Biomedical subjects

J de Bono

Publications and source records attributed to J de Bono.

8 recordsLinked to original sources

PubMed2006

Participation of patients with gynecological cancer in phase I clinical trials: two years experience in a major cancer center.

OBJECTIVES: This study aims at analyzing the clinico-demographic features that influence the recruitment of gynecological cancer (GC) patients to phase I trials. The possible clinical benefit to patients resulting from the participation in these trials has been also investigated. METHODS: We performed a retrospective analysis of GC patients referred to the Phase I Unit of the Royal Marsden Hospital in Sutton (Surrey, UK), over 2 years. RESULTS: Overall 68 GC patients were referred, and subsequently 32 (47.1%) enrolled. The percentage of patients enrolled increased as the distance to travel between the patient's residence and the hospital shortened (8.3% through 47.8% to 60.8%, for travel time >2, 1-2 or < or =1 h, respectively; p=0.008). Better performance status (PS) was found to be associated with higher enrollment rate with percentages increasing from 0 through 51.2 to 58.8 in cases with PS> or =2, PS=1, PS=0, respectively (p=0.015). Among the biochemical parameters, only hepatobiliary dysfunction was found to be associated with lower enrollment (p=0.012). Minimal response/disease stabilization was observed in 11 patients (34.4%). An increased median survival following the first visit was observed in patients enrolled compared to those not enrolled (8 versus 4 months, respectively, p=0.0055). In the multivariate analysis, only PS and enrollment in trials retained an independent prognostic role (p=0.031 and p=0.040, respectively). CONCLUSIONS: This study, suggesting liver function and PS as important factors influencing the recruitment of GC patients to phase I trials could guide referral of patients to phase I Units. Moreover, the practical limitations imposed by long distance travel, together with the potential clinical benefit due to the participation to these trials, should encourage more investigators to develop phase I units in major cancer centers.

Adult↗

PubMed2005

Clinical anticancer drug development: targeting the cyclin-dependent kinases.

Cell division involves a cyclical biochemical process composed of several step-wise reactions that have to occur once per cell cycle. Dysregulation of cell division is a hallmark of all cancers. Genetic and epigenetic mechanisms frequently result in deranged expression and/or activity of cell-cycle proteins including the cyclins, cyclin-dependent kinases (Cdks), Cdk inhibitors and checkpoint control proteins. The critical nature of these proteins in cell cycling raises hope that targeting them may result in selective cytotoxicity and valuable anticancer activity.

Antineoplastic Agents↗

PubMed2005

Drugging cell cycle kinases in cancer therapy.

Cell cycle kinases are comprised of cyclin-dependent kinases (Cdks), non-Cdk kinases such as Plk-1 and Aurora and checkpoint proteins such as Chk1 and Chk2. Though ubiquitous to dividing cells, many cell cycle kinases are amplified or over-expressed in malignancy and are potential targets for anti-cancer therapies. Cdk inhibiting drugs (such as flavopiridol, UCN-01, E7070, R-Roscovitine and BMS-387032) have shown preclinical and clinical anticancer activity. However, many of these agents are promiscuous and undiscerning, targeting other non-cell cycle kinases and affecting normal cells, thereby causing significant toxicity. To overcome this, a new generation of Cdk inhibitors are in development with greater target specificity, as well as others that inhibit non-Cdk cell cycle kinases, both directly and indirectly. The outcome of early clinical trials involving these agents is awaited, but these certainly represent a promising new area of anticancer drug development.

Adenosine Triphosphate↗

PubMed2003

Use of positron emission tomography in pharmacokinetic studies to investigate therapeutic advantage in a phase I study of 120-hour intravenous infusion XR5000.

PURPOSE: XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) is a topoisomerase I and II inhibitor. Because the cytotoxicity of XR5000 increases markedly with prolonged exposure, we performed a phase I study of weekly XR5000 by 120-hour continuous infusion over 3 weeks. PATIENTS AND METHODS: Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m2/120 hrs) for a total of 67 cycles. Three patients underwent positron emission tomography (PET) studies at the maximum-tolerated dose (MTD) to evaluate normal tissue and tumor carbon-11 radiolabeled XR5000 ([11C]XR5000) pharmacokinetics. RESULTS: The dose-limiting toxicity was National Cancer Institute Common Toxicity Criteria (version 1) grade 4 chest and abdominal pain affecting the single patient receiving 4,060 mg/m2/120 hours, and the MTD was 3,010 mg/m2/120 hours. Other grade 3-4 toxicities, affecting single patients at the MTD, were myelosuppression (grade 4), raised bilirubin, vomiting, and somnolence (all grade 3). There was one partial response (adenocarcinoma of unknown primary); the remainder had progressive disease. [11C]XR5000 distributed well into the three tumors studied by PET. Tumor uptake (maximum concentration or area under the concentration versus time curve [AUC]) was less than in normal tissue in which the tumors were located. Tumor exposure (AUC; mean +/- SD in m2/mL/sec) increased when [(11)C]XR5000 was administered during an infusion of XR5000 (0.242 +/- 0.4), compared with [11C]XR5000 given alone (0.209 +/- 0.04; P <.05), indicating that tumor drug exposure was not saturated [corrected]. CONCLUSION: The recommended dose for XR5000 in phase II studies is 3,010 mg/m2/120 hours. PET studies with 11C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.

Acridines↗

PubMed1999

Phase I and pharmacokinetic study of DACA (XR5000): a novel inhibitor of topoisomerase I and II. CRC Phase I/II Committee.

DACA, also known as XR5000, is an acridine derivative active against both topoisomerase I and II. In this phase I study, DACA was given as a 3-h intravenous infusion on 3 successive days, repeated every 3 weeks. A total of 41 patients were treated at 11 dose levels between 9 mg m(-2) d(-1) and the maximum tolerated dose of 800 mg m(-2) day(-1). The commonest, and dose-limiting, toxicity was pain in the infusion arm. One patient given DACA through a central venous catheter experienced chest pain with transient electrocardiogram changes, but no evidence of myocardial infarction. At the highest dose levels, several patients also experienced flushing, pain and paraesthesia around the mouth, eyes and nose and a feeling of agitation. Other side-effects, such as nausea and vomiting, myelosuppression, stomatitis and alopecia, were uncommon. There was one minor response but no objective responses. DACA pharmacokinetics were linear and did not differ between days 1 and 3. The pattern of toxicity seen with DACA is unusual and appears related to the mode of delivery. It is possible that higher doses of DACA could be administered using a different schedule of administration.

Acridines↗

PubMed1999

Occupational asthma: a community based study.

The incidence and prevalence of occupational asthma has been extensively studied in industry settings and specialist clinics. However, it has been much less studied in the community. This study looked at the general practice notes of asthmatics in an attempt to assess the overall load of occupational asthma in the community. Eighty-six per cent of the patients with adult onset asthma in the practice population studied had at least one occupation recorded in their notes. Nearly a third of these (32%) were in jobs known to be significant causes of occupational asthma, yet a potential link between their occupation and symptoms had only been recorded in 18% of patients in these jobs. Overall 4% of the patients with adult onset asthma had been given a diagnosis of occupational asthma although in nearly half these cases the diagnosis had been made by a general practitioner and not a specialist.

Adolescent↗

PubMed1999

Attentional bias for emotional faces in generalized anxiety disorder.

OBJECTIVES: Recent cognitive theories propose that attentional biases cause or maintain anxiety disorders. This study had several aims: (i) to investigate such biases in generalized anxiety disorder (GAD) using naturalistic, ecologically valid stimuli, namely, emotional facial expressions; (ii) to test the emotionality hypothesis by examining biases for happy as well as threat faces; and (iii) to assess the time course of the attentional bias. DESIGN: The dependent variable was an index of attentional bias derived from manual RTs to probe stimuli. There were four independent variables: one between-subjects variable of group (2: GAD, control), and three within-subjects variables: Type of emotional face (2: threat, happy), Stimulus duration (2: 500 ms, 1250 ms) and Half of task (2: first, second). METHOD: Attentional bias was assessed with a dot probe task. The stimuli comprised photographs of threatening, happy and neutral faces, presented using two exposure durations: 500 ms and 1250 ms. RESULTS: Anxious patients showed greater vigilance for threatening faces relative to neutral faces, compared with normal controls. This effect did not significantly vary as a function of stimulus duration. Anxious patients also showed enhanced vigilance for happy faces, but this was only significant in the second half of the task. CONCLUSIONS: The study confirmed not only that GAD patients show a bias in selective attention to threat, relative to controls, but also that this bias operates for naturalistic, non-verbal stimuli. As the attentional biases for threat and happy faces appeared to develop over a different time frame, different underlying mechanisms may be responsible.

Adult↗

PubMed1997

Time course of attentional bias for threat information in non-clinical anxiety.

A modified version of the probe detection task was used to investigate the effect of stimulus exposure duration on attentional bias for threat stimuli in a non-clinical sample of subjects. Stimulus duration was manipulated in order to examine different components of the anxiety-related attentional bias, i.e. initial orienting versus maintenance of attention to threat. Word pairs were presented on a computer screen for 100, 500 or 1,500 msec, and immediately after the termination of the display of each pair, a dot probe appeared in the position of one of the words. Higher levels of state anxiety were associated with faster response latencies for probes that replaced threat words, rather than neutral words (i.e. attentional vigilance for threat). This bias was not significantly affected by the exposure duration of the word stimuli. Thus, the attentional bias for threat does not appear to vary significantly over this range (100-1,500 msec) in non-clinical anxiety; it is recommended that the time course of the attentional bias be investigated further in clinical anxiety.

Adult↗