Biomedical subjects

G Attard

Publications and source records attributed to G Attard.

6 recordsLinked to original sources

PubMed2006

Improving the outcome of patients with castration-resistant prostate cancer through rational drug development.

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease.

Antineoplastic Agents↗

PubMed2006

A phase I study of intravenous TZT-1027 administered on day 1 and day 8 of a three-weekly cycle in combination with carboplatin given on day 1 alone in patients with advanced solid tumours.

BACKGROUND: TZT-1027 is a tubulin-binding drug and synthetic derivative of dolastatin-10 with cytotoxic and antivascular activity in vitro and in vivo. Studies have demonstrated anti-tumour activity in several tumour types. METHODS: Patients were treated with escalating doses of TZT-1027 and carboplatin at doses from 1.6 to 2.0 mg/m2 and AUC 4 and 5 respectively. For pharmacokinetic analysis, plasma sampling was done during the first course using a high-performance liquid chromatographic assay. RESULTS: 14 patients received a total of 55 cycles at three dose levels. Dose limiting toxicities (DLTs) were first observed with 1.6 mg/m2 TZT-1027 and carboplatin AUC 5; 1 patient had grade 4 neutropenia and a delay in day 8 treatment occurred in two patients (gr 2 fatigue, gr 3 diarrhoea). At TZT-1027 2 mg/m2 and carboplatin AUC 5, one patient experienced grade 3 paralytic ileus. The most frequent toxicities were neutropenia, anaemia, fatigue, constipation, infection and vomiting. Peripheral neuropathy was reported in 36% of patients. One patient (pancreatic adenocarcinoma) achieved a partial response lasting 181 days. Pharmacokinetic analysis did not demonstrate any interaction between TZT-1027 and carboplatin. CONCLUSIONS: The recommended phase II dose is TZT-1027 1.6 mg/m2 and carboplatin AUC 5. No evidence of a PK interaction between these agents was observed.

Adult↗

PubMed2006

Familial factors in diabetic nephropathy: an offspring study.

AIMS: Familial clustering of diabetic nephropathy in patients with Type 2 diabetes suggests that inherited factors predispose to diabetic nephropathy, but the nature of these factors is uncertain. The aim of the study was to compare the prevalence of known risk factors for nephropathy in non-diabetic offspring of Type 2 diabetic patients with and without nephropathy and in control subjects. METHODS: Three groups of patients were recruited with 40 or 41 subjects in each group. These were subjects having one Type 2 diabetic parent with nephropathy (DN); subjects having one parent with Type 2 diabetes without nephropathy (DnoN), and non-diabetic unrelated control subjects with no personal or parental history of diabetes (Control subjects). RESULTS: The median (interquartile range) albumin/creatinine ratio (ACR) was 1.40 (0.96-2.90) mg/mmol in DN; 0.94 (0.50-1.46) mg/mmol in DnoN and 1.22 (0.66-1.83) mg/mmol in Controls (ANOVA: P = 0.03). ACR was higher in group DN than in DnoN (P < 0.006) and in Control subjects (P < 0.03), but there was no difference between DnoN and Control subjects. Twenty-four-hour ambulatory blood pressure monitoring showed mean daytime systolic blood pressure to be significantly higher in group DN than in DnoN (P < 0.02) or Control subjects (P < 0.01) (ANOVA: P = 0.004). Fasting insulin, HOMA-IR, interleukin-6 (IL-6) and C-reactive protein (CRP) were similar in the three groups. CONCLUSION: Our data provide further evidence that genetic factors are important in determining urinary albumin excretion and renal disease associated with Type 2 diabetes and suggest that genes that affect systemic arterial blood pressure but not those relating to insulin resistance or inflammation are likely to be implicated.

Adult↗

PubMed2005

Prostate epithelial stem cells.

The prostate gland is the site of the most commonly diagnosed cancer in men in USA and UK, accounting for one in five of new cases of male cancer. Common with many other cancer types, prostate cancer is believed to arise from a stem cell that shares characteristics with the normal stem cell. Normal prostate epithelial stem cells were recently identified and found to have a basal cell phenotype together with expression of CD133. Preliminary data have now emerged for a prostate cancer stem cell that also expresses cell surface CD133 but lacks expression of the androgen receptor. Here we examine the evidence supporting the existence of prostate cancer stem cells and discuss possible mechanisms of stem cell maintenance.

Animals↗

PubMed2004

Reversing resistance to targeted therapy.

The development of molecular targeted anticancer drugs is rapidly changing cancer therapeutics. However, drug resistance to these novel agents remains a real clinical concern. Reports now indicate that resistance to many of these molecular targeted agents--including hormone therapies, trastuzumab, imatinib, and gefitinib--occurs via common resistance mechanisms. These include 1) inadequate target blockade due to sub-optimal drug delivery; 2) altered target expression at the DNA (gene amplification), mRNA or protein level; 3) an altered target such as a mutated kinase domain; 4) modified target regulating proteins (e.g. altered expression of co-activators and/or co-repressors for nuclear steroid hormone receptors); 5) signalling by alternative proteins (functional redundancy) or different signalling pathways. It is envisioned that the molecular evaluation of clinical anticancer drug resistance, which requires the detailed study of pharmacokinetics, pharmacogenetics and pharmacodynamics, will allow the development of rational reversal strategies and improved patient outcome.

Antibodies, Monoclonal↗

PubMed1986

The use of the Foley catheter in the emergency room treatment of penetrating cardiac injuries.

The invaluable use of a Foley catheter is well known to cardiac surgeons, having been originally advocated in dealing with an atrial tear at valvotomy. Its use is reported in a case in the emergency room, where it acted as a simple, rapid and highly efficient means of providing immediate control of a penetrating cardiac injury, and for maintaining control while the patient was transferred to the main operating theatre. Its use in such circumstances is recommended.

Adolescent↗