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Biomedical subjects

Laurent P Rivory

Publications and source records attributed to Laurent P Rivory.

At least 19 recordsLinked to original sources
PubMed2006

Transcriptional repression of hepatic cytochrome P450 3A4 gene in the presence of cancer.

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.

Adjuvants, Anesthesia↗
PubMed2006

Altered deoxyuridine and thymidine in plasma following capecitabine treatment in colorectal cancer patients.

AIMS: To investigate the relationship between changes in plasma deoxynucleoside concentrations and response and toxicity in patients treated with capecitabine. METHODS: Twenty-six patients received 2 g capecitabine twice daily orally for 2 weeks of a 3-week cycle. Blood samples were collected on day 0 (baseline), day 8, day 15 and day 22 of the first cycle for the determination of plasma thymidine (TdR) and deoxyuridine (UdR) concentrations. Patients were reviewed weekly during the first cycle, then 3-weekly for toxicity assessment. Response was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. RESULTS: The plasma UdR and UdR/TdR ratios were significantly elevated (P < 0.001) compared with baseline (49.3 +/- 20.8 nmol l(-1)) for the entire 3-week treatment period. In contrast, the plasma TdR concentrations of these patients were significantly reduced only on day 8 (P < 0.01) compared with baseline (12.1 +/- 3.83 nmol l(-1)), but returned gradually to basal levels by day 15. There were no significant correlations demonstrated between pretreatment or maximal post-treatment plasma nucleoside ratio and either toxicity or response. The TSER genotype frequencies of homozygous TSER*2, TSER*3 and heterozygous TSER*2/*3 were 7.7%, 42.3% and 50%, respectively. These preliminary data also indicate no direct relationship between thymidylate synthase (TS) genotype and plasma nucleoside levels. CONCLUSIONS: Capecitabine mimics continuous infusion of 5-FU to achieve sustained cellular TS inhibitory effects and suggests the antiproliferative mechanism of capectabine is at least partly due to TS inhibition through its active metabolite FdUMP. Although plasma UdR and TdR concentrations and the UdR/TdR ratio can provide some pharmacodynamic indication of TS inhibition, they are unlikely to predict therapeutic response or toxicity accurately following capecitabine treatment in cancer patients.

Antimetabolites, Antineoplastic↗
PubMed2006

Predictors of vinorelbine pharmacokinetics and pharmacodynamics in patients with cancer.

PURPOSE: Marked interindividual variation in drug disposition and toxicity pose an ongoing challenge to chemotherapy dosage individualization. The aim of this study was to evaluate pretreatment clinical features, genotype and functional indicators of drug clearance as predictors of vinorelbine clearance, and myelotoxicity that could inform dosage optimization. PATIENTS AND METHODS: Forty-one patients with cancer received a 60 mg intravenous dose of vinorelbine. Pretreatment routine body size measurements and blood tests were performed. Midazolam clearance and hepatic technetium labeled sestamibi (99mTc-MIBI) clearance were used to investigate CYP3A and ABCB1 (MDR1, P-glycoprotein) phenotype respectively and selected single nucleotide polymorphisms in CYP3A and ABCB1 were documented. A limited blood sampling strategy was employed and vinorelbine concentrations were determined by high-performance liquid chromatography. Posterior Bayesian estimates of vinorelbine clearance were obtained for each patient using population pharmacokinetic modeling. Myelotoxicity was estimated from the fractional survival of neutrophils post-treatment. RESULTS: There was 4.3-fold variation in vinorelbine clearance across the cohort. In a multivariable analysis, pretreatment estimated creatinine clearance (P < .01) and hepatic (99m)Tc-MIBI clearance (P = .01) were independent predictors of vinorelbine clearance. Fractional survival of neutrophils ranged from 1.3% to 100% and was significantly correlated with vinorelbine clearance (P < .01). Body-surface area was the only pretreatment predictor of fractional survival of neutrophils independent of vinorelbine clearance (P = .02). CONCLUSION: Specific indicators of drug clearance provide predictive information about vinorelbine pharmacokinetics, and body-surface area, probably reflecting normal bone marrow reserve, provides an additional pharmacodynamic indicator. Use of a fixed dose of vinorelbine with modifications guided by pretreatment measures is worthy of prospective evaluation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Predicting the toxicity of weekly docetaxel in advanced cancer.

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.

Adult↗
PubMed2005

A pilot study on the safety of combining chrysin, a non-absorbable inducer of UGT1A1, and irinotecan (CPT-11) to treat metastatic colorectal cancer.

PURPOSE: Recently, it was shown that chrysin causes upregulation of UGT1A1 in Caco-2 intestinal cells. Therefore, we proposed that oral chrysin may reduce irinotecan (CPT-11) induced diarrhoea by shifting the SN-38G/SN-38 equilibrium towards the inactive SN-38G in the gastrointestinal mucosa. The purpose of this study was to examine the safety of combining single agent CPT-11 with chrysin. PATIENTS AND METHODS: Twenty patients with previously treated advanced colorectal cancer were administered chrysin twice daily for 1 week preceding and succeeding treatment with single agent CPT-11 (350 mg/m(2) over 90 min every 3 weeks). Loperamide usage and bowel frequency/consistency were recorded by patients into a study diary and blood samples were collected for CPT-11 pharmacokinetic analysis. RESULTS: There were no observable toxicities that could be attributed to chrysin use. The grades and frequency of delayed diarrhoea were mild, with only 10% of patients experiencing grade 3 toxicity. Loperamide usage was also modest with a median of 1-5 tablets per cycle (range: 0-22). Pharmacokinetic results revealed a mass ratio of plasma SN-38G/SN-38, which was very similar to historical controls (7.15 +/- 5.67, n = 18). CONCLUSIONS: These findings, combined with the observation of clinical activity and grade 3/4 neutropenia in 25% of patients, suggest that combining chrysin with CPT-11 may be a safe and potentially useful means of preventing diarrhoea, although this needs to be further investigated in the setting of a randomised trial.

Administration, Oral↗
PubMed2005

Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients.

A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue capecitabine (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of thymidylate synthase (TS). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other TS inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of TS inhibitors in several species.

Atmospheric Pressure↗
PubMed2005

Hepatic technetium Tc 99m-labeled sestamibi elimination rate and ABCB1 (MDR1) genotype as indicators of ABCB1 (P-glycoprotein) activity in patients with cancer.

BACKGROUND AND OBJECTIVE: The adenosine triphosphate-binding cassette transporter ABCB1 (P-glycoprotein) mediates terminal excretion of many chemotherapeutic agents, and variable ABCB1 activity may be an important contributor to interpatient variability in the clearance of chemotherapeutic agents. Our objective was to determine the elimination constant (kH) for hepatic elimination of technetium Tc 99m-labeled sestamibi (99mTc-MIBI) in patients with cancer and to compare this putative indicator of ABCB1 phenotype with clinical features and common ABCB1 genetic variants. METHODS: 99mTc-MIBI kH was determined from the time-dependent elimination profile of 99mTc-MIBI over a 90-minute hepatic scanning period in 66 patients with cancer. Single nucleotide polymorphisms (SNPs) in ABCB1 exons 12 (C1236T), 21 (G2677T/A), and 26 (C3435T) were documented by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: There was a 12-fold variation in 99mTc-MIBI kH across the cohort, which was not correlated with sex, age, conventional liver function test results, previous chemotherapy treatment, or history of liver metastasis. Mean 99mTc-MIBI kH was significantly reduced in patients with SNPs in exons 21 and 26 such that mean 99mTc-MIBI kH was 1.90 times (95% confidence interval, 1.14-2.66; P = .02) and 2.21 times (95% confidence interval, 1.47-2.97; P < .01) higher in subjects homozygous for the wild-type alleles than in those homozygous for these SNPs, respectively. CONCLUSION: Hepatic elimination of 99mTc-MIBI is a potential in vivo probe of hepatic ABCB1 activity that is significantly associated with the presence of common SNPs in ABCB1. 99mTc-MIBI hepatic scanning may provide a useful pretreatment indicator of ABCB1-mediated drug clearance in cancer patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Loperamide inhibits the biliary excretion of irinotecan (CPT-11) in the rat isolated perfused liver.

Patients treated with irinotecan (CPT-11) occasionally suffer from severe diarrhoea and aggressive treatment with loperamide at the first signs of loose stools is recommended. We have examined the effect of loperamide on the hepatic metabolism and biliary excretion of CPT-11 in the isolated perfused rat liver (IPRL). CPT-11 (0.5 mumol) was injected as a bolus into the IPRL reservoir, and perfusate and bile samples were collected over 3 h. Experiments were conducted using loperamide-free perfusate (n = 5) or perfusate containing 10 muM loperamide (n = 6). Perfusate and bile concentrations of total CPT-11 and the major metabolites SN-38 (7-ethyl-10-hydroxy-camptothecin), SN-38G (7-ethyl-10-hydroxy-camptothecin glucuronide) and APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidine] carbonyloxycamptothecin) were determined by HPLC. The unchanged parent drug was the predominant species in bile, with approximately 4% of the dose recovered over 180 min as compared with only 1% for the metabolites. Loperamide significantly reduced the biliary excretion of CPT-11 by approximately 50% (2.0 +/- 0.9% dose compared with 3.8 +/- 1.0% in the control group, P = 0.019) over the same period. In contrast, the biliary excretion of SN-38, SN-38G and APC was not significantly affected by loperamide (P > 0.05). Furthermore, bile flow rate was not affected by loperamide. Loperamide appeared to selectively inhibit the biliary excretion of CPT-11, although the extent to which loperamide altered the disposition of CPT-11 in the clinical setting remains to be determined.

Animals↗
PubMed2005

The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance.

The fenestrated sinusoidal endothelium ('liver sieve') and space of Disse in the healthy liver do not impede the transfer of most substrates, including drugs and oxygen, from the sinusoidal lumen to the hepatocyte. Plasma components transfer freely in both directions through the endothelial fenestrations and into the space of Disse. The endothelium is attenuated, there is no basement membrane and there is minimum collagen in the space of Disse, thus minimising any barriers to substrate diffusion. Both cirrhosis and aging are associated with marked structural changes in the sinusoidal endothelium and space of Disse that are likely to influence bulk plasma transfer into the space of Disse, and diffusion through the endothelium and space of Disse. These changes, termed capillarisation and pseudocapillarisation in cirrhosis and aging, respectively, impede the transfer of various substrates. Capillarisation is associated with exclusion of albumin, protein-bound drugs and macromolecules from the space of Disse, and the progressive transformation of flow-limited to barrier-limited distribution of some substrates. There is evidence that the sinusoidal changes in cirrhosis and aging contribute to hepatocyte hypoxia, thus providing a mechanism for the apparent differential reduction of oxygen-dependent phase I metabolic pathways in these conditions. Structural change and subsequent dysfunction of the liver sieve warrant consideration as a significant factor in the impairment of overall substrate handling and hepatic drug metabolism in cirrhosis and aging.

Aging↗
PubMed2004

Factors affecting cytochrome P-450 3A activity in cancer patients.

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.

Adult↗
PubMed2004

Population pharmacokinetics of weekly docetaxel in patients with advanced cancer.

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.

Adult↗
PubMed2004

Population pharmacokinetics of raltitrexed in patients with advanced solid tumours.

AIMS: To investigate the population pharmacokinetics of raltitrexed in patients with advanced solid tumours and to identify patient covariates contributing to the interpatient variability in the pharmacokinetics of raltitrexed. METHODS: Patient covariate and concentration-time data were collected from patients receiving 0.1-4.5 mg m(-2) raltitrexed during the early clinical trials of raltitrexed. Data were fitted using nonlinear mixed effects modelling to generate population mean estimates for clearance (CL) and central volume of distribution (V). The relationship between individual estimates of the pharmacokinetic parameters and patient covariates was examined and the influence of significant covariates on the population parameter estimates and their variance was investigated using stepwise multiple linear regression. The performance of the developed model was tested using an independent validation dataset. All patient data were pooled in the total cohort to refine the population pharmacokinetic model for raltitrexed. RESULTS: three-compartment pharmacokinetic model was used to fit the concentration-time data of raltitrexed. Estimated creatinine clearance (CL(CR)) was found to influence significantly the CL of raltitrexed and explained 35% of variability in this parameter, whilst body weight (WT) and serum albumin concentrations (ALB) accounted for 56% of the variability in V. Satisfactory prediction (mean prediction error 0.17 micro g l(-1) and root mean square prediction error 4.99 micro g l(-1)) of the observed raltitrexed concentrations was obtained in the model validation step. The final population mean estimates were 2.17 l h(-1)[95% confidence interval (CI) 2.06, 2.28] and 6.36 l (95% CI 6.02, 6.70) for CL and V, respectively. Interpatient variability in the pharmacokinetic parameters was reduced (CL 28%, V 25%) when influential covariates were included in the final model. The following covariate relationships with raltitrexed parameters were described by the final population model: CL (l h(-1)) = 0.54 + 0.02 CL(CR) (ml min(-1)) and V (l) = 6.64 + 0.08 WT (kg) - 0.16 ALB (g l(-1)). CONCLUSIONS: A population pharmacokinetic model has been developed for raltitrexed in patients with advanced cancer. Pharmacokinetic parameters of raltitrexed are markedly influenced by the patient's renal function, body weight and serum albumin levels, which may be taken into account in dose individualization. The use of influential covariates to guide anticancer dosage selection may result in less variability in drug exposure and potentially a better clinical outcome.

Adult↗
PubMed2004

Effect of short-term morphine exposure on P-glycoprotein expression and activity in cancer cell lines.

Multidrug resistance (MDR) is a common problem in various types of cancer. One important factor in the development of MDR is overexpression of P-glycoprotein, encoded by the MDR1 gene. Morphine is the opioid of choice for moderate to severe cancer pain, and is a substrate of P-glycoprotein. Recently, morphine has been shown to induce P-glycoprotein expression in the rat brain. Using Western blot analysis and cytotoxicity assays respectively, we have investigated the effects of short-term (72 h) morphine treatment on P-glycoprotein expression in a panel of human cancer cell lines, and its effects on cellular resistance to the known P-glycoprotein substrates, vinblastine and colchicine. The effect of morphine on P-glycoprotein expression and activity in the mouse fibroblast NIH-3T3 cell was assessed to establish whether morphine effects are species specific. Short-term exposure to morphine did not result in any significant differences in P-glycoprotein expression or activity in any cancer cell lines. Morphine pre-treatment resulted in a moderate but significant increase in sensitivity of NIH-3T3 cells to vinblastine, but not colchicine. This study suggests that morphine effects may be cell-type specific. Importantly, however, it appears that short-term morphine treatment does not affect the MDR phenotype of tumour cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy.

An important limitation in the use of chemotherapy in cancer treatment is that cytotoxic agents have small margins of safety compared with other drugs. The largely unpredictable pharmacokinetics of cytotoxic agents contribute significantly to differences in toxicity and efficacy between individuals. Over the past few decades, evidence has accumulated that the inflammatory response to conditions such as infection, degenerative disease, and cancer can greatly affect the disposition of drugs. A more recent finding is that the presence of an inflammatory response identifies patients with more aggressive disease and may also compromise the pharmacodynamics of anticancer drugs. In this review, we discuss the changes in the pharmacokinetics of drugs caused by the presence of inflammation. Also, we discuss the modulating role of inflammatory mediators on the pharmacokinetics and pharmacodynamics of cytotoxic agents. We argue that, overall, these factors identify inflammatory response as a potentially important factor in the interindividual variability of response and toxic effects to cancer chemotherapy.

Animals↗
PubMed2003

Baseline nutritional assessment in advanced cancer patients receiving palliative chemotherapy.

Depletion of nutritional reserves and significant weight loss can lead to an increased risk of morbidity, reduced chemotherapy response, and shorter survival in patients with cancer. Weight loss and malnutrition are recognized to result from multifactorial processes, which if assessed and managed appropriately may lead to improved treatment outcome. Numerous methodologies are used for the assessment of nutritional status. However, it remains unclear which of these tools is the most appropriate in the setting of cancer chemotherapy. The aim of this study was to investigate the use of various fundamental assessment tools that could be applied to the routine clinical evaluation of nutritional status in patients with advanced solid malignancies before treatment with palliative chemotherapy. We investigated the interrelationships between biochemical indices, anthropometric measures, and a nutritional screening tool, the Mini-Nutritional Assessment, in 73 patients. Many of these measures were highly interrelated, but the baseline history of weight loss in these patients was strongly correlated to the Mini-Nutritional Assessment (MNA) score (P < 0.0005). In turn, baseline weight loss and the MNA score were strongly correlated to serum C-reactive protein (a marker of acute-phase response). In some patients, malnutrition was linked to disease- or treatment-related upper digestive tract morbidity. Testing for the serum concentration of C-reactive protein at baseline may identify a subset of patients for whom a decline in nutritional status is linked to the presence of an active inflammatory response, a recognized precursor of cachexia

Adult↗
PubMed2002

Pemetrexed: single-agent and combination phase I study overview.

Pemetrexed is a novel folic acid antimetabolite that exerts its activity by the inhibition of multiple enzyme targets. It has been evaluated in a series of phase I clinical trials that explored different administration schedules. The schedule that has been carried forward into phase II trials involves the administration of pemetrexed as a 10-minute intravenous infusion every 21 days with no standard pretreatment with folic acid or vitamin B(12). When given in this manner, the dose-limiting toxicities were neutropenia and thrombocytopenia. Other toxicities included mucositis, rash, and fatigue. The recommended phase II dose was 600 mg/m(2) administered intravenous every 21 days, although this was subsequently modified to 500 mg/m(2) when several early patients experienced toxicities requiring dose reduction in phase II studies. On the basis of preclinical studies suggesting additive or synergistic effects, pemetrexed has also been evaluated in phase I studies in combination with several other agents including cisplatin, carboplatin, oxaliplatin, irinotecan, the taxanes, and anthracyclines. Encouraging anticancer activity has been observed in many of these studies.

Antimetabolites, Antineoplastic↗
PubMed2002

The importance of tumor glucuronidase in the activation of irinotecan in a mouse xenograft model.

The anticancer drug irinotecan (CPT-11) is activated to the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin), by esterases. SN-38 is in turn conjugated to the inactive SN-38 glucuronide (SN-38G). The reverse reaction is mediated by beta-glucuronidases. Hence, production of SN-38 may occur through either pathway. In this study we conducted in vitro studies to examine these two reactions in neuroblastoma xenograft tumors (NB1691) and compared the rates of SN-38 production with those observed in the liver and plasma of the host SCID (severe-combined immunodeficient) mice. The rate of formation of SN-38 from CPT-11 by esterases slowed considerably during a 60-min incubation, consistent with the known deacylation-limited nature of this reaction. For xenograft tumor tissue, K(m) and V(max) values of 1.6 microM and 4.4 pmol/min/mg of protein, respectively, were observed. By comparison, these parameters were estimated to be 6.9 microM and 9.4 pmol/min/mg for mouse liver and 2.1 microM and 40.0 pmol/min/mg for mouse plasma, respectively. The formation of SN-38 from SN-38G was very pronounced in both liver and xenograft tumor tissue, in which it was nonsaturable (0.125-50 microM) and time-independent (0-60 min). The derived values of V(max)/K(m) were 0.65 microl/min/mg for the tumor and 2.12 microl/min/mg for the liver preparations. Microdialysate experiments revealed the concentrations of SN-38G and CPT-11 in tumor to be comparable. At equal substrate concentrations, production of SN-38 from SN-38G in tumor extracts was comparable with that from CPT-11. Therefore, reactivation of SN-38 in the tumor by beta-glucuronidases may represent an important route of tumor drug activation for CPT-11.

Algorithms↗