in the management of painful bone metastases.

Bone Neoplasms↗
PubMed1997

Cosmesis following complete local excision of breast cancer.

BACKGROUND: With the establishment of the safety of breast conservation in early breast cancer, cosmesis has become an increasingly important end-point of treatment. The aim of the present study was to establish a model to assess breast cosmesis after complete local excision and to assess cosmesis achieved in patients who had surgery using the seroma technique. METHODS: A total of 42 patients were retrospectively reviewed and assessed by independent clinical assessment by a surgeon, structured questionnaire and clinical photography. RESULTS: A total of 86% of patients were rated by surgeon and patient as having a good or excellent cosmetic outcome. There was a high degree of concordance between independent clinical assessment and clinical photographic analysis. CONCLUSIONS: A model has been established for the assessment of breast cosmesis; the technique of seroma formation without reconstruction of the defect results in good or excellent cosmesis in the majority of patients.

Activities of Daily Living↗
PubMed1996

4-Picoline-2,2':6',2"-terpyridine-platinum(II) - a potent intercalator of DNA.

4-Picoloine-2,2':6',2"-terpyridine-platinum(II) is shown in a ligation assay to unwind and so intercalate into DNA. Circular dichroism is used to determine an equilibrium binding constant of approximately 2 x 10(7) M(-1) for the most stable binding mode of 4-picoline-2,2':6',2"-terpyridine-platinum(II) to poly[d(A-T)2] with a site size of about 4 base pairs, and about 1 x 10(6) M(-1) for a second binding mode with a site size of about 2 base pairs. Fluorescence spectroscopy provides further evidence for the strong equilibrium binding constant of 4-picoline-2,2':6',2"-terpyridine-platinum(II) in that it displaces ethidium bromide bound to DNA. The double positive charge on 4-picoline-2,2':6',2"-terpyridine-platinum(II), together with the intercalative binding mode is probably responsible for the large binding constant.

Binding Sites↗
PubMed1996

Interactions of intercalative and minor groove binding ligands with triplex poly(dA).[poly(dT)]2 and with duplex poly(dA).poly(dT) and poly[d(A-T)]2 studied by CD, LD, and normal absorption.

The binding of 9-aminoacridine and one bis-acridine compound to double helical poly(dA).poly-(dT) and poly[d(A-T)]2 and triple helical poly(dA).[poly(dT)]2 has been investigated using linear dichroism (LD) and circular dichroism (CD). A close examination of the negative reduced LD and the induced CD for the first pi-->pi* transition absorption region leads us to conclude that the acridine moiety of the 9-aminoacridine and bis-acridine molecule intercalates with both duplex and triplex DNA. Binding geometries of the acridine moieties in the examined polynucleotides are similar to those found for the ligands with DNA (Hansen et al. (1984) J. Chem. Soc., Chem. Commun., 509-511). It is also found that both 9-aminoacridine and bis-acridine effectively enhance the thermal stability of the triplex DNA. The corresponding spectra for the complexes of the minor groove binders DAPI and Hoechst with poly-(dA).[poly(dT)]2 were studied for comparison. They both show a positive LD and a mixing ratio dependent positive CD in the ligand absorption region, similar to those of their duplex complexes. This indicates that these ligands bind in the grooves of the triplex, probably to the one corresponding to the minor groove of the template duplex.

Acridines↗
PubMed1996

Psychosocial support, treatment of metastatic disease and palliative care.

This article deals with four linked but distinct aspects of care for women with breast cancer, with an emphasis on the pivotal role of the general practitioner: 1. Modern medicine is fast recognising the need for psychosocial support of patients; in fact, for an integrated approach to caring for the whole person at all stages of illness. 2. Oncological treatment of metastatic disease needs to be individualised and based on realistic expectations of outcome balanced against side effects. 3. An open dialogue about the role and appropriateness of so-called "alternative" or "complementary" therapies is needed. 4. Despite significant improvements in palliative care quality and access in Australia in the last decade, many practitioners still require support and advice in this demanding area of care (particularly about difficult symptom control).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

DNA structural features responsible for sequence-dependent binding geometries of Hoechst 33258.

The complexes of Hoechst 33258 with poly[d(A-T)2], poly[d(I-C)2], and poly[d(G-C)2], and poly[d(G-m5C)2] were studied using linear dichroism, CD, and fluorescence spectroscopies. The Hoechst-poly[d(I-C)2] complex, in which there is no guanine amino group protruding in the minor groove, exhibits spectroscopic properties that are very similar to those of the Hoechst-poly[d(A-T)2] complex. When bound to both of these polynucleotides, Hoechst exhibits an average orientation angle of near 45 degrees relative to the DNA helix axis for the long-axis polarized low-energy transition, a relatively strong positive induced CD, and a strong increase in fluorescence intensity--leading us to conclude that this molecule also binds in the minor groove of poly[d(I-C)2]. By contrast, when bound to poly[d(G-C)2] and poly[d(G-m5C)2], Hoechst shows a distinctively different behavior. The strongly negative reduced linear dichroism in the ligand absorption region is consistent with a model in which part of the Hoechst chromophore is intercalculated between DNA bases. From the low drug:base ratio onset of excitonic effects in the CD and fluorescence emission spectra, it is inferred that another part of the Hoechst molecule may sit in the major groove of poly[d(G-C)2] and poly[d(G-m5C)2] and preferentially stacks into dimers, though this tendency is strongly reduced for the latter polynucleotide. Based on these results, the importance of the interactions of Hoechst with the exocyclic amino group of guanine and the methyl group of cytosine in determining the binding modes are discussed.

Base Sequence↗
PubMed1996

Theoretical studies of the intercalation of 9-hydroxyellipticine in DNA.

Extensive molecular dynamics (MD) simulations have been used to investigate the intercalative binding of 9-hydroxyellipticine to the DNA oligonucleotide d(ATATATATATAT)2. Four independent simulations differing in the initial orientation of the drug at the intercalation site were carried out, and compared both with each other and a control simulation of the free DNA sequence. The structure of the latter was compared with structures obtained from x-ray crystallography and nmr spectroscopy, as well as the theoretically derived "alternating B-DNA" model [A. Klug et al. (1979), Journal of Molecular Biology, Vol. 131, p. 669]. The alternation of twist angles observed in experimental structures was reproduced in the simulation. All four independent simulations of the drug-DNA intercalation complex converged in placing the pyridine ring of the ellipticine chromophore in the major groove; in one case this involved a 180 degrees rotation of the drug at the intercalation site. At a more detailed level, the drug is seen to be capable of adopting several distinct orientations, each stable over a period of hundreds of pico-seconds. Despite the presence of several polar groups in the drug, however, no direct hydrogen bonding to the DNA occurs; instead, interactions between the methyl groups of the drug and the thymine bases at the intercalation site appear important in determining the orientational preferences of the drug. Comparison of the intercalation complexes with the free DNA sequence shows a degree of unwinding resulting from intercalation, in good agreement with experimental results, but spread over the three central base-pair steps, not confined to the intercalation site itself. Measurements of torsional rigidity indicate only a slight stiffening of the DNA restricted to the immediate site of intercalation. The structures obtained from the MD simulations were used to calculate theoretical CD spectra, with separate simulations giving very different results. This appears to indicate that given an accurate assignment of the main electronic transition dipole moment of the ellipticine chromophore, discrimination of the more realistic binding geometries may be possible. The relative merits of the various drug orientations observed in the simulations are discussed and a perpendicular orientation of the drug at the intercalation site is considered to be the most consistent with experimental data. While the simulations themselves represent a total of over 2 ns, however, the differences apparent between independent runs indicate that longer simulation times will be required before a complete, unequivocal view of DNA intercalation is obtained.

Base Sequence↗
PubMed1995

Multiple DNA binding modes of anthracene-9-carbonyl-N1-spermine.

The poly(dAdT)2 complex of anthracene-9-carbonyl-N1-spermine, a spermine derivative terminally substituted with an anthracene moiety, has been studied using fluorescence, linear dichroism, circular dichroism, normal absorption spectroscopy (as a function of temperature) and computer modelling. For comparison, some data are also provided for the same ligand with poly(dGdC)2 and calf thymus DNA. Following detailed fluorescence and CD spectroscopic studies, we propose that anthracene-9-carbonyl-N1-spermine intercalates in at least two different binding orientations with poly(dAdT)2. Based on computer simulation data, we deduce that the ligand can intercalate from both the minor groove and the major groove. In contrast, intercalation with poly(dGdC)2 probably occurs only from the major groove. At high ligand concentrations, the CD spectra suggest anthracene-anthracene interactions, whilst the LD data point towards a groove-bound anthracene. Again from computer simulations, we propose binding modes consistent with these observations. Other data from the LD spectra suggest a sequential nature to the binding of the ligand to calf thymus DNA, with GC-rich sites being occupied first. At low ligand concentrations, anthracene-9-carbonyl-N1-spermine is able to stabilize poly(dAdT)2 against thermal decomposition, but not as effectively as spermine. The reverse is found to be true with calf thymus DNA. Both the anthracene-9-carbonyl-N1-spermine and spermine complexes of poly(dAdT)2 show pre-melt transitions in their melting curves. The anthracene-9-carbonyl-N1-spermine complex with poly(dAdT)2 also shows a post-melt transition.

Antineoplastic Agents↗
PubMed1995

Adjuvant therapy with 5-fluorouracil for breast cancer of likely poor prognosis: 15-year results of a randomized trial.

In a trial conducted in southeast Scotland between April 1974 and December 1979, 332 women with invasive breast cancer of Stage I and II with histological evidence of node involvement, or who had operable or inoperable Stage III disease, were randomized, after primary local therapy (mastectomy, node biopsy and radiotherapy for all except the inoperable disease patients who underwent radiotherapy alone) to receive 12 4-weekly intravenous injections of 5-fluorouracil (5-FU), 700 mg/m2 or no systemic therapy. After a median follow-up of 15 years from randomization, no difference is shown between the two groups in terms of distant relapse (hazard ratio (HR) = 1.02; 95% CI 0.78-1.32), event free survival (HR = 1.23; 95% CI 0.97-1.56), or total survival (HR = 1.19; 95% CI 0.93-1.52). Locoregional relapse is significantly reduced by 5-FU administration (HR = 1.88; 95% CI 1.20-2.96). The results are similar for the trial as a whole or when mastectomy patients are considered alone. Toxicity was minimal with marrow suppression in only 19 of 147 patients receiving more than one injection; only five patients discontinued therapy due to nausea and vomiting. However, retrosternal pain occurred in 16 patients, nine of whom had their treatment curtailed as a result. Seventy-seven per cent of patients have died, the majority from breast cancer. Only 1.2% of deaths are considered attributable to cardiac causes of 5-FU is not associated with excess cardiac deaths in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗