TY - JOUR. T1 - Camptothecin analogues. T2 - studies from The Johns Hopkins Oncology Center. AU - Slichenmyer, William J.. AU - Rowinsky, Eric K.. AU - Grochow, Louise B.. AU - Kaufmann, Scott H.. AU - Donehower, Ross C.. PY - 1994/1/1. Y1 - 1994/1/1. N2 - The camptothecin analogues topotecan and irinotecan (CPT-11) are active anticancer drugs. This article reviews the accumulated results of clinical and laboratory studies performed with these agents at The Johns Hopkins Oncology Center. In a phase I clinical and pharmacology trial of topotecan given as a 30-min infusion daily for 5 days every 3 weeks, profound neutropenia precluded dose escalation above 1.5-2.0 mg/m2 per day, the maximum tolerated dose (MTD). The daily ×5 schedule has been developed further with dose escalation using granulocytecolony-stimulating factor support in patients who have kidney or liver dysfunction and given in combination with cisplatin. In addition, a phase I trial of topotecan given as a 5-day continuous ...

Brain tumor news: Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine-DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial.

We report here a tumor-targeting masked phototherapeutic agent 1 (PT-1). This system contains SN-38-a prodrug of the topoisomerase I inhibitor irinotecan. Topoisomerase I is a vital enzyme that controls DNA topology during replication, transcription, and recombination. An elevated level of topoisomerase I is found in many carcinomas, making it an attractive target for the development of effective anticancer drugs. In addition, PT-1 contains both a photo-triggered moiety (nitrovanillin) and a cancer targeting unit (biotin). Upon light activation in cancer cells, PT-1 interferes with DNA re-ligation, diminishes the expression of topoisomerase I, and enhances the expression of inter alia mitochondrial apoptotic genes, death receptors, and caspase enzymes, inducing DNA damage and eventually leading to apoptosis. In vitro andin vivo studies showed significant inhibition of cancer growth and the hybrid system PT-1 thus shows promise as a programmed photo-therapeutic (phototheranostic).. ...

We developed previously a resistant cell line, CEM/C2, from the human leukemia cell line CCRF-CEM by stepwise selection in camptothecin. This cell line is 974-fold more resistant to camptothecin than parental cells. Resistance is only partially explained by 2-fold reductions in topoisomerase I protein and mRNA levels. We further investigated biochemical and molecular features of topoisomerase I in the resistant cell line. Sequence analyses of the top1 cDNA from CEM/C2 identified mutations corresponding to two amino acid substitutions, Met370Thr and Asn722Ser. Asn722Ser is next to the catalytic Tyr723 in a region highly conserved among type I eukaryotic DNA topoisomerases. Recombinant top1 with the corresponding substitution was found to be catalytically active and resistant to camptothecin. These results indicate that camptothecin resistance of CEM/C2 is due to the mutation Asn722Ser and strongly suggest that the asparagine immediately flanking the catalytic tyrosine is important for the ...

TY - JOUR. T1 - Determination of the glucuronide metabolites of the topoisomerase I inhibitors, 7-ethyl-10-hydroxy-camptothecin (SN-38) and NU-ICRF 505 by high performance liquid chromatography. AU - Cummings, J.. AU - Ethell, B T.. AU - Boyd, Gary. AU - Burchell, B.. AU - Smyth, J F.. AU - Jodrell, D I.. PY - 2002. Y1 - 2002. N2 - HPLC methods are presented for the determination of the topoisomerase I inhibitors 7-ethyl 10-hydroxycamptothecin (SN-38) and NU/ICRF 505, their chemical/enzymatic hydrolysis products and glucuronide metabolites in both aqueous media and biological specimens. Chromatographic conditions were optimised for baseline resolution of the water-soluble metabolites from their non-water soluble parent compounds while eetaining compatibility with both atmospheric pressure electrospray ionisation and electron impact ionisation mass spectrometric detection. Solid phase extraction sample preparation utilising a C2-bonded silica sorbent enabled simultaneous recovery of parent ...

FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival

Depletion of glutathione (GSH) in MCF-7 and MDA-MB-231 cell lines by pretreatment with the GSH synthesis inhibitor buthionine sulfoximine potentiated the activity of 10,11-methylenedioxy-20(S)-camptothecin, SN-38 [7-ethyl-10-hydroxy-20(S)-camptothecin], topotecan, and 7-chloromethyl-10,11-methylenedioxy-20(S)camptothecin (CMMDC). The greatest potentiation was observed with the alkylating camptothecin CMMDC. Buthionine sulfoximine pretreatment also increased the number of camptothecin-induced DNA-protein crosslinks, indicating that GSH affects the mechanism of action of camptothecin.

Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold; however, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan [see Clinical Pharmacology (12.3)]. The precise contribution of SN-38 to the activity of CAMPTOSAR is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms such that an ...

BACKGROUND: Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. METHODS: In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a

OBJECTIVES: I. Determine the maximum tolerated dose of intravenous irinotecan when administered weekly for 4 weeks in patients with recurrent malignant gliomas. II. Describe the pharmacokinetics of this route of administration, measuring both irinotecan and the active metabolite SN-38, and determine the effects of hepatic enzyme inducing drugs, such as anticonvulsants, on the pharmacokinetics in these patients. III. Determine preliminary response data and activity of irinotecan in this patient population. IV. Correlate response with topoisomerase I levels in brain tumor tissue from patients undergoing treatment. OUTLINE: Patients are stratified based on their use/kind of anticonvulsant drugs. This stratification yields two arms for this study. Arm I consists of patients who use anticonvulsant drugs that induce hepatic metabolic enzymes. Arm II consists of patients who use anticonvulsant drugs that cause modest to no induction of hepatic metabolic enzymes or no anticonvulsant drug. Three patients ...

Irinotecan is a relatively new anticancer agent of interest for both its clinical activity and its complex clinical pharmacology. It is a prodrug, requiring activation by carboxylesterases to SN-38, an inhibitor of topoisomerase I. Recent studies suggest that human carboxylesterase-2 is the primary carboxylesterase involved in the hydrolysis at pharmacological concentrations (1) . Irinotecan is also oxidized by CYP3A43 to the inactive metabolite 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin as well as to 7-ethyl-10-[4-(piperidino)-1-amino]carbonyloxycamptothecin, which can undergo hydrolysis to SN-38 (2, 3, 4) . SN-38 undergoes glucuronidation by UGT1A1 (5) and is possibly oxidized by CYP3A4 as well (6) . Mass balance studies have demonstrated that 64% of the total dose is excreted in the feces, confirming the important role of biliary excretion (7) . Studies suggest that canalicular multispecific organic anion transporter is the major transporter of irinotecan and ...

Cells maintain genomic stability by the coordination of DNA-damage repair and cell-cycle checkpoint control. In replicating cells, DNA damage usually activates intra-S-phase checkpoint controls, which are characterized by delayed S-phase progression and increased Rad53 phosphorylation. We show that in budding yeast, the intra-S-phase checkpoint controls, although functional, are not activated by the topoisomerase I inhibitor camptothecin (CPT). In a CPT-hypersensitive mutant strain that lacks the histone 2A (H2A) phosphatidylinositol-3-OH kinase (PI(3) K) motif at Ser 129 (h2a-s129a), the hypersensitivity was found to result from a failure to process full-length chromosomal DNA molecules during ongoing replication. H2A Ser 129 is not epistatic to the RAD24 and RAD9 checkpoint genes, suggesting a non-checkpoint role for the H2A PI(3) K site. These results suggest that H2A Ser 129 is an essential component for the efficient repair of DNA double-stranded breaks (DSBs) during replication in yeast, ...

Genotype-directed Phase II Study of Irinotecan Dosing in Metastatic Colorectal Cancer (mCRC) Patients Receiving FOLFIRI + Bevacizumab study is currently recruiting healthy volunteers at Indiana CTSI, IN

Nanjing Sunsure Chemical Technology Co.,Ltd. provides 9-Nitrocamptothecin (91421-42-0) purchasing information,includeing 9-Nitrocamptothecin purity : 99%,Lead Time,price.And provide 9-Nitrocamptothecin to submit purchase information online.

PRIMARY OBJECTIVES:. I. Determine whether thalidomide alters the pharmacokinetics of irinotecan in patients with advanced solid tumors.. II. Determine whether irinotecan alters the pharmacokinetics of thalidomide in these patients.. III. Determine the toxicity of this regimen in these patients. IV. Determine the observed antitumor response in patients treated with this regimen.. OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms.. Arm I: Patients receive irinotecan IV over 90 minutes on days 1 and 22 and oral thalidomide once daily on days 15-28.. Arm II: Patients receive irinotecan as in arm I and oral thalidomide once daily on days -6 to 7.. All patients undergo disease re-evaluation at 6 weeks. Patients with stable or responsive disease may receive additional courses comprising irinotecan IV on day 1 and oral thalidomide once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.. PROJECTED ACCRUAL: A ...

BACKGROUND: The identification of new therapies for high-risk (HR) hepatoblastoma is challenging. Childrens Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk hepatoblastoma. METHODS: Patients with newly diagnosed metastatic hepatoblastoma or those with a serum alpha-fetoprotein (AFP) level /mL were eligible. Patients received 2 cycles of V at a dose of 1.5 mg/m2 /day intravenously on days 1 and 8 and I at a dose of 50 mg/m2 /day intravenously on days 1 to 5. Patients were defined as responders if they had either a 30% decrease in tumor burden according to Response Evaluation Criteria In Solid Tumors (RECIST) or a 90% ( | 1 log10 ) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD)

This is an open label uncontrolled phase IB/II study to determine the maximum tolerated dose (MTD) and assess the efficacy of everolimus, irinotecan and panitumumab when given in combination for patients with metastatic colorectal cancer and KRAS wild-type (WT). Patients with metastatic colorectal cancer (mCRC) that have failed fluorouracil based first line therapy will be included. It is anticipated that approximately 50 patients will be enrolled over a period of 24 ...

A phase II study was conducted to assess the response rate and toxicity profile of the combination of irinotecan (CPT-11, Camptosar) and cisplatin (Platinol) administered weekly to patients with untreated advanced 1

In vivo neuroblastoma (NB) xenograft model, resistant to the DNA-topoisomerase I inhibitor irinotecan (CPT-11), has been established to study resistance mechanisms acquired in a therapeutic setting. Common mechanisms of resistance were not involved in this resistance. Thus, we compared the gene expression profiles of sensitive, resistant, and reverted tumors using cDNA expression arrays. Expression of selected transcripts was confirmed by quantitative real-time PCR. We found that pleiotrophin (PTN), a heparin-binding growth factor, was the only gene significantly affected: PTN gene expression was downregulated in all resistant tumors (8-14-fold) as compared to sensitive tumors, and was increased (2-4-fold) in all reverted tumors as compared to resistant tumors. PTN thus appeared to be a likely candidate gene associated with resistance to CPT-11 in this in vivo model. To investigate the direct implication of PTN in NB, we transfected two NB cell lines with RNA interferences in order to silence PTN. PTN

This study investigated the efficacy and tolerability of first-line polysaccharide-K [Krestin] + irinotecan + cisplatin versus irinotecan + cisplatin in

TY - JOUR. T1 - 11H-Isoquino[4,3-c]cinnolin-12-ones. T2 - Novel anticancer agents with potent topoisomerase I-targeting activity and cytotoxicity. AU - Ruchelman, Alexander L.. AU - Singh, Sudhir K.. AU - Ray, Abhijit. AU - Wu, Xiaohua. AU - Yang, Jin Ming. AU - Zhou, Nai. AU - Liu, Angela. AU - Liu, Leroy-Fong. AU - LaVoie, Edmond J.. PY - 2004/2/15. Y1 - 2004/2/15. N2 - Recent studies have identified 2,3-dimethoxy-8,9-methylenedioxy-11-[(2- dimethylamino)ethyl]-11H-isoquino[4,3-c]cinnolin-12-one (1a) as a novel topoisomerase I-targeting agent with potent cytotoxic activity. The effect of varied substituents at the 11-position of 2,3-dimethoxy-8,9-methylenedioxy-11H- isoquino[4,3-c]cinnolin-12-ones on topoisomerase I-targeting activity and cytotoxicity was evaluated. Potent TOP1-targeting activity was observed when the 11-position was substituted with either a 2-(N,N-dimethylamino)ethyl, a 2-(N,N-diethylamino)ethyl, a n-butyl, or a 2-(pyrrolidin-1-yl)ethyl group. The addition of a β-methyl ...

There is a clear and unmet clinical need for biomarkers to predict responsiveness to chemotherapy for cancer. We developed an in vitro test based on patient-derived tumor organoids (PDOs) from metastatic lesions to identify nonresponders to standard-of-care chemotherapy in colorectal cancer (CRC). In a prospective clinical study, we show the feasibility of generating and testing PDOs for evaluation of sensitivity to chemotherapy. Our PDO test predicted response of the biopsied lesion in more than 80% of patients treated with irinotecan-based therapies without misclassifying patients who would have benefited from treatment. This correlation was specific to irinotecan-based chemotherapy, however, and the PDOs failed to predict outcome for treatment with 5-fluorouracil plus oxaliplatin. Our data suggest that PDOs could be used to prevent cancer patients from undergoing ineffective irinotecan-based chemotherapy.. ...

In southern China, where Camptotheca acuminata is native, people call these big-leafed trees Happy Trees. Chinese herbalists have been prescribing medicine from the leaves for centuries to treat various ailments, including leukemia. In the 1950s, National Cancer Institute researchers in the U.S. isolated the alkaloid camptothecin from the leaves, and today, several drugs derived from camptothecin help treat ovarian and colon cancer.. (Podcast: The Plant Detective, 8/16/14). ...

MeSH-minor] Aged. Aged, 80 and over. Area Under Curve. Camptothecin / administration & dosage. Camptothecin / adverse effects. Camptothecin / analogs & derivatives. Camptothecin / pharmacokinetics. Carcinoma, Small Cell / drug therapy. Cholangiocarcinoma / drug therapy. Deoxycytidine / administration & dosage. Deoxycytidine / adverse effects. Deoxycytidine / analogs & derivatives. Deoxycytidine / pharmacokinetics. Diarrhea / chemically induced. Dose-Response Relationship, Drug. Drug Interactions. Female. Gastrointestinal Hemorrhage / chemically induced. Half-Life. Humans. Infusions, Intravenous. Lung Neoplasms / drug therapy. Male. Middle ...

The present invention provides generally a compound having the following general formula (1): wherein R1 and R2 are independently the same or different and are hydrogen, an alkyl group, an alkenyl group, a benzyl group, an alkynyl group, an alkoxyl group, an aryloxy group, an acyloxy group, -OC(O)ORd, wherein Rd is an alkyl group, a carbamoyloxy group, a halogen, a hydroxyl group, a nitro group, a cyano group, an azido group, a formyl group, a hydrazino group, an acyl group, an amino group, -SRc, wherein, Rc is hydrogen, an acyl group, an alkyl group, or an aryl group, or R1 and R2 together form a group of the formula -O(CH2)nO- wherein n represents the integer 1 or 2; R3 is H, F, a halogen atom, a nitro group, an amino group, a hydroxyl group, or a cyano group; or R2 and R3 together form a group of the formula -O(CH2)nO- wherein n represents the integer 1 or 2; R4 is H, F, a C1-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, or a C1-3 alkoxyl group; R5 is a C1-10 alkyl group, or a propargyl

The objective of this study is to evaluate the safety and efficacy of Irinotecan Bead in the neoadjuvant treatment (i.e. the Irinotecan Bead is administ

Tumor profiling and response data were available for 12 patients. No difference in clinical activity was seen between the classical and basal-like subtypes, but the numbers were very small, commented Dr. Wainberg.. Safety Overview. Treatment-related adverse events grade ≥ 3 were observed in 69% of patients. The most common toxicity grade ≥ 3 was neutropenia, occurring in 31%; febrile neutropenia developed in 12% of patients, but none discontinued treatment, reported Dr. Wainberg. Of note, granulocyte colony-stimulating factors were not given prophylactically or mandated. This was left up to the institution.. Our findings suggest that NALIRIFOX is tolerable in newly diagnosed metastatic pancreatic cancer. No new safety signals were identified, and its antitumor activity is promising, Dr. Wainberg concluded.. The regimen is now being evaluated in the global randomized phase III NAPOLI-3 trial of previously untreated metastatic pancreatic adenocarcinoma. In NAPOLI-3, NALIRIFOX is being ...

Irinotecan, sold under the brand name Camptosar among others, is a medication used to treat colon cancer, and small cell lung cancer.[3] For colon cancer it is used either alone or with fluorouracil.[3] For small cell lung cancer it is used with cisplatin.[3] It is given by slow injection into a vein.[3] Common side effects include diarrhea, vomiting, bone marrow suppression, hair loss, shortness of breath, and fever.[3] Other severe side effects include blood clots, colon inflammation, and allergic reactions.[3] Those with two copies of the UGT1A1*28 gene variant are at higher risk for side effects.[3] Use during pregnancy can result in harm to the baby.[3] Irinotecan is in topoisomerase inhibitor family of medication.[4] It works by blocking topoisomerase 1 which results in DNA damage and cell death.[3] Irinotecan was approved for medical use in the United States in 1996.[3] It is on the World Health Organizations List of Essential Medicines, the safest and most effective medicines needed in ...

RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the

Randomized phase III trial to compare the overall survival of S-1 alone to that of irinotecan plus S-1 in patients with advanced gastric cancer.

Kessel, D, Effects of camptothecin on rna synthesis in leukemia l1210 cells. (1971). Subject Strain Bibliography 1971. 891 ...

Patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity, and a dose reduction is recommended. Patients with elevated AST, creatinine or prior pelvic radiation do not appear to have increased sensitivity to irinotecan, but the data are not adequate to support a specific dosing recommendation.

Health,... - Offers Unique Formulation of Important Cancer Medication -...LAKE FOREST Ill. Feb. 27 /- Hospira Inc.(NY... We are continuing to grow our leading portfolio of generic medication...Hospiras irinotecan product portfolio extends beyond the formulations...,Hospira,Launches,Generic,Irinotecan,Injection,medicine,medical news today,latest medical news,medical newsletters,current medical news,latest medicine news

Anwendungsgebiete Panitumumab Vectibix ist indiziert zur Behandlung von erwachsenen Patienten mit metastasiertem kolorektalem Karzinom (mCRC, metastatic colorectal cancer) mit RAS-Wildtyp in der Erstlinientherapie in Kombination mit FOLFOX oder FOLFIRI. in der Zweitlinientherapie in Kombination mit FOLFIRI bei Patienten, die in der Erstlinientherapie eine Fluoropyrimidin-haltige Chemotherapie erhalten haben (ausgenommen Irinotecan). als Monotherapie nach Versagen von Fluoropyrimidin-, Oxaliplatin- und Irinotecan-haltigen Chemotherapieregimen. Fachinformation Vectibix, Stand März 2015 Zulassungserweiterung März 2015

Hi Craig,. I was the first one on Zaltrap in Minnesota, right after it was approved. I havent been around CSN, but am very active everywhere else. I heard about your troubles and thought Id pop in to share my experiences with you in case they may help. Ive still not had any organ involvement, but I have been chasing distant lymph nodes for 4 years, and bone mets for over a year. Other than my original emergency resection, I have not qualified for surgery ever - chemo only. I know it is a bummer to hear chemo for life but at least Im still here, and so are many others who are managing a chronic disease this way. Ive had chemo breaks - Ive done radiation a few times and RFA, and lots of chemo, and taken some breaks.. Last summer when I had more progression to distant nodes and they finally found my bone mets (CT missed them, PET/CT found them), we had to decide a new plan of action. I do NOT do 5-FU anymore and have not for over over 2 years. Ive been on Irinotecan since August 2010, with ...

This study was performed to explore the influence of alternate sequences of CPT-11 and CDDP on the observed side effects and pharmacokinetic behavior of both drugs. Using a randomized cross-over design for the administration sequence, no substantial differences in any toxicity were observed between the two treatment schedules. The pharmacokinetics of the lactone form of CPT-11 revealed a substantial degree of interpatient variability, in line with previous observations (17) . In addition, the observed kinetic parameters of CPT-11 were similar to single agent data (18) , indicating no apparent interaction between CDDP and CPT-11. The sequence of drug administration had also no influence on the pharmacokinetics of CPT-11 and its metabolites SN-38 and SN-38G and the CYP450 3A4-mediated metabolites APC and NPC at the dose levels administered. This contrasts the reduction of topotecan clearance observed previously in patients after CDDP administration (5) . Our findings, however, are consistent with ...

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DSpace-CRIS consists of a data model describing objects of interest to Research and Development and a set of tools to manage the data. Standard DSpace is used to deal with publications and data sets, whereas DSpace-CRIS involves other CRIS entities: Researcher Pages, Projects, Organization Units and Second Level Dynamic Objects (single entities specialized by a profile, such as Journal, Prize, Event etc; because any profile can define its own set of properties and nested objects ...

Adding liposomal irinotecan to 5-fluorouracil and leucovorin reduced the risk of death by 25% for patients with metastatic pancreatic cancer following progression on a gemcitabine-based regimen.

OConnell BC, Adamson B, Lydeard JR, Sowa ME, Ciccia A, Bredemeyer AL, et al. A genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability. Mol Cell. 2010 ;40(4):645-57. ...

inproceedings{318597, author = {MONSAERT, ELS and De Vos, Martine and Peeters, Marc}, booktitle = {ACTA GASTRO-ENTEROLOGICA BELGICA}, issn = {0001-5644}, pages = {D59-D59}, title = {A retrospective analysis of the efficacy and toxicity of irinotecan and 5FU/FA in patients with advanced carcinoma of the stomach or oesophagogastric junction}, volume = {66}, year = {2003 ...

Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study. J Clin Oncol. 2010 Jun 20; 28(18):3069-75 ...

The U.S. Food and Drug Administration (FDA) has approved panitumumab (Vectibix) for use in combination with FOLFOX (fluorouracil, leucovorin, oxaliplatin) as first-line treatment in patients with wild-type KRAS (exon 2) metastatic colorectal cancer.. This approval converts the accelerated monotherapy approval granted in 2006 to a full approval. Panitumumab was previously approved by the FDA as a monotherapy for patients with EGFR-expressing metastatic colorectal cancer after disease progression and prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. The agent is not indicated for the treatment of patients with KRAS-mutant metastatic colorectal cancer or for whom KRAS mutation status is unknown.. The FDA has also approved the therascreen KRAS test as a companion diagnostic to guide use of panitumumab in the treatment of metastatic colorectal cancer.. Phase III Studies. The approval is based on results from the phase III PRIME and -ASPECCT trials. The ...

Camptothecin-resistant DC3F Chinese hamster lung fibroblast cell lines were obtained after mutagenic treatment with ethylmethanesulfonate and subsequent exposure to 1 µm camptothecin (CPT). The most resistant cell line, which was obtained after exposure to CPT for 10 days, was designated DC3F/C-10. Comparison of 50% inhibitory concentration values after 8-h CPT treatments showed that DC3F/C-10 cells were 134-fold resistant to CPT. Resistance was associated with marked reduction of CPT-induced DNA single-strand breaks and DNA-protein cross-links. This reduction was not due to reduced amounts of immunoreactive DNA topoisomerase I protein, although nuclear extracts from DC3F/C-10 cells had less enzyme catalytic activity than those from DC3F cells. Also, fast protein liquid chromatography-purified DNA topoisomerase I from DC3F/C-10 had lower specific catalytic activity than that from DC3F cells. DNA topoisomerase I from DC3F/C-10 was resistant to inhibition of catalytic activity and induction of ...

Currently, DNA topoisomerase I (Topo I) inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors. In recent years, during our ongoing research on natural antitumor products, a collection of low cytotoxic or non-cytotoxic compounds with various structures were identified from marine invertebrates, plants, and their symbiotic microorganisms. In the present study, new Topo I inhibitors were discovered from low cytotoxic and non-cytotoxic natural products by virtual screening with docking simulations in combination with bioassay test. In total, eight potent Topo I inhibitors were found from 138 low cytotoxic or non-cytotoxic compounds from coral-derived fungi and plants. All of these Topo I inhibitors demonstrated activities against Topo I-mediated relaxation of supercoiled DNA

1. ________Zhang, H. et al. Human mitochondrial topoisomerase I. Proc Natl Acad Sci U S A 98, 10608-13. (2001).. 2. ________Furuta, T. et al. Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA-double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. J Biol Chem 278, 20303-20312 (2003).. 3. ________Khan, Q. A. et al. Position-specific trapping of topoisomerase II by benzo[a]pyrene diol epoxide adducts: Implications for interactions with intercalating anticancer agents. Proc Natl Acad Sci U S A 100, 12498-12503 (2003).. 4. ________Meng, L.-H., Liao, Z.-H. & Pommier, Y. Non-camptothecin DNA topoisomerase I inhibitors in cancer chemotherapy. Curr Topics Med Chem 3, 305-320 (2003).. 5. ________Pommier, Y. & Kohn, K. W. Cell cycle and checkpoints in oncology: new therapeutic targets. Med Sci (Paris) 19, 173-86 (2003).. 6. ________Pommier, Y. et al. Repair of and Checkpoint Response to Topoisomerase I-Mediated DNA ...

Metastatic Colorectal Cancer - Pipeline Review, H1 2014SummaryGlobal Markets Directs, Metastatic Colorectal Cancer - Pipeline Review, H1 2014, provides an overview of the Metastatic Colorectal Cancers therapeutic pipeline.This report provides comprehensive information on the therapeutic development for Metastatic Colorectal Cancer, complete with comparative analysis at various stages, therapeutics

In this thesis, the method development and investigation of different liposomal formulations to incorporate and retain Camptothecin (CPT) is described. CPT is a potent anticancer drug that has shown to be active against a broad spectrum of cancers. However, due to its challenging physicochemical properties, like poor water solubility, severe toxic effects to normal tissues and instability, its clinical development has been limited for nearly 40 years. A strategy to overcome CPTs challenging properties is to use liposome-based carrier system. By taking advantage of this carrier system, we may solubilise CPT in the phospholipid bilayer of liposomes, protect it from blood proteins and achieve a selective drug accumulation in tumor tissues or tumor-associated cells by enhanced permeability and retention effect (EPR). A good liposome formulation of clinical utility must fulfil two important criteria. The liposomal drug carrier must incorporate CPT in the liposomal bilayer in a relevant therapeutic ...

Fingerprint Dive into the research topics of Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy. Together they form a unique fingerprint. ...

This is an open-label, nonrandomized phase I trial to determine the safety and maximum tolerated dose of irinotecan with a fixed dose of UFT plus oral leucovorin in patients with advanced or metastatic colorectal cancer.

Irinotecan is a common cytotoxic agent used in advanced colorectal cancers. However, a major clinical problem with this cytotoxic is that it causes gastrointestinal mucositis manifest by severe diarrhoea. To date there is no established single dose of irinotecan in rats to enable determination of changes occurring following administration. Therefore, the primary aim of this study was to determine a single dose of irinotecan that induced reproducible gastrointestinal mucositis in DA rats. The secondary aim was to determine if the presence of tumour altered the development of mucositis.Eighty-eight rats were divided into two groups, 44 received tumours and 44 remained tumour naïve. These were randomized to receive a single dose of irinotecan at 150, 200, 250 or 300 mg/kg. Two control groups of rats received either no treatment or 2 doses of 150 mg/kg irinotecan, shown previously to induce reproducible gastrointestinal mucositis. Rats were monitored closely for incidence and severity of diarrhoea, ...

Human carboxylesterase 2 (hCE-2) is a member of the serine esterase superfamily and is responsible for hydrolysis of a wide variety of xenobiotic and endogenous esters. hCE-2 also activates an anticancer drug, irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin, CPT-11), into its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). In this study, a comprehensive haplotype analysis of the CES2 gene, which encodes hCE-2, in a Japanese population was conducted. Using 21 single nucleotide polymorphisms (SNPs), including 4 nonsynonymous SNPs, 100C,T (Arg34Trp, *2), 424G,A (Val142Met, *3), 1A,T (Met1Leu, *5), and 617G,A (Arg206His, *6), and a SNP at the splice acceptor site of intron 8 (IVS8-2A,G, *4), 20 haplotypes were identified in 262 Japanese subjects. In 176 Japanese cancer patients who received irinotecan, associations of CES2 haplotypes and changes in a pharmacokinetic parameter, (SN-38 + SN-38G)/CPT-11 area under the plasma concentration curve (AUC) ratio, ...

Effect of BSO on the Toxicity of the Camptothecins. To assess the contribution of GSH in the sensitivity to the camptothecins, cells were pretreated with BSO before the cytotoxicity assays. BSO is an inhibitor of γ-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis (23). Treatment of MCF-7 and MDA-MB-231 cells for 24 h with 50 μm BSO led to a reduction in GSH levels of at least 75% in the cell lines tested (Table 1) without affecting cell growth. Pretreatment with BSO also resulted in lower IC50 values for each of the analogues tested in all of the cell lines (Table 1). GSH depletion had the greatest effect on CMMDC, the alkylating camptothecin analogue.. Effect of BSO on the Formation of topo I-DNA Complexes. To determine whether GSH depletion directly affected the stabilization of the camptothecin-topo I cleavage complex, the levels of camptothecin-induced DPCs were measured in control cells and in cells pretreated with BSO. These DPCs correspond to topo I cleavage ...

TY - JOUR. T1 - Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer. AU - Elez, Elena. AU - Chianese, Chiara. AU - Sanz-García, Enrique. AU - Martinelli, Erica. AU - Noguerido, Alba. AU - Mancuso, Francesco Mattia. AU - Caratù, Ginevra. AU - Matito, Judit. AU - Grasselli, Julieta. AU - Cardone, Claudia. AU - Esposito Abate, Riziero. AU - Martini, Giulia. AU - Santos, Cristina. AU - Macarulla, Teresa. AU - Argilés, Guillem. AU - Capdevila, Jaume. AU - Garcia, Ariadna. AU - Mulet, Nuria. AU - Maiello, Evaristo. AU - Normanno, Nicola. AU - Jones, Frederick. AU - Tabernero, Josep. AU - Ciardello, Fortunato. AU - Salazar, Ramon. AU - Vivancos, Ana. PY - 2019/1/1. Y1 - 2019/1/1. N2 - Despite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RAS-mutant allele fraction (MAF) in plasma in mCRC. Forty-seven plasma samples from 37 ...

TY - JOUR. T1 - Colorectal tumor cells treated with 5FU, oxaliplatin, irinotecan and cetuximab exhibit changes in 18F-FDG incorporation corresponding with hexokinase activity and glucose transport. AU - Sharma, Rituka I.. AU - Smith, Tim A. D. PY - 2008/8. Y1 - 2008/8. N2 - The purpose of this study was to determine therapy-induced changes in F-18-FDG incorporation at the colorectal tumor cell level in response to conventional and novel chemotherapy agents and examine how these changes relate to factors involved in F-18-FDG incorporation. Methods: SW620 cells were treated with inhibitory concentration of 50% (IC50) doses (determined by MTT) of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan; HCT-8 cells were treated with IC50 doses of irinotecan, cetuximab, and irinotecan plus cetuximab. F-18-FDG incorporation, glucose transport, hexokinase (HK) activity, adenosine triphosphate (ATP) content, annexin V binding, and cell cycle distribution were determined after 24-, 48-, and 72-h treatments. ...

Mice and primary neuronal cultures. Hq, Apaf1-/-, and Bax-/- mice were maintained and genotyped as described previously (Fortin et al., 2001; Klein et al., 2002). Cortical neurons and cerebellar granule neurons (CGNs) were cultured from cortices of E15.5 mice and cerebellums of postnatal day 7 mice, respectively, as described previously (Fortin et al., 2001). Recombinant adenoviral vectors carrying human AIF or LacZ expression cassettes were prepared and used at 50 multiplicity of infection as described previously (Cregan et al., 2002).. Camptothecin treatment and cell viability assays. Neurons were treated with 10 μm camptothecin with or without 10 μm Boc-aspartyl (Ome)-fluoromethylketone (BAF) (Enzyme System Products, Livermore, CA) after 2 d in vitro (DIV). Cell survival was measured by the following: live/dead staining (Molecular Probes, Eugene, OR), Hoechst staining, MTT assay (Cell Titer kit; Promega, Madison, WI), terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end ...

This project is supported by the Canadian Institutes of Health Research (award #111062), Alberta Innovates - Health Solutions, and by The Metabolomics Innovation Centre (TMIC), a nationally-funded research and core facility that supports a wide range of cutting-edge metabolomic studies. TMIC is funded by Genome Alberta, Genome British Columbia, and Genome Canada, a not-for-profit organization that is leading Canadas national genomics strategy with funding from the federal government. Maintenance, support, and commercial licensing is provided by OMx Personal Health Analytics, Inc. Designed by Educe Design & Innovation Inc. ...

First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. (ClinicalTrials.gov number, NCT00154102.)

Several distinct innate lymphoid cell (ILC) populations have been recently identified and shown to play a critical role in the immediate immune defense. In the context of tumors, there is evidence to support a dual role for ILCs with pro-or antitumor effects, depending on the ILC subset and the type of cancer. This ambivalent role has been particularly well-described in colorectal cancer models (CRC), but the presence and the evolution of ILCs in the peripheral blood of metastatic CRC (mCRC) patients have not yet been explored. Here, we investigated the distribution of ILC subsets in 96 mCRC patients who were prospectively included in the Epitopes-CRCO2 trial. Peripheral bloodmononuclear cells (PBMCs) were analyzed by flow cytometry at metastatic diagnosis and after 3-months of treatment. The treatments consisted of Oxaliplatin-based chemotherapies for 76% of the patients or Folfiri (5FU, Irinotecan) chemotherapies for 14% of patients. Compared to healthy donors, the frequency of tot

Bevacizumab (B) and cetuximab (C) are both approved for use in the treatment of metastatic colorectal cancer (mCRC) in the second-line. We examined patient reported symptom burden during second-line treatment of mCRC. Adult mCRC patients treated in the second-line setting with a regimen that included B, C, or chemotherapy only (O) and who had completed ≥ 1 Patient Care Monitor (PCM) surveys as part of routine clinical care were drawn from the ACORN Data Warehouse. Primary endpoints were rash, dry skin, itching, nail changes, nausea, vomiting, fatigue, burning in hands/feet, and diarrhea. Linear mixed models examined change in PCM scores across B, C and O (B = reference). 182 patients were enrolled (B: n = 106, C: n = 38, O: n = 38). Patients were 51% female, 67% Caucasian, with mean age of 62.0 (SD = 12.6). Groups did not differ on demographic or clinical characteristics. The most common second-line regimens were FOLFIRI ± B or C (23.1%) and FOLFOX ± B or C (22.5%). Results showed baseline scores to

TY - JOUR. T1 - Therapeutic targeting of CPT-11 induced diarrhea. T2 - a case for prophylaxis.. AU - Swami, Umang. AU - Goel, Sanjay. AU - Mani, Sridhar. PY - 2013/6. Y1 - 2013/6. N2 - CPT-11 (irinotecan), a DNA topoisomerase I inhibitor is one of the main treatments for colorectal cancer. The main dose limiting toxicities are neutropenia and late onset diarrhea. Though neutropenia is manageable, CPT-11 induced diarrhea is frequently severe, resulting in hospitalizations, dose reductions or omissions leading to ineffective treatment administration. Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT-11 induced late onset diarrhea. It is predicted that prophylaxis of CPT-11 induced diarrhea will reduce sub-therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates. This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity. ...

5-Fluorouracil (5-FU) is the most common chemotherapeutic agent used in the treatment of colorectal cancer, yet objective response rates are low. Recently, camptothecin (CPT) has emerged as an effective alternative therapy. Decisive means to determine treatment, based on the likelihood of response to each of these agents, could greatly enhance the management of this disease. Here, the ability of cDNA microarray-generated basal gene expression profiles to predict apoptotic response to 5-FU and CPT was determined in a panel of 30 colon carcinoma cell lines. Genes whose basal level of expression correlated significantly with 5-FU- and CPT-induced apoptosis were selected, and their predictive power was assessed using a leave one out jackknife cross-validation strategy. Selection of the 50 genes best correlated with 5-FU-induced apoptosis, but not 50 randomly selected genes, significantly predicted response to this agent. Importantly, this gene expression profiling approach predicted response more ...

Objectives. Further the session inspired their desire for learning more about pharmacogenomics and their professional functions in personalized medicine. 2006 60 [PMC free article] [PubMed] 3 Sjoblom T Jones S Solid wood LD et al. The consensus coding sequences of human breast and colorectal cancers. 2006;314(5797):268-274. PP242 [PubMed] 4 Moroni M Veronese S Benvenuti S et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal malignancy: a cohort study. 2005;6(5):279-286. [PubMed] 5 Cunningham D Humblet Y Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal malignancy. 2004;351(4):337-345. [PubMed] 6 Herbst RS Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for malignancy therapy. 2002;94(5):1593-1611. [PubMed] 7 Lynch DH Yang XD. Therapeutic potential of ABX-EGF: a fully human anti-epidermal growth factor ...

A French team of investigators evaluated whether irinotecan and bevacizumab added to temozolomide-based chemoradiation would improve the prognosis of patients with unresectable glioblastoma. The study results show a trend towards improved progression-free survival and are presented by Dr B. Chauffert at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.. This phase II, randomized trial enrolled 120 patients, aged 18 to 70 years with de novo unresectable glioblastoma, Karnofsky performance status , 50 and recursive partitioning analysis (RPA) class 5. Patients were randomized, 60 patients per arm, to receive four cycles of neo-adjuvant bevacizumab plus irinotecan prior to radiotherapy with concurrent temozolomide and bevacizumab or to receive control treatment of concomitant temozolomide plus radiotherapy for 6 months.. Clinical factors were well balanced between arms and cross-over was allowed upon progression. An evaluation done at 16 months after the treatment ...

Non-P-glycoprotein-mediated multidrug-resistant C-A120 cells that overexpressed multidrug resistance protein (MRP) were 10.8- and 29.6-fold more resistant to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and SN-38, respectively, than parental KB-3-1 cells. To see whether MRP is involved in CPT-11 and SN-38 resistance,MRP cDNA was transfected into KB-3-1 cells. The transfectant, KB/MRP, which overexpressed MRP, was resistant to both CPT-11 and SN-38. 2-[4-Diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) and MK571, which reversed drug resistance in MRP overexpressing multidrug-resistant cells, significantly increased the sensitivity of C-A120 and KB/MRP cells, but not of KB-3-1 cells, to CPT-11 and SN-38. The accumulation of both CPT-11 and SN-38 in C-A120 and KB/MRP cells was lower than that in KB-3-1 cells. The treatment with 10 μM PAK-104P increased the ...

Ramucirumab plus FOLFIRI or irinotecan as second-line therapy in advanced or metastatic gastric or gastroesophageal junction adenocarcinoma

Increased the risk of death when administered to target a hemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy or radiation therapy. ESAs are not indicated for this population. Patients receiving ESAs pre-operatively for reduction of allogeneic red blood cell transfusions: A higher incidence of deep venous thrombosis was documented in patients receiving Epoetin alfa who were not receiving prophylactic anticoagulation. Aranesp(R) is not approved for this indication.. Aranesp is contraindicated in patients with uncontrolled hypertension.. About Vectibix. Vectibix(TM) is indicated for the treatment of EGFr-expressing, metastatic colorectal cancer with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.. The effectiveness of Vectibix for the treatment of EGFr-expressing, metastatic colorectal cancer is based on progression-free survival. Currently no data are available that demonstrate an ...

Background: Gastrointestinal cancer is one of the most common cancers worldwide. Researchers think an unmet need exists to understand and improve treatment options. They want to see if a combination of drugs can help people with metastatic colorectal cancer. Objective: To see if using a combination of VB-111 and nivolumab is safe and will cause colorectal tumors to shrink. Eligibility: People ages 18 and older with microsatellite stable colorectal cancer that has spread to the liver Design: Participants must consent to sample collection protocol 11C0112. Participants will be screened with: Blood tests Scans Tumor samples. If these are not available, participants will have a biopsy. Before they start treatment and with every treatment cycle, participants will have: Physical exams Blood tests Heart tests Before they start treatment and every 4 cycles, participants will have CT or MRI scans. For these, they will lie in a machine that takes pictures of the body. For the MRI, a soft padding or coil will be

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In this case-based interview series, Tanios Bekaii-Saab, MD, FACP, discusses the treatment of a patient with metastatic colorectal cancer who progresses on upfront and second-line therapy.

Percentage of adult patients (aged 18 or over) with metastatic colorectal cancer and RAS (KRAS or NRAS) gene mutation spared treatment with anti-EGFR monoclonal antibodies.

Fingerprint Dive into the research topics of Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3. Together they form a unique fingerprint. ...

The Report Metastatic Colorectal Cancer - Pipeline Review, H2 2015 provides information on pricing, market analysis, shares, forecast, and company profiles for key industry participants. - MarketResearchReports.biz

Researchers evaluated the noninferiority of a modified XELIRI regimen vs a FOLFIRI regimen in terms of overall survival among patients with mCRC.

Shop Liver carboxylesterase ELISA Kit, Recombinant Protein and Liver carboxylesterase Antibody at MyBioSource. Custom ELISA Kit, Recombinant Protein and Antibody are available.

BackgroundThis multicenter phase II study investigated temozolomide + irinotecan (TEMIRI) treatment in children with relapsed or refractory medulloblastoma.MethodsPatients received temozolomide 100-125 mg/m2/day (days 1-5) and irinotecan 10 mg/m2/day (days 1-5 and 8-12) every 3 weeks. The primary endpoint was tumor response within the first 4 cycles confirmed ≥4 weeks and assessed by an external response review committee (ERRC). In a 2-stage Optimum Simon design, ≥6 responses in the first 15 evaluable patients were required within the first 4 cycles for continued enrollment; a total of 19 responses from the first 46 evaluable patients was considered successful.ResultsSixty-six patients were treated. Seven responses were recorded during stage 1 and 15 in the first 46 ERRC evaluated patients (2 complete responses and 13 partial responses). The objective response rate during the first 4 cycles was 32.6% (95% confidence interval [CI], 19.5%-48.0%). Median duration of response was 27.0 weeks ...