%0 Journal Article %~ Pubmed %A Chua, Wei %A Clarke, Stephen J %A Charles, Kellie A %T Systemic inflammation and prediction of chemotherapy outcomes in patients receiving docetaxel for advanced cancer. %B Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer %D 2012 %V %N %P %@ 1433-7339 %X BACKGROUND: Inflammatory markers are strong prognostic factors for survival in a variety of cancers. This study aimed to investigate the relationships between known inflammatory markers and their ability to predict overall survival (OS) in patients receiving docetaxel therapy. METHODS: Sixty-eight patients with advanced cancer were enrolled in a clinical trial of single agent docetaxel from 2000 to 2002. Inflammation was measured using baseline cytokine concentrations, acute phase reactant proteins and white blood cell counts. The neutrophil/lymphocyte ratio (NLR) and Glasgow Prognostic Score (GPS) were calculated. Associations between inflammatory markers and their predictive value for OS were tested. RESULTS: The majority of patients had elevated inflammatory markers (50-70%). Strong inter-relationships were observed between the different inflammatory indices. Only NLR and GPS were independently predictive of OS. A combined NLR and GPS score demonstrated 11??month differences in overall OS between patients with normal and elevated inflammatory status. Normalisation of NLR after three doses of chemotherapy was associated with significant improvement in survival. CONCLUSION: This study found that NLR predicts the clinical outcomes for patients with advanced cancer treated with docetaxel. The clinical utilisation of NLR should be validated in a larger patient population to confirm its utility. %Z FOR Codes: 111205 %0 Journal Article %~ Pubmed %A Chua, W %A Charles, K A %A Baracos, V E %A Clarke, S J %T Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. %B British Journal of Cancer %D 2011 %V 104 %N 8 %P 1288-95 %@ 1532-1827 %X Background:Advances in the treatment of metastatic colorectal cancer (mCRC) in the last decade have significantly improved survival; however, simple biomarkers to predict response or toxicity have not been identified, which are applicable to all community oncology settings worldwide. The use of inflammatory markers based on differential white-cell counts, such as the neutrophil/lymphocyte ratio (NLR), may be simple and readily available biomarkers.Methods:Clinical information and baseline laboratory parameters were available for 349 patients, from two independent cohorts, with unresectable mCRC receiving first-line palliative chemotherapy. Associations between baseline prognostic variables, including inflammatory markers such as the NLR and tumour response, progression and survival were investigated.Results:In the training cohort, combination-agent chemotherapy (P=0.001) and NLR???5 (P=0.003) were associated with improved clinical benefit. The ECOG performance status ???1 (P=0.002), NLR>5 (P=0.01), hypoalbuminaemia (P=0.03) and single-agent chemotherapy (P<0.0001) were associated with increased risk of progression. The ECOG performance status ???1 (P=0.004) and NLR>5 (P=0.002) predicted worse overall survival (OS). The NLR was confirmed to independently predict OS in the validation cohort (P<0.0001). Normalisation of the NLR after one cycle of chemotherapy in a subset of patients resulted in improved progression-free survival (P=0.012).Conclusion:These results have highlighted NLR as a potentially useful clinical biomarker of systemic inflammatory response in predicting clinically meaningful outcomes in two independent cohorts. Results of this study have also confirmed the importance of a chronic systemic inflammatory response influencing clinical outcomes in patients with mCRC. %Z FOR Codes: 111205 %0 Journal Article %~ Pubmed %A Clarke, S J %A Chua, W %A Moore, M %A Kao, S %A Phan, V %A Tan, C %A Charles, K %A McMillan, D C %T Use of inflammatory markers to guide cancer treatment. %B Clinical pharmacology and therapeutics %D 2011 %V 90 %N 3 %P 475-8 %@ 1532-6535 %X %Z FOR Codes: 111205 %0 Journal Article %~ Pubmed %A Chua, Wei %A Kho, Patricia S %A Moore, Melissa M %A Charles, Kellie A %A Clarke, Stephen J %T Clinical, laboratory and molecular factors predicting chemotherapy efficacy and toxicity in colorectal cancer. %B Critical reviews in oncology/hematology %D 2011 %V 79 %N 3 %P 224-50 %@ 1879-0461 %X Colorectal cancer (CRC) treatment has evolved significantly over the last ten years with the use of active chemotherapeutic agents including fluoropyrimidines, oxaliplatin and irinotecan plus targeted monoclonal antibodies bevacizumab, cetuximab and panitumumab. The addition of newer chemotherapeutic agents and targeted therapies has improved patient outcomes at the cost of increased toxicity with not all patients benefiting from these treatments. It is necessary for clinicians to more accurately predict clinical outcomes particularly in the predominantly elderly CRC patient population. This review aims to summarise existing data regarding the use of clinical and laboratory variables plus molecular markers in predicting response, survival and toxicity to chemotherapy agents and targeted monoclonal antibodies currently used in the treatment of CRC. %Z FOR Codes: 111205 %0 Journal Article %~ Pubmed %A Moore, M M %A Chua, W %A Charles, K A %A Clarke, S J %T Inflammation and cancer: causes and consequences. %B Clinical pharmacology and therapeutics %D 2010 %V 87 %N 4 %P 504-8 %@ 1532-6535 %X The link between chronic inflammation and increased risk of developing some cancers is well established. The molecular mechanisms that underlie this process (cause) as well as the chronic inflammation that accompanies cancer (consequence) continue to be elucidated. Cancer-associated inflammation has effects on the ability of cancers to metastasize, on the clinical manifestations of cancer, and on the ability of the patient to tolerate anticancer therapy. The identification of biomarkers of cancer-associated inflammation will assist in identifying patients at risk of its consequences. %Z FOR Codes: 111202 %0 Journal Article %~ Pubmed %A Chua, Wei %A Moore, Melissa M %A Charles, Kellie A %A Clarke, Stephen J %T Predictive biomarkers of clinical response to targeted antibodies in colorectal cancer. %B Current opinion in molecular therapeutics %D 2009 %V 11 %N 6 %P 611-22 %@ 2040-3445 %X Targeted mAbs to VEGFR and EGFR are well-established therapies for the treatment of colorectal cancer. The costs and toxicities associated with these novel treatments are not insignificant, and therefore molecular markers that predict treatment efficacy are needed to individualize the therapy administered to each patient. Recent data in this research field support KRAS mutation testing to guide the selection of EGFR inhibitors for the treatment of colorectal cancer. This review discusses the evidence that KRAS mutation analysis can indicate a beneficial response to EGFR inhibitors, and the potential and limitations of other mutations in the VEGF and EGF signaling pathways as predictive molecular markers in this setting. %Z FOR Codes: 111205 %0 Journal Article %~ Pubmed %A Morgan, Edward T %A Goralski, Kerry B %A Piquette-Miller, Micheline %A Renton, Kenneth W %A Robertson, Graham R %A Chaluvadi, Madhusudana R %A Charles, Kellie A %A Clarke, Stephen J %A Kacevska, Marina %A Liddle, Christopher %A Richardson, Terrilyn A %A Sharma, Rohini %A Sinal, Christopher J %T Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer. %B Drug metabolism and disposition: the biological fate of chemicals %D 2008 %V 36 %N 2 %P 205-16 %@ 1521-009X %X This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 07 meeting in Washington, DC. The presentations discussed the phenomenology, clinical consequences, and underlying mechanisms of cytochrome P450 and drug transporter regulation by inflammatory and infectious stimuli. Although considerable insights into the links between inflammatory mediators and altered hepatic drug clearance pathways have been gained from previous studies with acute inflammatory stimuli, this symposium highlighted recent advances in understanding how these processes operate in other organs and chronic inflammatory states relevant to human diseases. The development of mouse models of live bacterial infection provides excellent opportunities to explore the impact of infection on drug metabolism beyond the well characterized effects of bacterial endotoxin. Altered levels of cytochromes P450 and especially drug transporters due to inflammation in brain, intestine, and placenta have significant implications for the use of many drugs in diverse clinical settings. The consequences of inflammatory cytokine production by tumors for drug safety and efficacy in cancer patients were outlined. Repression of drug clearance pathways by tumor-derived cytokines may result in extreme toxicity to chemotherapy, compromising treatment of many cancers. It is fitting that, in honoring the career contributions and achievements of Dr. Kenneth W. Renton, this symposium reinforced the clinical relevance of this field. %Z FOR Codes: 110302 %0 Journal Article %~ Pubmed %A Charles, Kellie A %A Rivory, Laurent P %A Brown, Sandie L %A Liddle, Christopher %A Clarke, Stephen J %A Robertson, Graham R %T Transcriptional repression of hepatic cytochrome P450 3A4 gene in the presence of cancer. %B Clinical Cancer Research %D 2006 %V 12 %N 24 %P 7492-7 %@ 1078-0432 %X PURPOSE: Many chemotherapeutic drugs have an inherent lack of safety due to interindividual variability of hepatic cytochrome P450 (CYP) 3A4 drug metabolism. This reduction in CYP3A4 in cancer patients is possibly mediated by cytokines associated with tumor-derived inflammation. We sought to examine this link by using an explant sarcoma in a novel transgenic mouse model of human CYP3A4 regulation. EXPERIMENTAL DESIGN: Engelbreth-Holm-Swarm sarcoma cells were injected into the hindlimb of transgenic CYP3A4/lacZ mice. Hepatic expression of the human CYP3A4 transgene was analyzed by direct measurement of the reporter gene product, beta-galactosidase enzyme activity. Hepatic expression of murine Cyp3a was analyzed at the mRNA, protein, and function levels. The acute phase response was assessed by examining cytokines [interleukin-6 (IL-6) and tumor necrosis factor] in serum, liver, or tumor as well as hepatic expression of serum amyloid protein P. RESULTS: Engelbreth-Holm-Swarm sarcoma elicited an acute phase response that coincided with down-regulation of the human CYP3A4 transgene in the liver as well as the mouse orthologue Cyp3a11. The reduction of murine hepatic Cyp3a gene expression in tumor-bearing mice resulted in decreased Cyp3a protein expression and consequently a significant reduction in Cyp3a-mediated metabolism of midazolam. Circulating IL-6 was elevated and IL-6 protein was only detected in tumor tissue but not in hepatic tissue. CONCLUSIONS: The current study provides a mechanistic link between cancer-associated inflammation and impaired drug metabolism in vivo. Targeted therapy to reduce inflammation may provide improved clinical benefit for chemotherapy drugs metabolized by hepatic CYP3A4 by improving their pharmacokinetic profile. %Z FOR Codes: 110502 %0 Journal Article %~ Pubmed %A Hagemann, Thorsten %A Wilson, Julia %A Burke, Frances %A Kulbe, Hagen %A Li, Ninfeng Fiona %A Pl?ddemann, Annette %A Charles, Kellie %A Gordon, Siamon %A Balkwill, Frances R %T Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. %B Journal of Immunology %D 2006 %V 176 %N 8 %P 5023-32 %@ 0022-1767 %X Tumor-associated macrophages (TAM) may have tumor-promoting activity, but it is not clear how their phenotype is achieved. In this study, we demonstrate that ovarian cancer cells switch cocultured macrophages to a phenotype similar to that found in ovarian tumors. Tumor cells caused dynamic changes in macrophage cytokine, chemokine, and matrix metalloprotease mRNA, and protein-inducing mediators that are found in human cancer. Macrophage mannose, mannose receptor, and scavenger receptors (SR-As) were also up-regulated by coculture, but not by conditioned medium. To further validate the model, we studied SR-A regulation on TAM in vitro and in vivo. Coculture of murine macrophages from mice deficient in TNF-alpha or its receptors revealed that TNF-alpha was key to SR-A induction via its p75 receptor. SR-A expression was also reduced in TAM from ovarian cancers treated with anti-TNF-alpha Abs or grown in TNF-alpha(-/-) mice. Chemical communication between tumor cells and macrophages may be important in regulating the cancer cytokine microenvironment. %Z FOR Codes: 111299 %0 Journal Article %~ Pubmed %A Szlosarek, Peter %A Charles, Kellie A %A Balkwill, Frances R %T Tumour necrosis factor-alpha as a tumour promoter. %B European journal of cancer %D 2006 %V 42 %N 6 %P 745-50 %@ 0959-8049 %X It is becoming more evident that many aspects of tumour promotion arise from persistent and unresolving inflammation. One of the key molecules mediating the inflammatory processes in tumour promotion is the cytokine, tumour necrosis factor-alpha (TNF-alpha). Clinically, elevated serum concentrations and increased expression of TNF-alpha are present in various pre-neoplastic and malignant diseases, compared with serum and tissue from healthy individuals. Although over the last few decades high-dose administration of TNF-alpha has been used as a cytotoxic agent, recent pre-clinical cancer models have provided critical evidence to support the link between chronic, low level TNF-alpha exposure and the acquisition of pro-malignant phenotype (i.e., increased growth, invasion and metastasis). Furthermore, sophisticated cellular systems are being utilised to dissect the crucial role TNF-alpha plays in the communication of stromal/inflammatory cells and tumour cells. Understanding the intricate roles of TNF-alpha in the process of tumour promotion will assist in the development of novel cancer therapeutics. %Z FOR Codes: 111209 %0 Journal Article %~ Pubmed %A Charles, Kellie A %A Rivory, Laurent P %A Stockler, Martin R %A Beale, Philip %A Beith, Jane %A Boyer, Michael %A Clarke, Stephen J %T Predicting the toxicity of weekly docetaxel in advanced cancer. %B Clinical pharmacokinetics %D 2006 %V 45 %N 6 %P 611-22 %@ 0312-5963 %X OBJECTIVES: To determine the safety profile of 40 mg/m(2) docetaxel administered weekly to a mixed population of advanced cancer patients and identify predictors of toxicity and survival following treatment with weekly docetaxel in this population. PATIENTS AND METHODS: 68 patients with advanced cancer were enrolled into the study. Various patient characteristics, including inflammatory and nutritional status, docetaxel pharmacokinetics and liver function were investigated. Predictors of treatment-related toxicity and survival were analysed using multivariate logistic regression and Cox proportional hazards analysis, respectively. RESULTS: 27 patients (40%) experienced grade 3 or 4 toxicity, mainly gastrointestinal toxicities (20%), leukopenia (16%) and neutropenia (12%), during the first 8 weeks of docetaxel treatment. Docetaxel pharmacokinetics were the only predictive factor for haematological toxicity. The odds of severe haematological toxicity were approximately 9-fold higher for patients with reduced docetaxel clearance (e.g. <30 L/h). The odds of non-haematological toxicity were about 3-fold higher for patients with elevated levels of inflammatory markers: alpha(1)-acid glycoprotein (AAGP) >1.5 g/L or C-reactive protein >10 mg/L). Multivariate analysis indicated that weight loss, liver dysfunction and elevated levels of AAGP were independently significant predictors of survival. CONCLUSION: This is the first description of factors predictive of the toxicity and survival following weekly administration of docetaxel. Patients with reduced clearance of docetaxel and elevated markers of inflammation experienced worse adverse effects, while patients with weight loss, liver dysfunction and elevated markers of inflammation had worse survival. %0 Journal Article %~ Pubmed %A Balkwill, Frances %A Charles, Kellie A %A Mantovani, Alberto %T Smoldering and polarized inflammation in the initiation and promotion of malignant disease. %B Cancer cell %D 2005 %V 7 %N 3 %P 211-7 %@ 1535-6108 %X %Z FOR Codes: 111299 %0 Journal Article %~ Pubmed %A Hagemann, Thorsten %A Wilson, Julia %A Kulbe, Hagen %A Li, Ningfeng Fiona %A Leinster, David A %A Charles, Kellie %A Klemm, Florian %A Pukrop, Tobias %A Binder, Claudia %A Balkwill, Frances R %T Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. %B Journal of Immunology %D 2005 %V 175 %N 2 %P 1197-205 %@ 0022-1767 %X Tumor-associated macrophages may influence tumor progression, angiogenesis and invasion. To investigate mechanisms by which macrophages interact with tumor cells, we developed an in vitro coculture model. Previously we reported that coculture enhanced invasiveness of the tumor cells in a TNF-alpha- and matrix metalloprotease-dependent manner. In this report, we studied intracellular signaling pathways and induction of inflammatory genes in malignant cells under the influence of macrophage coculture. We report that coculture of macrophages with ovarian or breast cancer cell lines led to TNF-alpha-dependent activation of JNK and NF-kappaB pathways in tumor cells, but not in benign immortalized epithelial cells. Tumor cells with increased JNK and NF-kappaB activity exhibited enhanced invasiveness. Inhibition of the NF-kappaB pathway by TNF-alpha neutralizing Abs, an NF-kappaB inhibitor, RNAi to RelA, or overexpression of IkappaB inhibited tumor cell invasiveness. Blockade of JNK also significantly reduced invasiveness, but blockade of p38 MAPK or p42 MAPK had no effect. Cocultured tumor cells were screened for the expression of 22 genes associated with inflammation and invasion that also contained an AP-1 and NF-kappaB binding site. EMMPRIN and MIF were up-regulated in cocultured tumor cells in a JNK- and NF-kappaB-dependent manner. Knocking down either MIF or EMMPRIN by RNAi in the tumor cells significantly reduced tumor cell invasiveness and matrix metalloprotease activity in the coculture supernatant. We conclude that TNF-alpha, via NF-kappaB, and JNK induces MIF and EMMPRIN in macrophage to tumor cell cocultures and this leads to increased invasive capacity of the tumor cells. %Z FOR Codes: 111201 %0 Journal Article %~ Pubmed %A Slaviero, Kellie A %A Clarke, Stephen J %A McLachlan, Andrew J %A Blair, Elaine Y L %A Rivory, Laurent P %T Population pharmacokinetics of weekly docetaxel in patients with advanced cancer. %B British Journal of Clinical Pharmacology %D 2004 %V 57 %N 1 %P 44-53 %@ 0306-5251 %X AIMS: Previous pharmacokinetic studies of the 3-weekly regimen (100 mg m(-2) every 3 weeks) of docetaxel have shown that docetaxel clearance is affected by liver function, body surface area, age, serum alpha1-acid glycoprotein and cytochrome P450 3A4 (CYP3A4) activity. However, the pharmacokinetics of a weekly docetaxel (40 mg m(-2) week(-1)) schedule are not well characterized. The aims of this study were (a) to investigate the pharmacokinetics of docetaxel (40 mg m(-2) week(-1)) using sparse concentration-time data collected from patients with advanced cancer and (b) to utilize a population pharmacokinetic approach to identify patient covariates that significantly influence the clearance of docetaxel when administered according to this regimen. METHODS: A two-compartment pharmacokinetic model was used to describe the docetaxel concentration-time data from 54 patients with advanced cancer. The mean population and individual posterior Bayesian estimates of docetaxel clearance were estimated using P-PHARM. The relationships between docetaxel clearance and 21 covariates were investigated. This included estimates of CYP3A4 function in each patient using the erythromycin breath test (1/tmax). Significant covariates were included into the final population pharmacokinetic model. Pharmacokinetic models were validated using a data splitting approach with a dataset consisting of 16 patients. RESULTS: Significant relationships were found between docetaxel clearance and 1/tmax (erythromycin breath test parameter) and several of the liver function enzymes and CL was best described by the equation; CL = 21.51 + 217 (1/tmax) - 0.13 (ALT). This final population pharmacokinetic model provided both precise and unbiased predictions of docetaxel concentrations in a validation group of patients and an estimate of the population mean (95% confidence interval) clearance of docetaxel was 30.13 l h(-1) (12.54, 46.04 l h(-1)) with an intersubject variability 30%. CONCLUSIONS: A population pharmacokinetic model has been developed and validated for weekly docetaxel (40 mg m(-2)) in patients with advanced cancer. These results indicate that CYP3A4 activity and hepatic function have an impact on the pharmacokinetics of docetaxel when administered weekly. %0 Journal Article %~ Pubmed %A Baker, Sharyn D %A van Schaik, Ron H N %A Rivory, Laurent P %A Ten Tije, Albert J %A Dinh, Kimberly %A Graveland, Wilfried J %A Schenk, Paul W %A Charles, Kellie A %A Clarke, Stephen J %A Carducci, Michael A %A McGuire, William P %A Dawkins, Fitzroy %A Gelderblom, Hans %A Verweij, Jaap %A Sparreboom, Alex %T Factors affecting cytochrome P-450 3A activity in cancer patients. %B Clinical Cancer Research %D 2004 %V 10 %N 24 %P 8341-50 %@ 1078-0432 %X PURPOSE: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patients. EXPERIMENTAL DESIGN: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6). RESULTS: CYP3A activity (AUC(0-40 min)) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by approximately 50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, alpha-1 acid glycoprotein, explained approximately 18% of overall variation in CYP3A activity (P < 0.001). CONCLUSIONS: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.