Publications (42) View all
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Chapter: One Step Closer to the Target: Intracellular Pharmacokinetics of Gemcitabine
04/2012; , ISBN: 978-953-51-0533-6 -
Article: Randomized phase 2 sequencing and pharmacokinetic study of gemcitabine and oxaliplatin in advanced non-small cell lung cancer.
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ABSTRACT: This multicentre phase II trial examined the combination of gemcitabine and oxaliplatin in patients with advanced non-small cell lung cancer (NSCLC). The effect of sequence administration was randomized and pharmacokinetics (PK) assessed. Eligible patients had stage IIIB or IV or recurrent NSCLC, no prior chemotherapy, World Health Organization performance status ≤2 and measurable disease. Treatment comprised: gemcitabine (1250 mg/m(2)) and oxaliplatin (70 mg/m(2)), each given on days 1 and 8 of a 21-day cycle. Patients were randomized 1:1 to the sequencing of the two drugs for the duration of their treatment. The primary end-point was response rate (RR). Secondary end-points included progression-free survival (PFS), overall survival (OS), toxicity, PK and the effect of drug sequencing. A total of 46 patients were enrolled of whom 43 were evaluable for response. Overall 13 patients (30%) achieved a partial response, PFS was 4.2 months (95% CI 2.8-5.8 months), and OS was 6.8 months (95% CI 4.4-10.1 months). There was only one case of grade 3 neurosensory toxicity despite a median cumulative oxaliplatin dose in excess of 500 mg/m(2) . No differences in clinical or PK end-points were observed between the two different sequencing arms. This oxaliplatin and gemcitabine schedule has shown activity in advanced NSCLC with modest toxicity. Neither clinical nor PK outcomes were influenced by the sequencing of these agents, although definite conclusions are limited by small patient numbers. The favorable toxicity profile of this doublet, in light of an encouraging RR, warrants its further investigation in NSCLC.Asia-Pacific Journal of Clinical Oncology 12/2011; 7(4):376-84. · 0.58 Impact Factor -
Article: Implementing a multi-professional web-based learning environment for a comprehensive cancer centre: obstacles, solutions and reflections.
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ABSTRACT: There is an urgent need for efficient cancer education programmes to promote safe practice in a comprehensive cancer centre. Educational practice has developed historically in an unplanned and inefficient way. Developments in educational theory and information technology provide an opportunity to develop systems with better educational methodology, better efficiency and potential for better impact on safety outcomes. We have developed such a programme at St. George Comprehensive Cancer Centre in Sydney, Australia, and describe here our experience in the first 2 years of implementing such a programme. In this article, we describe the programme, the obstacles and solutions we encountered and our reflections on the journey so far.Journal of Cancer Education 08/2011; 27(1):37-41. · 0.76 Impact Factor -
Article: The pharmacological advantage of prolonged dose rate gemcitabine is restricted to patients with variant alleles of cytidine deaminase c.79A>C.
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ABSTRACT: Controversy exists over the optimal dosing for the nucleoside analogue gemcitabine. A pharmacological advantage is achieved by prolonging infusion times but evidence for a clinical benefit has been conflicting. We hypothesized that polymorphisms in genes involved in gemcitabine accumulation, particularly the cytidine deaminase CDA c.79A>C, may influence the optimal dosing regimen in individual patients. DNA was collected from 32 patients participating in a randomized crossover study comparing 30-min with 100-min infusions of gemcitabine. The relationships between seven polymorphisms among three genes (CDA, RRM1 and DCK) and (i) gemcitabine triphosphate accumulation; (ii) gemcitabine-induced toxicity; and (iii) dose delivery were examined for each infusion time and week of administration. There were trends for increased accumulation of gemcitabine-triphosphate (GEM-TP) with the variant alleles of CDA c.79A>C, and RRM1-37C>A and -524T>C but none of these reached statistical significance in a univariate analysis. In a multivariable model there were significant effects of infusion duration and week of administration on GEM-TP accumulation. There were significant interactions between CDA c.79A>C (P=0.01) and RRM1-37C>A (P=0.019) genotypes, infusion time, and arm. More patients with one or two CDA c.79 variant alleles had doses delays (57 vs 13 %, P=0.03) and a pharmacological advantage for prolonged infusion after week 1. It is important to consider both pharmacokinetics and pharmacogenetics in optimizing gemcitabine accumulation. This represents a classical interaction between genes and environment and provides support for the consideration of both CDA genotype and infusion duration in development of an individualized dosing strategy.Asia-Pacific Journal of Clinical Oncology 03/2011; 7(1):65-74. · 0.58 Impact Factor -
Article: ERK phosphorylation predicts synergism between gemcitabine and the epidermal growth factor receptor inhibitor AG1478.
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ABSTRACT: Clinical trials combining epidermal growth factor receptor (EGFR) inhibitors with gemcitabine-based chemotherapy in non-small cell lung cancer (NSCLC) have not produced a survival advantage. This may be caused by antagonism between the two drugs or mutations that promote such, possibly RAS mutation. Furthermore, ERK, a critical growth regulator downstream of RAS, may play a role. This study aimed to explore the relationship between ERK, synergy/antagonism and cell cycle arrest in combination treatment. A549 (mutant KRAS), H322 (wildtype KRAS) and siRNA-mediated KRAS knockdown A549 were treated with gemcitabine and/or the EGFR inhibitor AG1478 and analyzed with median effect analysis. Cell cycle distribution and ERK phosphorylation were assessed using flow cytometry and ELISA, respectively. Effect on cytotoxicity after ERK inhibition by U0126 was also assessed. Cytotoxic interaction was dose dependent with antagonism at high dose AG1478. G1 arrest was observed with both high dose AG1478 and high dose gemcitabine and therefore was inconsistently associated with antagonism. Furthermore, ERK phosphorylation was increased by gemcitabine and its suppression by AG1478 was related to antagonism particularly in H322. ERK's effect in antagonism was further confirmed by using U0126. Greater antagonism was observed in the KRAS mutant cell line and KRAS knockdown by siRNA resulted in increased sensitivity to AG1478 as well as combination treatment. Our findings are consistent with a model in which ERK phosphorylation favors synergy and the outcome depends on the balance between gemcitabine-induced and AG1478-inhibited ERK phosphorylation. KRAS mutation confers resistance to AG1478 as well as combination treatment.Lung cancer (Amsterdam, Netherlands) 01/2011; 73(3):274-82. · 3.14 Impact Factor
