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Biomedical subjects

R L Souhami

Publications and source records attributed to R L Souhami.

At least 37 records · Page 2Linked to original sources
PubMed1996

A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign trial.

We report the results of a randomised trial in extensive small-cell lung cancer (SCLC) of a novel approach to palliative chemotherapy. A widely used 3 weekly regimen was compared with the same drugs given at half the dose but twice the frequency with the same intended overall dose intensity (DI). A total of 167 patients defined as having extensive SCLC with adverse prognostic features were randomised to receive either a 3 weekly regimen of cisplatin 60 mg m-2 i.v. on day 1 and etoposide 120 mg m-2 i.v. on day 1 and 100 mg b.d. orally on days 2 and 3 alternating with cyclophosphamide 600 mg m-2 i.v., doxorubicin 50 mg m-2 i.v. and vincristine 2 mg i.v. all on day 1 for a maximum of six courses (3 weekly); or treatment with the same drugs but with each course consisting of half the 3 weekly dose given every 10 or 11 days for a maximum of 12 courses. In the 10/11 day regimen overall response rate was 58.9% (95% CI, 47.9-69.2%) with 12.8% complete responses (CR). For the 3 weekly treatment the overall response rate was 44.9% (95% CI, 35.0-55.5%) with 10.1% CR. Median survival was similar in the two arms at 6.4 months (95% CI, 4.9-7.3 months) and 5.8 months (95% CI, 4.0-6.6 months) respectively. Survival at 1 year was 9.9% (95% CI, 5.0-18.5%) and 8.9% (95% CI, 4.6-16.6%). The 95% CI for the difference in survival at 1 year is -7.09% to +9.09%. Haematological toxicity and treatment delays owing to infection were more frequent with the 10/11 day regimen but other toxicities were equal in both arms. Other aspects of quality of life were measured in a small representative cohort of patients using a daily diary card (DDC). There was a trend of improved quality of life on the 10/11 day arm, but there was little difference between the two treatments. The trial shows that a low-dose/high-frequency regimen with the same DI as conventionally scheduled chemotherapy gives similar response rates and survival. This and other modifications of the schedule may offer new approaches to palliative treatment of advanced cancer. However, in this trial there was no significant benefit in toxicity or other aspects of quality of life.

Adult↗
PubMed1996

Emotional support for cancer patients: what do patients really want?

For many cancer patients and their families the experience of cancer is an intensely stressful one. Emotional support is important for most cancer patients during their illness and can be gained from different people and services. This study evaluates patients' attitudes to different sources of support and rates their satisfaction with sources already used. A total of 431 patients completed a questionnaire covering the use of different sources, including individuals, support groups and information sources. The questionnaire also incorporated validated measurements of anxiety, depression and locus of control. The results revealed that the three most important sources of emotional support were senior registrars (73%) and family (73%), followed by consultants (63%). Patients would prefer doctor- and nurse-led support groups to patient only-led groups (26% vs 12%). Pamphlets, such as the BACUP booklets, proved the most important of the informational sources sought (50%). A total of 86% of patients were satisfied or very satisfied with the emotional support received. Patients who expressed dissatisfaction with their emotional support were significantly more likely to be anxious and depressed (P < 0.001). Patients who used information sources were more likely to have a higher locus of control over the course of their disease. These results show how important the doctor's role is in the provision of emotional support.

Adolescent↗
PubMed1995

Sequence specificity of alkylation for a series of nitrogen mustard-containing analogues of distamycin of increasing binding site size: evidence for increased cytotoxicity with enhanced sequence specificity.

The covalent sequence specificity of a series of nitrogen mustard-containing analogues of distamycin was determined using modified sequencing techniques. The analogues tether benzoic acid mustard (BAM) and possess either one, two, or three pyrrole-amide units. Previous characterization of the biological profile of the series revealed an increase in cytotoxicity for each corresponding increase in the number of pyrrole units, while showing poor cross-link formation in isolated and cellular DNA. Examination of the sequence specificity revealed that BAM produced guanine-N7 lesions in similar manner to other conventional nitrogen mustards. The monopyrrole BAM conjugate also produced guanine-N7 alkylation in a similar pattern to BAM. However, alkylation of adenines was also seen that was found to be minor groove adenine-N3 lesions. The dipyrrole and tripyrrole conjugates did not produce detectable guanine-N7 alkylation but only alkylated in AT tracts. In addition, the tripyrrole conjugate preferentially alkylated only a subset of those sites alkylated by the monopyrrole and dipyrrole conjugates. Two sites, 5'-TTTTGG and 5'-TTTTGA, confirmed as guanine-N3 and adenine-N3 lesions, respectively, were strongly alkylated by the tripyrrole conjugate in preference to other similar sites including three occurrences of 5'-TTTTAA. Footprinting studies comparing distamycin and the tripyrrole conjugate showed identical non-covalent recognition of AT-rich sites. Hence, the drug that possessed the most enhanced sequence specificity for alkylation was also the most cytotoxic of this series.

Antineoplastic Agents, Alkylating↗
PubMed1995

The effect of AT and GC sequence specific minor groove-binding agents on restriction endonuclease activity.

The ability of the naturally occurring A/T specific DNA minor groove binders netropsin and diastamycin A and two synthetic G/C selective oligopeptide analogues (1 and 2), to interfere with the catalytic activity of restriction endonucleases has been investigated. Enzymes were chosen to have A/T rich (EcoRI, EcoRV) or G/C rich (BalI, NruI) recognition sequences. An agarose gel assay was used to measure the cleavage of 32P-labelled DNA and ligand-DNA binding data was obtained using methidium-propyl EDTA footprinting. Netropsin and distamycin bind at the recognition sites, and dose-dependently inhibited cleavage by, EcoRI and EcoRV, (EcoRI > EcoRV). They were also more effective at inhibiting the catalytic activity of BalI than either 1 or 2. NruI was inhibited by distamycin and 2, but not by netropsin or 1. DNA footprinting revealed that neither 1 or 2 bound to the BalI or NruI recognition sequences under the conditions used whereas netropsin and distamycin footprint at adjacent sites. 1 binds to two of the three recognition sequences for the enzyme Fnu4HI (GCNGC) in the fragment studied and was shown to inhibit DNA cleavage only at these two sites. 2 binds strongly to two GGGCTC sequences which are recognition sites for the enzyme BanII. In this case a pronounced stimulation of cleavage was observed in the presence of 2 over a wide dose range. The results indicate that enzyme inhibition does not necessarily result from simultaneous occupancy of a common site, or at nearby flanking sequences, and in some circumstances, a pronounced stimulation of enzyme cleavage can occur.

Autoradiography↗
PubMed1995

Persistence of cisplatin-induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and young individuals.

DNA interstrand crosslinks (ISCL) produced by the incubation of human peripheral blood mononuclear cells (PBMs) with cisplatin (CDDP) were measured in two populations of volunteers, one aged less than 25 years and the other, greater than 72 years. The technique of fluorometric alkaline elution was used to measure DNA interstrand crosslinking with time after a 1-h exposure to drug. The samples from the young group showed a more consistent pattern of crosslink formation and removal, with extensive, or in some cases complete, repair at 48 h. Those from the elderly group showed considerable inter-individual variation and significantly higher mean levels of crosslinking at 24 and 48 h. No samples showed complete repair at 48 h in this population. These results indicate an impaired DNA repair capacity in the cells from the elderly group. This may be a factor in the poor tolerance of chemotherapy in the ageing population.

Adult↗
PubMed1995

Adjuvant chemotherapy for soft-tissue sarcoma: review and meta-analysis of the published results of randomised clinical trials.

Fifteen published randomised trials comparing adjuvant chemotherapy with no chemotherapy in soft-tissue sarcoma (STS) were identified (1546 patients). A qualitative review and a meta-analysis of this published literature were performed. With the qualitative review it was not possible to synthesise the apparently conflicting results of individual trials. The meta-analysis of the published data suggests an improvement in survival at 2 years (OR = 0.73, 95% CI = 0.53-0.99, P = 0.044) and at 5 years (OR = 0.59, 95% CI = 0.45-0.78, P = 0.0002) in favour of chemotherapy. However, the assumptions and approximations required to conduct this quantitative summary demand that the results are interpreted with caution. The only reliable means of assessing the current evidence on whether adjuvant chemotherapy has a role in the treatment of patients with STS, is to collect, check and reanalyse individual patients data (IPD) from each trial centrally, and formally combine the results in a stratified time-to-event analysis. Such an IPD analysis is currently being undertaken by an international collaborative group.

Adult↗
PubMed1995

Assessment of 'quality of life' using a daily diary card in a randomised trial of chemotherapy in small-cell lung cancer.

BACKGROUND: Quality of life (QOL) was assessed using a daily diary-card within a multicentre randomised trial of treatment of small-cell lung cancer. The trial compared a weekly dose-intensive regimen with a 3-weekly conventional treatment in good prognosis patients, that is patients with limited disease or extensive disease with a good performance status (ECOG 0or 1) and alkaline phosphatase of less than one and a half times the upper limit of normal. The trial which has been previously reported detected no difference in response or survival. PATIENTS AND METHODS: Daily diary cards (DDCs) were collected for up to eight months from the first day of chemotherapy in a cohort of 75 patients at one centre. Percentages of scores over a specified level were calculated for each of the eight diary card questions and comparisons were made between treatment arms. RESULTS: During the period of chemotherapy compliance in completing DDCs was 72.5% in the weekly arm and 77.2% in the 3 weekly. Significantly worse scores were reported with weekly chemotherapy during this period for six of the eight parameters, namely: ;nausea, vomiting, happiness, appetite, general well-being and sleep. Recognised problems of QOL data collection, in particular, compliance, attrition and generalisability are highlighted by this study and are discussed in the paper. CONCLUSIONS: The QOL measurements indicate that 3 weekly chemotherapy is the preferred treatment. This study demonstrates that QOL measurements may be helpful in choosing between treatment alternatives where no difference in outcome is observed.

Adult↗
PubMed1994

DNA damage by anti-cancer agents resolved at the nucleotide level of a single copy gene: evidence for a novel binding site for cisplatin in cells.

A new PCR based technique has been developed to investigate the sequence selectivity of adduct formation by DNA damaging agents in a single copy gene in isolated genomic DNA or in drug treated cells. Single-strand ligation PCR (sslig-PCR) demonstrated that cisplatin and nitrogen mustards reacted with guanine in an N-ras fragment with varying sequence specificity similar to that observed previously in plasmid DNA. In cisplatin-treated cells sslig-PCR demonstrated all the adducts found in isolated DNA and with the same sequence selectivity showing a preference for GG and AG sites. However, in cells an additional site of DNA binding of cisplatin was observed at the two occurrences of the sequence 5'-TACT-3' on the transcribed and non-transcribed strands. This sequence is not a recognised target for cisplatin and represents a novel adduct formed in cells.

Antineoplastic Agents↗
PubMed1994

DNA damage by anticancer agents and its repair: mapping in cells at the subgene level with quantitative polymerase chain reaction.

The quantitative polymerase chain reaction (QPCR)-based assay was used to measure DNA damage and repair to a small (523 bp) fragment of the single-copy human N-ras gene in K562 cells. Compared with previous methods DNA preparation from treated cells and the subsequent detection of the radioactive product were considerably simplified. The results demonstrated that QPCR can be used to measure damage in a small gene segment, caused by cisplatin, nitrogen, and quinacrine mustards. Drug-DNA adducts produced by two novel minor groove binding, sequence-specific molecules (AT-486 and DSB-120) could be detected at physiologically relevant concentrations of drug. For both cisplatin and nitrogen mustard the concentrations required to cause damage in cells were higher than those needed to cause equivalent damage in isolated DNA. In contrast both AT-486 and quinacrine mustard caused more damage at equimolar concentrations in cells than in isolated DNA. DSB-120, which is closely related to AT-486, was found to be 15-fold less effective than the latter at causing damage in treated cells despite similar reactivity with isolated DNA. Repair of damage caused by quinacrine mustard to the same small gene fragment was found to proceed at a constant rate over 24 h. The QPCR assay presented here is a simple quantitative method to measure damage and repair in subgene functional units such as promoters, introns, and exons.

Antineoplastic Agents↗
PubMed1994

Phase II study of fotemustine in untreated inoperable non-small-cell lung cancer.

A total of 43 patients with advanced, previously untreated non-small-cell lung cancer (NSCLC) were treated with a novel nitrosourea, fotemustine, given at 100 mg/m2 on days 1 and 8. Maintenance treatment consisted of a single injection of 100 mg/m2 given every 21 days. 37 patients were evaluable for response. Of these, 5 patients had a partial response (13.5%; 95% confidence interval, 6%-28%). Toxicity comprised mainly anaemia and thrombocytopenia. Other toxicities were mild. This phase II study confirms that fotemustine is a moderately active and well-tolerated drug in NSCLC.

Aged↗