Assessment of efficacy of postinfusion tubing flushing in reducing risk of cytotoxic contamination.

Purpose: Infusion of cytotoxic drugs carries the risk of occupational exposure of healthcare workers. Since disconnecting an infusion line is a source of contamination, flushing of tubing after infusion of cytotoxic agents is recommended, but the optimal volume of rinsing solution is unknown. The objective of this study was to assess whether postinfusion line flushing completely eliminates cytotoxics.

Inhibition of OCT2, MATE1 and MATE2-K as a possible mechanism of drug interaction between pazopanib and cisplatin.

We hypothesized that pazopanib is an inhibitor of cisplatin renal transporters OCT2, MATE1 and MATE2-K based on previous studies demonstrating an interaction between tyrosine kinase inhibitors and these transporters. Because several combinations of targeted therapies and cytotoxics are currently in development for cancer treatment, such an interaction is worth investigating. Experiments on HEK293 cells stably transfected to express OCT2, MATE1, MATE2-K or an empty vector (EV) were conducted.

Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio.

Despite the growing evidence that dihydropyrimidine dehydrogenase deficiency (DPD, encoded by the DPYD gene) confers a higher risk of developing severe toxicity, most patients are not screened for DPD deficiency before fluoropyrimidine treatment. We report here the genetic and phenotypic analyses of DPD in a family related to a patient who died after a first cycle of 5-fluorouracil and in 15 additional retrospective patients having a partial DPD deficiency (as measured by plasma dihydrouracil/uracil ratio). The patient with lethal toxicity was found to be a compound heterozygote for two DPYD mutations: a novel 8-bp duplication (c.

Irreversible hepatotoxicity after administration of trabectedin to a pleiomorphic sarcoma patient with a rare ABCC2 polymorphism: a case report.

We describe here the case of a 60-year old male patient treated for an extensive local progression of a pleiomorphic sarcoma on the right tibial crest with second-line trabectedin. Two cycles were administrated before a major liver toxicity was retrieved, with both cytolytic and cholestatic hepatitis quickly associated with irreversible jaundice. The radiological, histological, chemistry and pharmacogenetic investigations led us to diagnose chronic hepatobiliary toxicity with portal fibrosis, cholangiolitis damages and chronic hepatopathy.

Ovarian ascites-derived Hospicells promote angiogenesis via activation of macrophages.

Within the microenvironment, Carcinoma-associated mesenchymal stem cells (Hospicells) are able to influence ovarian tumor development via, among others, the facilitation of angiogenesis in the tumor site allowing an accelerated tumor growth. We demonstrate the presence of a chemotactism between endothelial cells and Hospicells, and a cell line specific increased secretion of pro-angiogenic cytokines such as IL-6, IL-8 and VEGF from ovarian adenocarcinoma cells. Hospicells are also able to attract and activate macrophages to a M2 phenotype and allow them to secrete a huge quantity of pro-angiogenic cytokines, favorable to tumor progression of all the associated ovarian adenocarcinoma cells tested.

Gene expression profiling on pre- and post-erlotinib tumors from patients with head and neck squamous cell carcinoma.

Background: The purpose of our work was to identify genomic predictive markers of erlotinib response in patients with head and neck squamous cell carcinoma (HNSCC).

Methods: Tumor tissue biopsies were collected before and after treatment for 39 patients. We analyzed genomic expression of the tumors using microarrays to (1) identify genes differentially expressed in baseline samples in patients who were responders vs nonresponders, (2) characterize erlotinib's effect on gene expression, and (3) identify the pharmacodynamic marker of erlotinib.

Multifactorial pharmacogenetic analysis in colorectal cancer patients receiving 5-fluorouracil-based therapy together with cetuximab-irinotecan.

Aim: To examine the predictive value of gene polymorphisms potentially linked to toxicity, clinical response, time to progression and overall survival, following cetuximab-tegafur-uracil (UFT)-irinotecan therapy.

Methods: Fifty-two patients with advanced colorectal cancer were enrolled in an ancillary pharmacogenetic study of the phase II CETUFTIRI trial. Treatment consisted of 21 day cycles of cetuximab (day 1-day 8-day 15, 250 mg m(-2) week(-1) following a 400 mg m(-2) initial dose) together with irinotecan (day 1, 250 mg m(-2)) and UFT-folinic acid (days 1-14, 250 mg m(-2) day(-1) UFT, 90 mg day(-1) folinic acid).

Unexpected high levels of vorinostat when combined with vinorelbine in patients with advanced cancer.

Background: This study was a multi-centre, dose-escalation trial in patients with advanced cancers. Primary objective was to determine maximum tolerated dose (MTD) of vorinostat, a competitive inhibitor of histone deacetylase (HDAC), in combination with vinorelbine. Secondary aims were to determine (1) corresponding pharmacokinetics, (2) safety of this regimen, and (3) impact of UGT1A1 and 2B17 polymorphisms on vorinostat pharmacokinetics.

Population analysis of erlotinib in adults and children reveals pharmacokinetic characteristics as the main factor explaining tolerance particularities in children.

Purpose: The aim of this pharmacokinetic-pharmacodynamic (PK-PD) analysis was to evaluate the pharmacologic characteristics of erlotinib and its main metabolite (OSI-420) in pediatric patients compared with those in adult patients.

Experimental Design: Plasma concentrations of erlotinib and OSI-420 of 46 children with malignant brain tumors included in a phase I study and 42 adults with head and neck carcinoma were analyzed by a population-pharmacokinetic method (NONMEM). The effect of several covariates and single nucleotide polymorphisms (SNP) in ABCB1, ABCG2, and CYP3A5 on pharmacokinetic parameters was evaluated.

Trastuzumab induced in vivo tissue remodelling associated in vitro with inhibition of the active forms of AKT and PTEN and RhoB induction in an ovarian carcinoma model.

Background: The incidence of ovarian cancer has been increasing worldwide and it is currently the leading cause of death from gynaecological malignancy. Unlike breast cancer, the prognostic role of the human epidermal growth factor receptor-2 (HER-2) in ovarian carcinoma remains controversial.

Methods: The aim of this preclinical study was to further characterise the biological, molecular and cellular effects of trastuzumab (Herceptin) using NIH-OVCAR-3 and derived cell lines both in vitro and in vivo.

[Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC): evaluation, prevention and policies to avoid occupational exposure for operating room personnel].

To develop a treatment strategy for peritoneal carcinomatosis using a combination of extended peritoneal resections, local destructive procedures and hyperthermic intraperitoneal chemotherapy creates great concern between healthcare workers involved in these procedures. New professional risks exist: risk of exposure to cytotoxic drugs, environmental risks (inhalation of smoke, aerosolization of chemotherapy agents). Information, education and training of healthcare workers is mandatory in order to ensure proper evaluation, prevention, and management of professional exposure risks in coordination with the occupational health office.

Hospicells (ascites-derived stromal cells) promote tumorigenicity and angiogenesis.

The microenvironment is known to play a dominant role in cancer progression. Cells closely associated with tumoral cells, named hospicells, have been recently isolated from the ascites of ovarian cancer patients. Whilst these cells present no specific markers from known cell lineages, they do share some homology with bone marrow-derived or adipose tissue-derived human mesenchymal stem cells (CD9, CD10, CD29, CD146, CD166, HLA-1).

Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma.

Unlabelled: A clinical study was conducted to determine the safety and efficacy of neoadjuvant erlotinib treatment in patients with head and neck squamous cell carcinoma [Thomas F, Rochaix P, Benlyazid A, et al. Pilot study of neoadjuvant treatment with erlotinib in non-metastatic head and neck squamous cell carcinoma. Clin Cancer Res 2007;13:7086-92].

Preclinical study of an ex vivo gene therapy protocol for hepatocarcinoma.

Preclinical studies in several animal models as well as clinical trials have shown a reduction in tumor growth following immunotherapy with interleukin-12 (IL-12). This cytokine is appropriate to test in therapeutic clinical trials to treat hepatocarcinoma (HC), a pathology often associated with hepatitis B or C-induced cirrhosis. The local delivery into the liver would be achieved through ex vivo gene transfer using retroviral (rv) vectors in autologous fibroblast carriers.

In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR.

This study aimed to assess the effect of cetuximab (C225, Erbitux, a chimeric anti-epidermal growth factor receptor (EGFR) monoclonal antibody) in combination with oxaliplatin in vitro and in vivo on four colon cancer cell lines (HCT-8; HT-29, SW620, HCT-116) expressing different levels of EGFR. In vitro, cetuximab combined with oxaliplatin significantly decreased the IC50 values of oxaliplatin in HCT-8 (EGF-R moderate) and HT-29 (EGF-R weak) cell lines, while SW620 (EGF-R negative) and HCT-116 (EGFR strong) cell lines remained unresponsive. This combination was synergistic in HCT-8 and HT-29 cell lines while cetuximab induced no major modification of the IC50 of oxaliplatin in HCT-116 or SW620 cell lines.

Selective inhibition of HER2 inhibits AKT signal transduction and prolongs disease-free survival in a micrometastasis model of ovarian carcinoma.

Although first-line chemotherapy induces complete clinical remission in many cases of epithelial ovarian cancer, relapse usually occurs 18-28 months from diagnosis owing to micrometastases. The present study aimed to evaluate the effect of trastuzumab on disease-free and overall survival in a specially designed murine model of ovarian cancer (OVCAR-3), which mimicked the natural history of human micrometastatic disease. Trastuzumab can cure the mice if started soon after induction chemotherapy.

Dexamethasone as a probe for docetaxel clearance.

Purpose: A pilot study was conducted in 23 patients in order to assess the correlation between docetaxel clearance (CL) and pharmacokinetics of dexamethasone. Dexamethasone is mainly 6-beta hydroxylated by CYP3A4, and is regularly used as standard docetaxel premedication. Genotyping of known functional single nucleotide polymorphism (SNP) of CYP3A5 (G22893A) and mdr-1 (G2677T, G2677A, and C3435T) have been performed in order to tentatively correlate genotype with docetaxel and dexamethasone pharmacokinetics.

Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines.

Oxaliplatin (L-OHP) is a new platinum analogue that has shown antitumour activity against colon cancer both in vitro and in vivo and is now used in the chemotherapeutic treatment of metastatic colon and rectal cancer. L-OHP like cisplatin (CDDP), is detoxified by glutathione (GSH)-related enzymes and forms platinum (Pt)-DNA adducts lesions that are repaired by the nucleotide excision repair system (NER). We investigated the cytotoxicity and the pharmacology of L-OHP and CDDP on a panel of six colon cell lines in vitro.

Contribution of apoptosis in the cytotoxicity of the oxaliplatin-irinotecan combination in the HT29 human colon adenocarcinoma cell line.

Interactions between the topoisomerase I inhibitor irinotecan (CPT-11) and the platinum derivative oxaliplatin (L-OHP) were investigated in HT29 colon cancer cell line. Synergism was observed when cells were simultaneously exposed to drugs or when cells were first exposed to CPT-11. Flow cytometric studies showed a G(2)/M accumulation when cells were exposed to the simultaneous and CPT-11-->L-OHP combinations whereas a persistent S phase delay was observed when cells were first exposed to L-OHP.

Schedule-dependent activity of topotecan in OVCAR-3 ovarian carcinoma xenograft: pharmacokinetic and pharmacodynamic evaluation.

Topotecan is a topoisomerase (Topo) I inhibitor used in ovarian carcinoma chemotherapy. Topo I inhibitors are thought to be more cytotoxic using protracted schedules of administration. We tested this hypothesis on a preclinical model: human ovarian carcinoma OVCAR-3 implanted i.

Combination of oxaliplatin and irinotecan on human colon cancer cell lines: activity in vitro and in vivo.

The in vitro and in vivo combination of oxaliplatin and irinotecan was investigated in a panel of four human colon cancer cell lines and their counterpart xenografts. In vitro and in vivo experiments demonstrated a synergistic or additive interaction in three cell lines (HCT-116, HCT-8 and HT-29) and an antagonism in SW-620 cells. Since there were clearly opposite interactions depending on the cell line, we further investigated cellular determinants possibly involved in the interaction between the two drugs in HCT-8 and SW-620 cells.

Characterization of CPT-11 converting carboxylesterase activity in colon tumor and normal tissues: comparison with p-nitro-phenylacetate converting carboxylesterase activity.

Irinotecan (CPT-11) is a topoisomerase I inhibitor commonly used in the treatment of colorectal tumors. It is a prodrug, converted to an active metabolite, SN-38, by carboxylesterases (CEs). CEs are ubiquitary enzymes that react with numerous substrates.

CPT-11 converting carboxylesterase and topoisomerase activities in tumour and normal colon and liver tissues.

CPT-11 is a prodrug activated by carboxylesterases to the active metabolite SN-38 which is a potent inhibitor of topoisomerase I. CPT-11 is of clinical interest in the treatment of colorectal cancer. We evaluated the activities of CPT-11 converting carboxylesterase (CPT-CE) and topoisomerase I (topo I) in 53 colorectal tumours, in eight liver metastases and in normal tissue adjacent to the tumours.

Cellular interactions of 5-fluorouracil and the camptothecin analogue CPT-11 (irinotecan) in a human colorectal carcinoma cell line.

CPT-11 (irinotecan) is a DNA topoisomerase I inhibitor active against metastatic colorectal carcinoma. We investigated, in a human colon carcinoma cell line, HT-29, the effects of CPT-11 and 5-fluorouracil (5FU) combinations. A strong synergism between CPT-11 and 5FU was observed after sequential exposure and only additivity or antagonism after simultaneous exposure.

Sequence-dependent activity of the irinotecan-5FU combination in human colon-cancer model HT-29 in vitro and in vivo.

Irinotecan, a DNA-topoisomerase-I inhibitor, is active against metastatic colon carcinoma. We investigated the effects of irinotecan and 5FU combinations in human colon-carcinoma cell line HT-29, both in vitro and in vivo. Cytotoxicity of 24-hr exposure was evaluated by SRB technique and the nature of interactions were determined by median-effect analysis.