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S G Spiro,
R M Rudd, R L Souhami,
J Brown,
D J Fairlamb,
N H Gower,
L Maslove,
R Milroy,
V Napp,
M K B Parmar,
M D Peake,
R J Stephens,
H Thorpe,
D A Waller,
P West
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ABSTRACT: In 1995 a meta-analysis of randomised trials investigating the value of adding chemotherapy to primary treatment for non-small cell lung cancer (NSCLC) suggested a small survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings. However, the meta-analysis included many small trials and trials with differing eligibility criteria and chemotherapy regimens.
The aim of the Big Lung Trial was to confirm the survival benefits seen in the meta-analysis and to assess quality of life and cost in the supportive care setting. A total of 725 patients were randomised to receive supportive care alone (n = 361) or supportive care plus cisplatin-based chemotherapy (n = 364).
65% of patients allocated chemotherapy (C) received all three cycles of treatment and a further 27% received one or two cycles. 74% of patients allocated no chemotherapy (NoC) received thoracic radiotherapy compared with 47% of the C group. Patients allocated C had a significantly better survival than those allocated NoC: HR 0.77 (95% CI 0.66 to 0.89, p = 0.0006), median survival 8.0 months for the C group v 5.7 months for the NoC group, a difference of 9 weeks. There were 19 (5%) treatment related deaths in the C group. There was no evidence that any subgroup benefited more or less from chemotherapy. No significant differences were observed between the two groups in terms of the pre-defined primary and secondary quality of life end points, although large negative effects of chemotherapy were ruled out. The regimens used proved to be cost effective, the extra cost of chemotherapy being offset by longer survival.
The survival benefit seen in this trial was entirely consistent with the NSCLC meta-analysis and subsequent similarly designed large trials. The information on quality of life and cost should enable patients and their clinicians to make more informed treatment choices.
Thorax 11/2004; 59(10):828-36. · 6.84 Impact Factor
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M H Cullen,
L J Billingham,
C M Woodroffe,
A D Chetiyawardana,
N H Gower,
R Joshi,
D R Ferry,
R M Rudd,
S G Spiro,
J E Cook,
C Trask,
E Bessell,
C K Connolly,
J Tobias, R L Souhami
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ABSTRACT: Chemotherapy for non-small-cell lung cancer (NSCLC) remains controversial. We describe the two largest reported, randomized, parallel trials designed to determine whether the addition of chemotherapy influences duration and quality of life in localized, unresectable (mitomycin, ifosfamide, cisplatin [MIC]1 trial) and extensive (MIC2 trial) disease.
Ambulatory patients with NSCLC, aged 75 years or younger, with localized disease, were randomized in MIC1 to receive up to four cycles of chemotherapy (CT: mitomycin 6 mg/m(2), ifosfamide 3 g/m(2), and cisplatin 50 mg/m(2)) every 21 days, followed by radical radiotherapy (CT + RT) or radiotherapy (RT) alone. Extensive-stage patients were randomized in MIC2 to identical chemotherapy plus palliative care (CT + PC) or palliative care (PC) alone. Short-term change in quality of life (QOL) was assessed in a subgroup of patients. Data from the two trials were combined to allow multivariate and stratified survival analyses.
Seven hundred ninety-seven eligible patients were randomized, 446 in MIC1 and 351 in MIC2. MIC CT improved survival in both trials (significantly in MIC2). The median survival time in MIC1 was 11.7 months (CT + RT) versus 9.7 months (RT alone) (P =.14); whereas in MIC2, median survival time was 6.7 months (CT + PC) compared with 4. 8 months (PC alone) (P =.03). QOL, assessed in 134 patients from start of trial to week 6, showed improvement with chemotherapy and deterioration with standard treatment. In the combined analysis of 797 randomized patients, the positive effect of MIC on survival was significant overall (P =.01) and after adjusting for prognostic factors (P =.01).
MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL.
Journal of Clinical Oncology 11/1999; 17(10):3188-94. · 18.37 Impact Factor
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ABSTRACT: The single cell gel electrophoresis comet assay has become established as a sensitive technique for measuring DNA strand breaks. The technique has been modified to allow the sensitive detection and quantitation of DNA interstrand cross-linking at the single cell level. Cells are irradiated immediately before analysis to deliver a fixed level of random strand breakage. After embedding of cells in agarose and lysis, the presence of cross-links retards the electrophoretic mobility of the alkaline denatured cellular DNA. Cross-links are, therefore, quantitated as the decrease in the comet tail moment compared with irradiated controls. Using this method, a linear response of cross-linking versus dose of chlorambucil over a wide dose range was demonstrated in human lymphocytes after drug treatment ex vivo. The method was also sensitive enough to determine cross-linking in clinical samples after chemotherapy. For example, crosslinking was observed in the lymphocytes of patients receiving ifosfamide (3 g/m2/day) as a continuous infusion for 3-5 days or as a 3-h infusion daily for 3 days. Cross-links were detected in all patients within 3 h, with no evidence of DNA single strand break formation. In patients receiving continuous infusion, a plateau of cross-linking was reached by 24 h. In the patients receiving ifosfamide over 3 h, a clear decrease in the peak level of cross-linking was observed before subsequent infusions.
Clinical Cancer Research 04/1999; 5(3):507-12. · 7.74 Impact Factor
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ABSTRACT: The levels of N-alkyl purine and DNA interstrand crosslink formation, produced by the clinically used nitrogen mustard antitumour drug mechlorethamine (HN2), were quantitated at the level of specific genes in a panel of human tumour cell lines using modified Southern blotting methods. When purified genomic DNA was treated with HN2 in vitro, no significant difference in the extent of N-alkyl purine or interstrand crosslink formation in the N-ras, c-myc or CD3delta genes was observed. When the cell lines LS174T, Colo320HSR, J6 and U937 were treated with HN2, however, there was significant heterogeneity in the levels of N-alkyl purine formation in the three genes. The rank order of the extent of damage in the three genes was also different in the cell lines. The level of alkylation did not correlate with either the transcriptional activity of a gene or drug sensitivity. Crosslinks were not detectable in the N-ras or c-myc genes of LS174T, J6 or U937 cells treated with HN2, and only detectable in the amplified c-myc gene of the Colo320HSR cell line. In the related cell line Colo320DM, which has both native and translocated c-myc alleles which are both amplified and episomal, crosslinks were detected in the amplified native and rearranged c-myc alleles, and also in the N-ras gene which is also amplified in this cell line. For bifunctional alkylating agents such as HN2, therefore, heterogeneity of DNA damage can occur between different genes in human cells and can also vary for different lesions produced by the same agent. In addition, this heterogeneity can differ between human tumour cell lines.
Nucleic Acids Research 01/1999; 26(24):5617-23. · 8.03 Impact Factor
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ABSTRACT: The aim of this study was to test an instrument which might be useful for doctors in explaining the randomisation procedure to an individual patient. The sample comprised 323 patients with cancer attending for out-patient appointments and/or chemotherapy treatment in two major cancer centres in the U.K. 315 patients completed a self-report questionnaire--The Attitudes to Randomised Trials Questionnaire (ARTQ). The results show that the majority of subjects 287 (91.1%) believe that patients should be asked to take part in medical research, but only 242 (76.8%) would be prepared to take part in a study comparing two treatments. If treatment was randomised, only 141 (44.8%) would agree to participate. When given further information about the randomisation procedure, 119 (68.4%) of the 174 (55.2%) who initially said 'no' to randomisation or who were unsure, would change their minds and take part in a trial. The ARTQ discriminated between three categories of patient with the following prevailing attitudes: (a) those who seem comfortable with the concept of randomisation; (b) those with some concerns, who with fuller explanation are prepared to consider randomisation; and (c) those firmly against randomisation and participation in trials whatever information is provided. Prior knowledge of patients' attitudes might assist communication about trials and encourage more doctors to approach eligible patients.
European Journal of Cancer 10/1998; 34(10):1554-9. · 5.54 Impact Factor
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ABSTRACT: In a randomized cross-over trial, 11 patients received ifosfamide (IFOS) in 21-day cycles, which alternated between 3 g m(-2) x (2 or 3) days given as a 1-h bolus doses, or the same total dose as a continuous infusion. Patients who received four or more cycles also alternated between two cycles on dexamethasone 4 mg 8 hourly for 3 days starting 8 h before IFOS, and two cycles off dexamethasone. A total of 34 patient cycles were studied and serum and urinary levels of IFOS, 2 dechloroethylifosfamide (2DC), 3 dechloroethylifosfamide (3DC), carboxyifosfamide (CX) and isophosphoramide mustard (IPM) were measured by thin-layer chromatography. No significant differences could be detected in the areas under the curve (AUCs) of serum concentration, nor in the proportion of IFOS or its metabolites found in the urine. There was no significant effect of dexamethasone on IFOS metabolism. These results indicate that there is no identifiable pharmacokinetic basis for insistence on either bolus or infusional methods of IFOS administration.
British Journal of Cancer 03/1998; 77(6):978-84. · 5.04 Impact Factor
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ABSTRACT: Purpose. To study the long-term neurotoxicity of chemotherapy in adolescents and young adults treated for bone and soft tissue sarcomas.Patients and Methods. Thirty-six adolescents and young adults (median age 17 years) were examined following chemotherapy for bone and soft tissue sarcomas. Twenty-nine (29/36) had received cisplatin (median 400 mg/m(2)), 15/36 ifosfamide (median 20 g/m(2)), and 12/36 vincristine (median 16 mg). Neurotoxicity was assessed at a median of 8 months (range, 1-54 months) after completion of chemotherapy by clinical examination, nerve conduction studies, audiograms and autonomic function tests. The same nerve conduction studies were carried out in 20 normal volunteers to define normal ranges in this age group.Results. Sixteen patients (44%) had a significant reduction in deep tendon reflexes, and this clinical parameter correlated well with abnormalities detected in nerve conduction studies. Vibration perception threshold (VPT) was raised in 20/36 patients (55%) and this was the most sensitive single test in the assessment of neuropathy. There was a significant correlation between VPT and cumulative cisplatin dose received in mg/m(-2) (r=0.607, p<0.01). Ten of 29 patients (35%) had abnormal nerve conduction studies with a pattern characteristic of sensory axonal neuropathy. No patient complained of auditory symptoms, but minor high tone hearing loss was detected by audiograms in 5/28 patients who had received cisplatin. No patients had symptoms of autonomic neuropathy, but autonomic function tests showed minor abnormalities in 4/22 patients tested, and all had received cisplatin.Conclusions. This study demonstrates significant, although asymptomatic, long-term neurotoxicity of cisplatin in adolescents and young adults receiving chemotherapy for bone and soft tissue sarcomas. Follow-up studies are planned to assess whether these neurological deficits improve with time.
Sarcoma 01/1998; 2(2):97-105.
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ABSTRACT: Ifosfamide is an oxazophosphorine widely used in the treatment of cancer in children and adults. Nephrotoxicity and neurotoxicity are major side effects. The aim of this study was to use high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine to identify novel biochemical markers of ifosfamide-induced toxicity. Urine samples were collected from 10 nonencephalopathic patients (who had not previously received nephrotoxic chemotherapy) immediately prior to the first ifosfamide dose and at timed intervals for up to four treatment cycles. The findings were compared with those for urine samples collected from five patients during acute encephalopathic episodes. 1H NMR urinalysis identified a series of characteristic time-related changes in the excretion profiles of low molecular weight endogenous metabolites during ifosfamide therapy. These changes included a decreased excretion of hippurate and an increased excretion of glycine, histidine, glucose, lactate, and trimethylamine-N-oxide. Two nonencephalopathic patients had marked but transient glutaric or adipic aciduria during the second cycle of ifosfamide treatment. Urinary retinol-binding protein rose acutely after each treatment cycle but usually returned to baseline levels. Maximum renal toxicity was observed by the fourth treatment cycle. The ratio of the urinary excretion of the uroprotectant mesna (active form) to dimesna (inactive form) correlated with the degree of renal toxicity. For the encephalopathic patients, the ifosfamide-induced changes in the urinary low molecular weight metabolite profile were similar to those for the nonencephalopathic group. In contrast to previous reports, none of the encephalopathic group developed glutaric aciduria, and i.v. methylene blue did not reverse neurotoxicity in the two patients who received it. The results suggest that ifosfamide nephrotoxicity involves both cortical and medullary regions of the nephron and that the urinary mesna:dimesna ratio may be important in assessing the degree of cytoprotection. This study demonstrates that 1H NMR can provide novel biochemical information on ifosfamide-induced toxicity and will be of value in the optimization of ifosfamide therapy.
Clinical Cancer Research 10/1997; 3(9):1507-18. · 7.74 Impact Factor
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ABSTRACT: Adolescent cancer is uncommon and presents an exceptional stress for the young patient and their parents. The emotional needs of adolescents with cancer are a major factor in the recommendation for the establishment of adolescent cancer units in major cancer centres in the U.K. However, there have been no prospective, longitudinal studies assessing the psychological impact of a diagnosis of cancer on the adolescent patient and their family. In 1994 we began a longitudinal study of the emotional impact of the diagnosis of cancer in patients and their families presenting to an adolescent cancer unit and of the coping strategies they employ. This first report presents the results of the study at the time of diagnosis in 42 adolescents, 34 mothers and 27 fathers. The Beck Depression Inventory (BDI) was used to assess depression and anxiety levels were measured using Spielberger's State Trait Anxiety Inventory (STAI). Adolescents and their parents completed the questionnaires on first admission to the adolescent cancer unit. The median time since cancer diagnosis was approximately 3 weeks. To provide normative data for the U.K. adolescent population, control values were obtained from 173 pupils of the same age and background. The results showed that, contrary to expectation, adolescents with cancer were no more anxious or depressed than the control adolescent population. Nevertheless, a substantial minority of patients and controls had elevated anxiety or depression scores. Girls were significantly more anxious (P = 0.011) and depressed (P < 0.0001) than boys. Mothers were the most anxious family members and were significantly more anxious than fathers (P = 0.038). Parental anxiety scores, especially mothers, were much higher than reported norms. There was no significant difference between mothers' and fathers' depression scores. Although at the time of diagnosis adolescent cancer patients are not more anxious or depressed than their healthy peers, many adolescents without cancer are anxious or depressed. Staff on adolescent cancer units should therefore be aware of the frequency of emotional disturbance in this population. Mothers are the most anxious family members. Although the findings are relatively reassuring at the time of diagnosis, follow-up data from this cohort will show whether anxiety and depression change with treatment involving intensive chemotherapy, surgery and radiotherapy and will indicate the coping strategies which patients and their families adopt in dealing with both the disease and its treatment.
European Journal of Cancer 07/1997; 33(8):1250-5. · 5.54 Impact Factor
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ABSTRACT: Oral etoposide is an active single agent in small-cell lung cancer (SCLC) and is widely prescribed as first-line treatment as an alternative to intravenous combination chemotherapy in patients with extensive disease.
The intention of this study was to determine if the effects of oral etoposide therapy on survival and quality of life are equivalent to those of intravenous chemotherapy.
In a randomized trial of palliative treatment in advanced SCLC, oral etoposide (100 mg given twice daily for 5 days) was compared with intravenous chemotherapy consisting of alternating cycles of cisplatin and etoposide (PE) and cyclophosphamide, doxorubicin, and vincristine (CAV). Six cycles of chemotherapy were administered every 21 days in both regimens. Symptom control and quality of life were measured with the Rotterdam Symptom Checklist and a daily diary card. In January 1996, after 155 patients had been randomly assigned from a projected intake of 365 patients, an independent Data Monitoring Committee examined the interim results. Survival was determined by the Kaplan-Meier method, and the logrank test was used to compare treatments. For quality-of-life comparisons, average scores were calculated for each time point. The Mann-Whitney U test was used to determine any significant overall differences between treatments. For the Rotterdam Symptom Checklist, separate analyses were done for each subset (psychological well-being, physical symptoms, lung cancer symptoms, treatment symptoms, activity, and quality of life). Response rates and toxicity scores were compared by using chi2. All statistical tests were two-sided.
Survival was inferior at 1 year in the oral etoposide group compared with intravenous therapy (9.8% for oral versus 19.3% for intravenous; difference = 9.5%; 95% confidence interval of difference = 0.3%-18.7%; P<.05), and there was a trend toward inferior overall survival. Median survival was 4.8 months for oral treatment and 5.9 months for intravenous therapy. Progression-free survival was worse in the oral etoposide arm (median = 3.6 months versus 5.6 months; P<.001), as well as overall response rate (32.9% versus 46.3%; P<.01). With the exception of acute nausea and vomiting associated with intravenous chemotherapy, all aspects of symptom control and quality of life were either the same or worse in the oral etoposide group. Study closure was recommended.
These interim results show that this schedule of oral etoposide is inferior to intravenous chemotherapy in the treatment of advanced SCLC and should not be used as first-line treatment of this disease.
JNCI Journal of the National Cancer Institute 05/1997; 89(8):577-80. · 13.76 Impact Factor
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ABSTRACT: Data from a completed randomized trial in breast cancer are used to demonstrate and quantify the variation in estimated survival curves and log-rank statistics at different times throughout a trial. False 'plateaux' are common, as are wide fluctuations in chi2 values obtained from the log-rank test when there are few events. We show how analyses conducted at different times can demonstrate different effects. Long follow-up is often necessary to allow correct interpretation of results. We discuss the assumption of proportional hazards and the consequences of making that assumption inappropriately. We show how checking whether hazards are proportional can help in avoiding erroneous conclusions.
British Journal of Cancer 02/1997; 76(4):551-8. · 5.04 Impact Factor
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M L Slevin,
S E Nichols,
S M Downer,
P Wilson,
T A Lister,
S Arnott,
J Maher, R L Souhami,
J S Tobias,
A H Goldstone,
M Cody
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ABSTRACT: 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.
British Journal of Cancer 11/1996; 74(8):1275-9. · 5.04 Impact Factor
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Nucleic Acids Research 07/1996; 24(12):2456-7. · 8.03 Impact Factor
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ABSTRACT: 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.
British Journal of Cancer 07/1996; 73(12):1563-8. · 5.04 Impact Factor
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Nucleic Acids Research 04/1996; 24(5):987-9. · 8.03 Impact Factor
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ABSTRACT: 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.
Biochemistry 11/1995; 34(40):13034-41. · 3.42 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Annals of Oncology 08/1995; 6(6):575-80. · 6.43 Impact Factor
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ABSTRACT: 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.
Chemico-Biological Interactions 06/1995; 96(2):125-42. · 2.46 Impact Factor
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ABSTRACT: 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.
Cancer Chemotherapy and Pharmacology 02/1995; 35(4):323-6. · 2.83 Impact Factor
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ABSTRACT: Two series of tethered nitrogen mustards based on the minor groove-binding and A/T sequence-specific natural product distamycin have been synthesized and evaluated. The conjugates, which have a modified dimethylamino C-terminus, are comprised of one, two or three pyrrole carboxamide units linked to either benzoic acid mustard (BAM) or chlorambucil (CHL). The DNA binding properties, in vitro cytotoxicities and DNA cross-linking abilities were determined for each of the conjugates. The conjugates were found to bind preferentially to poly(dA.dT) compared to poly(dG.dC) DNA by ethidium displacement and circular dichroism. The di- and tripyrrole conjugates had higher binding affinities than the monopyrrole conjugates. All the conjugates were more cytotoxic than the nitrogen mustards themselves. Cytotoxicity increased with the increase from one to three pyrrole units and the CHL conjugates were more cytotoxic than the corresponding BAM analogues. The CHL conjugates were able to cross-link plasmid DNA at a 10-fold lower dose than CHL itself. The BAM conjugates showed < 10% cross-linking at doses which gave 100% cross-linking with the CHL conjugates. In cells, the CHL conjugates showed significant cross-linking at the IC50 values, while the BAM conjugates showed no evidence of cross-link formation even at 10 times the IC50 value. These results are discussed in reference to a series of previously reported GC-recognizing imidazole analogues possessing the same nitrogen mustard groups.
Anti-cancer drug design 12/1994; 9(6):511-25. · 2.38 Impact Factor
