Abstract:
:OSI-7836 (4'-thio-beta-D-arabinofuranosylcytosine) is a novel nucleoside analog in phase I clinical development for the treatment of cancer. As with other nucleoside analogs, the proposed mechanism of action involves phosphorylation to the triphosphate form followed by incorporation into cellular DNA, leading to cell death. This hypothesis has been examined by measuring and comparing the incorporation of ara-C, OSI-7836, and gemcitabine (dFdC) into DNA of cultured cells and by investigating the role of deoxycytidine kinase in OSI-7836 toxicity. We report here additional studies in which the role of cell cycling on OSI-7836 toxicity was investigated and incorporation of OSI-7836 into DNA of xenograft tumors measured. The role of the cell cycle was examined by comparing the toxicity of OSI-7836 in A549 NSCLC cells that were either in log phase growth or had reached confluence. A novel validated LC-MS/MS assay was developed to quantify the concentrations of OSI-7836 in DNA from Calu-6 and H460 human tumor xenografts in mice. Results showed that apoptosis induced by OSI-7836 was markedly greater in cycling cells than in confluent non-cycling cells despite only a modest increase in intracellular OSI-7836 triphosphate concentration. The LC-MS/MS assay developed to measure OSI-7836 incorporation into DNA had an on-column detection limit of 0.25 fmol, a quantification limit of 0.5 fmol, and a sensitivity of approximately 0.1 pmol OSI-7836/micromol dThy. Concentrations of OSI-7836 in splenic DNA (0.4 pmol OSI-7836/micromol dThy) averaged fivefold less than the average concentration in Calu-6 and H460 xenograft DNA (3.0 pmol OSI-7836/micromol dThy) following a 400 mg/kg dose of OSI-7836. Concentrations of OSI-7836 in Calu-6 tumor DNA isolated 24 h following a dose of 400, 1000, or 1600 mg OSI-7836/kg were approximately 1.3, 1 and 1.3 pmol OSI-7836/micromol dThy, respectively. Concentrations of OSI-7836 in DNA from H460 and Calu-6 xenografts did not appear to increase during repeated administration of 400 mg OSI-7836/kg on days 1, 4, 7, and 10. The majority of OSI-7836 in DNA from Calu-6 and H460 tumors of mice dosed with 1600 mg/kg was located at internal nucleotide linkages, similar to dFdC and ara-C. In conclusion, cell cycling studies supported the hypothesis that OSI-7836 cytotoxicity is dependent upon DNA synthesis. A validated LC-MS/MS assay was developed that could quantify OSI-7836 in DNA from tissues. The assay was used to show that OSI-7836 was incorporated in internal linkages in tumor DNA in a manner that was dose-independent at the doses tested and did not appear to accumulate during repeated dosing. The results suggest that if DNA incorporation is a toxic event, the relationships between administered dose, DNA incorporation, and toxicity are complex.
journal_name
Cancer Chemother Pharmacoljournal_title
Cancer chemotherapy and pharmacologyauthors
Richardson F,Black C,Richardson K,Franks A,Wells E,Karimi S,Sennello G,Hart K,Meyer D,Emerson D,Brown E,LeRay J,Nilsson C,Tomkinson B,Bendele Rdoi
10.1007/s00280-004-0844-8keywords:
subject
Has Abstractpub_date
2005-03-01 00:00:00pages
213-21issue
3eissn
0344-5704issn
1432-0843journal_volume
55pub_type
杂志文章abstract:BACKGROUND:In vitro data indicate that the sorafenib is a moderate inhibitor of cytochrome P450 (CYP) enzymes, including CYP3A4, CYP2C19, and CYP2D6. This phase I/II study in patients with advanced melanoma evaluated the potential effect of sorafenib on the pharmacokinetics of midazolam, omeprazole, and dextromethorpha...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-011-1585-0
更新日期:2011-11-01 00:00:00
abstract:PURPOSE:Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Because HCC usually presents as an advanced disease and occurs in the background of liver cirrhosis, most patients are not suitable for treatment with curative intent, thus effective systemic chemotherapy is required. However, the ...
journal_title:Cancer chemotherapy and pharmacology
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doi:10.1007/s00280-005-0067-7
更新日期:2006-04-01 00:00:00
abstract::Brain microdialysis was applied to sample free methotrexate (MTX) concentrations in brain extracellular fluid of normal and RG-2 glioma-bearing rats. All animals received 50 mg/kg of MTX intra-arterially following which serial blood and interstitial fluid samples were collected for 3 h and measured for MTX by an HPLC ...
journal_title:Cancer chemotherapy and pharmacology
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doi:10.1007/s002800050518
更新日期:1996-01-01 00:00:00
abstract::Sixty-seven patients with acute nonlymphoblastic leukemia (ANLL) and above the age of 60 years were randomly allocated to treatment with either prednimustine + vincristine or cycles with cytosine arabinoside and thioguanine. Of the 67 patients, 13 (19%) entered a complete remission and four a partial remission. Of 33 ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1982-01-01 00:00:00
abstract:PURPOSE:We have developed and evaluated a CNS-targeted chemotherapy regimen based on the pharmacokinetic properties of the individual drugs in the combination. PATIENTS AND METHODS:In a twin-track study, 16 patients with secondary CNS lymphoma (SCNSL) and 8 with primary CNS lymphoma (PCNSL) were treated with IDARAM wh...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章,多中心研究
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abstract:BACKGROUND:STAT3 overexpression has been detected in several cancers including head and neck squamous cell carcinoma (HNSCC). Previous studies using intratumoral administration of a STAT3 decoy oligonucleotide that abrogates STAT3-mediated gene transcription in preclinical cancer models have demonstrated antitumor effi...
journal_title:Cancer chemotherapy and pharmacology
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doi:10.1007/s00280-008-0823-6
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abstract:PURPOSE:To determine the efficacy and safety of the combination therapy with docetaxel and cisplatin (CDDP) at low doses in elderly patients with advanced NSCLC. PATIENTS AND METHODS:A total of 42 patients aged > or =70 years with previously untreated advanced NSCLC received docetaxel 75 mg/m(2) plus CDDP 50 mg/m(2) o...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-008-0749-z
更新日期:2009-02-01 00:00:00
abstract::Fifty-one patients with non-small cell lung cancer (NSCLC) were treated, during a phase II trial, with 4'demethylepipodophyllotoxin-beta-D-ethylidene glucoside (VP16-213). Forty-nine were evaluable for response, and of these two (4%) had partial responses lasting 5 and 6 months. Prior treatment with chemotherapy may h...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00254550
更新日期:1982-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
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更新日期:2011-04-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00685798
更新日期:1995-01-01 00:00:00
abstract::Tumor-tissue and plasma concentrations of platinum were studied prospectively in two groups of eight patients who were suffering from advanced non-small-cell lung cancer. Treatments including two different schedules of cisplatin administration (25 vs 100 mg/m2 on day 1) were compared. At 30 min after the beginning of ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00689280
更新日期:1990-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF02897202
更新日期:1990-01-01 00:00:00
abstract:PURPOSE:This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of linsitinib after multiple-dose administration was assessed in thos...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-016-2999-5
更新日期:2016-04-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 已发布勘误
doi:10.1007/s00280-016-3002-1
更新日期:2016-04-01 00:00:00
abstract::To evaluate the value of beta-2-microglobulin as an indicator of acute and long-term cis-platinum-induced nephrotoxicity, 51Cr-EDTA clearance and serum concentration and urinary excretion of beta-2-microglobulin were measured in 18 patients treated with a regimen including cis-platinum. Before treatment all values wer...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00258126
更新日期:1985-01-01 00:00:00
abstract::Leucovorin requirements for protection of the T cell line CCRF-CEM and the B cell line LAZ-007 against the cytotoxic effects of a variety of antifolates were studied. Differential leucovorin protection for DDMP-induced growth suppression occurred in the opposite direction to that for MTX, with CCRF-CEM requiring less ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00257519
更新日期:1985-01-01 00:00:00
abstract:PURPOSE:To compare the response rates, toxicities and survival durations of elderly patients (70 years of age or more) with those of younger patients (less than 70 years of age) with non-small-cell lung cancer (NSCLC) treated with cisplatin-based chemotherapy. PATIENTS AND METHODS:We analyzed retrospectively the data ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/s002800050689
更新日期:1997-01-01 00:00:00
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800000259
更新日期:2001-05-01 00:00:00
abstract:PURPOSE:This phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy. METHODS:Five cohorts of three patients received i.v. ascorbic acid administered at 1 g/min f...
journal_title:Cancer chemotherapy and pharmacology
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doi:10.1007/s00280-013-2179-9
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journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-007-0676-4
更新日期:2008-10-01 00:00:00
abstract::The effects of anticalmodulin agents, namely trifluoperazine (TFP) and two naphthalene sulfonamide derivatives (W-7 and W-13), were tested on the growth of a human breast cancer cell line (MDA-MB-231) using a soft agar clonogenic assay. The results of this in vitro study reveal that TFP, W-7, and W-13 had the ability ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00254251
更新日期:1983-01-01 00:00:00
abstract:INTRODUCTION:Hormone-refractory disseminated prostate cancer is a major oncological problem. Preclinical studies with temozolomide, an oral alkylating agent, in prostate cancer have shown encouraging results. In phase I studies the safety of temozolomide in non-prostate cancer patients has been demonstrated. Based on t...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s002800051027
更新日期:2000-01-01 00:00:00
abstract:PURPOSE:The aim of this study was to evaluate safety and toxicity of chronomodulated capecitabine administered in the morning and at noon according to a specific time schedule (Brunch Regimen: Breakfast and Lunch) as a part of first-line XELOX chemotherapy in patients with metastatic colorectal cancer. METHODS:A total...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-016-3067-x
更新日期:2016-07-01 00:00:00
abstract:UNLABELLED:Hypericin, a polycyclic aromatic dianthroquinone, is a natural pigment derived from the plant Hypericum perforatum (St John's Wort). The compound has been synthesized and shown to inhibit the growth of malignant glioma cell lines in vitro via inhibition of protein kinase C. Oral hypericin has entered clinica...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800000188
更新日期:2001-01-01 00:00:00
abstract::Over the last decade, metronomic chemotherapy has been increasingly considered as an attractive strategy for treating cancer in a variety of settings. Beside pharmaco-economic considerations making metronomics a unique opportunity in low- or middle-income countries, revisiting dosing schedules using continuous low dos...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00280-014-2546-1
更新日期:2014-09-01 00:00:00
abstract:PURPOSE:PF-00337210 is an oral, highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We evaluated a composite of biomarkers in real time to identify the recommended phase 2 dose (RP2D) and preliminary anticancer activity of PF-00337210. PATIENTS AND METHODS:Patients (Pts) with advanced cance...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-016-2958-1
更新日期:2016-03-01 00:00:00
abstract:PURPOSE:The chimeric protein BCR-ABL, a constitutively active protein-tyrosine kinase, triggers downstream signalling proteins, such as STAT3, ultimately resulting in the survival of myeloid progenitors in BCR-ABL-positive leukemias. Here, we evaluated the effect of LLL-3, an inhibitor of STAT3 activity, on cell viabil...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-009-1109-3
更新日期:2010-05-01 00:00:00
abstract:PURPOSE:Triple-negative breast cancer (TNBC) is an aggressive, lethal, and heterogeneous subtype of breast cancers, tending to have lower 5-year survival rates than other BC subtypes in response to conventional chemotherapies. This study's aim was to identify advanced regimens to effectively control TNBC tumor developm...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-019-04013-y
更新日期:2020-01-01 00:00:00
abstract::New active drugs are needed for the treatment of primary brain tumors in both children and adults. S16020 is a cytotoxic olivacine derivative that inhibits topoisomerase II. The aim of the study was to determine its antitumor activity in athymic mice bearing subcutaneous medulloblastoma (IGRM33, 34, 57) and glioblasto...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-003-0584-1
更新日期:2003-05-01 00:00:00
abstract::We determined the kinetic parameters that describe the effect of 20 different modulators of the multidrug resistance pump on the reversal of cytotoxin accumulation in a resistant strain of P388 leukemia cells (P388/ADR), and on the reversal of cell killing for these cells. When measured by a direct comparison of the a...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800050468
更新日期:1996-01-01 00:00:00