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Biomedical subjects

C J Squire

Publications and source records attributed to C J Squire.

11 recordsLinked to original sources
PubMed2000

Structures of m-iodo Hoechst-DNA complexes in crystals with reduced solvent content: implications for minor groove binder drug design.

The DNA photosensitisers m-iodo Hoechst and m-iodo, p-methoxy Hoechst have been co-crystallised with the oligonucleotide d(CGCGAATTCGCG)(2)and their crystal structures determined. The crystals were then subjected to slow dehydration, which reduced their solvent contents from 40 (normal) to 30 (partially dehydrated) and then 20% (fully dehydrated) and caused a reduction in cell volume from 68,000 to 60,000 then 51,000 A(3). The dehydration resulted in a dramatic enhancement of diffraction resolution from approximately 2.6 to beyond 1.5 A. Crystal structures have also been determined for the partially and fully dehydrated states. The fully dehydrated crystals consist of an infinite polymeric network, in which neighbouring dodecamer duplexes are crosslinked through phosphate oxygens via direct bonding to bridging magnesium cations. This unique three-dimensional structure for DNA is described in detail in the following companion paper. The present paper details evidence from the sequence of crystal structures that the DNA is able to breathe locally, allowing the ligand to leave the minor groove, re-orient in the surrounding solvent medium and then re-enter the groove in a different orientation and location. The rearrangement of the minor groove binding ligands during the dehydration process mimics the binding behaviour of these ligands in solution and in vivo. We also present details of the DNA-ligand interactions that are consistent with a hydrogen atom ion mechanism for photocleavage of DNA.

Animals↗
PubMed2000

Intermolecular interactions and water structure in a condensed phase B-DNA crystal.

By controlled dehydration, the unit cells of dodecamer DNA-drug crystals have been shrunk from 68,000 (normal state) to 60,000 (partially dehydrated intermediate state) to 51,000 A(3) (fully dehydrated state), beyond which no further solvent loss occurs. The total solvent content in the normal crystals is approximately 40% by volume, reducing to approximately 20% in the fully dehydrated phase. The 25% reduction in cell volume induced a dramatic enhancement in the resolution of the X-ray diffraction data (from 2. 6 to beyond 1.5 A). We have determined the structures of the normal, partially dehydrated and fully dehydrated crystals. Details of the ligand binding have been presented in the preceding article. The present paper describes the unique features of the structure of the fully dehydrated phase. This structure was refined with 9,015 unique observed reflections to R = 14.9%, making it one of the most reliable models of B -form DNA available. The crystals exist as infinite polymeric networks, in which neighbouring dodecamer duplexes are crosslinked through phosphate oxygens via direct bonding to magnesium cations. The DNA is packed so tightly that there is essentially only a single layer of solvent between adjacent molecules. The details of the crystal packing, magnesium bridging, DNA hydration and DNA conformation are described and compared with other experimental evidence related to DNA condensation.

Animals↗
PubMed1997

Minor groove binding of a bis-quaternary ammonium compound: the crystal structure of SN 7167 bound to d(CGCGAATTCGCG)2.

The X-ray crystal structure of the complex between the synthetic antitumour and antiviral DNA binding ligand SN 7167 and the DNA oligonucleotide d(CGCGAATTCGCG)2 has been determined to an R factor of 18.3% at 2.6 A resolution. The ligand is located within the minor groove and covers almost 6 bp with the 1-methylpyridinium ring extending as far as the C9-G16 base pair and the 1-methylquinolinium ring lying between the G4-C21 and A5-T20 base pairs. The ligand interacts only weakly with the DNA, as evidenced by long range contacts and shallow penetration into the groove. This structure is compared with that of the complex between the parent compound SN 6999 and the alkylated DNA sequence d(CGC[e6G]AATTCGCG)2. There are significant differences between the two structures in the extent of DNA bending, ligand conformation and groove binding.

Antineoplastic Agents↗
PubMed1996

Designer DNA-binding drugs: the crystal structure of a meta-hydroxy analogue of Hoechst 33258 bound to d(CGCGAATTCGCG)2.

An analogue of the DNA binding compound Hoechst 33258, which has the para hydroxyl group altered to be at the meta position, together with the replacement of one benzimidazole group by pyridylimidazole, has been cocrystallized with the dodecanucleotide sequence d(CGCGAATTCGCG)2. The X-ray structure has been determined at 2.2 A resolution and refined to an R factor of 20.1%. The ligand binds in the minor groove at the sequence 5'-AATTC with the bulky piperazine group extending over the CxG base pair. This binding is stabilised by hydrogen bonding and numerous close van der Waals contacts to the surface of the groove walls. The meta-hydroxyl group was found in two distinct orientations, neither of which participates in direct hydrogen bonds to the exocyclic amino group of a guanine base. The conformation of the drug differs from that found previously in other X-ray structures of Hoechst 33258-DNA complexes. There is significant variation between the minor groove widths in the complexes of Hoechst 33258 and the meta-hydroxyl derivative as a result of these conformational differences. Reasons are discussed for the inability of this derivative to actively recognise guanine.

Binding Sites↗
PubMed1995

Non-surgical management of early breast cancer in the United Kingdom: work-load, referral patterns and staging. Clinical Audit Sub-committee of the Faculty of Clinical Oncology, Royal College of Radiologists, and the Joint Council for Clinical Oncology.

This is the first of five papers describing the results of a national survey of the non-surgical treatment of early breast cancer in the UK. The topics include: work-load, referral patterns, participation in specialist clinics, use of treatment policies, availability of outcome data, quality of pathology reports, and staging investigations.

Breast Neoplasms↗
PubMed1993

Consultant episodes.

Explore the source record for details and available documents.

Delivery of Health Care↗
PubMed1993

Audit: the use of radiotherapy for NSCLC in the UK.

A questionnaire on the management of NSCLC was sent to all clinical oncologists in the UK. Responses were received from 121 individuals with at least one representative response from each of 54 British radiotherapy units. Results were then discussed at an open meeting attended by a cross section of clinical oncologists; a synopsis of responses to the questionnaire and discussion at this meeting is contained in this report. A majority of respondents estimated treatment of NSCLC to make up 10%-25% of their work-load. Radical and palliative treatments could be clearly distinguished, and aims of treatment, selection criteria and radiotherapy schedules were consistent with recommendations in the published literature. More than 90% of treatments were with palliative rather than radical intent. Radical treatment schedules could be divided according to dose (< 50 Gy, 50-55 Gy and >55 Gy), number of fractions (< 20, 20, > 20 fractions), overall time < 4/52, 4/52, > 4/52), dose per fraction (> 2.75 Gy, 2.1-2.75 Gy, < or = 2 Gy) and target volume (tumour alone, tumour and hilar nodes, or tumour, hilar and mediastinal nodes). Divided thus, radical techniques fell into three broad groups, each of the three techniques supported by a body of literature. Choice of schedule could be related to a heterogeneous referral pattern and unresolved controversies, identified as debate on the value of treating mediastinal lymphadenopathy with high dose radiation, the value of 'subradical doses' of radiation for microscopic disease, and the relative importance of volume treated, total dose, dose per fraction and overall treatment time in achieving an optimal therapeutic ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Non-Small-Cell Lung↗