Abstract:
PURPOSE:Many cell lines resistant to cisplatin (DDP) have reduced DDP accumulation. We postulated that reduced accumulation of DDP in resistant cells might be due to decreased intracellular DDP binding, leading to increased passive efflux. METHODS:The total cellular ([T-DDP]), intracellular ultrafiltrable ([F-DDP]) and precipitable cellular bound ([B-DDP]) DDP concentrations were all compared in the HTB56 human lung adenocarcinoma cell line and its E-8/0.7 variant that has acquired DDP resistance. Cells were exposed to 509 microM DDP for 20 min. Ultrafiltration with a 500 molecular weight cut-off separated cellular free from bound cisplatin. Fragmentation by sonication and microcentrifugal spinning precipitated cellular bound cisplatin. Flow cytometry was used to measure the intracellular pH (pHi) of the HTB56 cell line, the E-8/0.7 cell line, as well as of the OV2008 cell line and its C13 resistant variant. The DNA-bound DDP and protein-bound DDP ([P-DDP]) were also compared when equal [T-DDP] was achieved for both sensitive and resistant cells by exposing them for 1 h to two pairs of DDP concentrations, i.e. 509 vs 911 microM DDP, and 111 vs 666 microM DDP, respectively. Platinum was assayed by flameless atomic absorption spectrophotometry. RESULTS:At time 0 (end of cisplatin exposure), [T-DDP] and [B-DDP] were significantly higher in the sensitive HTB56 parent cell line (P < 0.02 and P < 0.001, respectively), whereas [F-DDP] did not differ significantly (P = 0.62). Two distinct phases of T-DDP efflux were observed. In the first 10 s after DDP exposure, the rate constant for resistant cells (KR1) was 0.17 s(-1), whereas that for sensitive cells (KS1) was 0.14 s(-1). From 10 s to 50 s, however, KR2 and KS2 became 0.005 s(-1) and 0.004 s, respectively. [T-DDP] remained lower in resistant cells than in sensitive cells at 10, 30 and 50 s (all P < 0.0001). For 1 h drug exposure to 509 vs 911 microM cisplatin concentrations designed to give comparable [T-DDP] in the sensitive and resistant cell lines, only [DNA-bound DDP] was found to be significantly higher in sensitive cells (P = 0.002), whereas both [F-DDP] and [P-DDP] did not differ significantly (P = 0.18, P = 0.75, respectively). On the other hand, there were no significant differences found in [F-DDP], [P-DDP] and [DNA-bound DDP] between the two cell lines when 111 vs 666 microM DDP was used. Flow cytometry data indicated that the pHi was significantly higher in the E-8/0.7 (P < 0.0186) and C13 (P < 0.0169) resistant variants than in the sensitive parent cell lines. CONCLUSIONS:DDP binds more slowly in resistant than in sensitive lung cancer cells, despite comparable amounts of free drug. Early efflux is higher in the resistant variant. Differences between the lines with respect to DNA binding may be DDP concentration-dependent. We speculate that the reduced early binding and increased early efflux in the resistant line may be related to the higher pH in this line. A higher pH is supposed to favor production of neutral hydroxyl metabolites rather than charged aquated metabolites, and these neutral metabolites would be expected to react less readily with intracellular molecules and to efflux more readily across cell membranes. Since we have previously documented a threefold increase in glucose utilization and lactate production in the DDP-resistant variants of the human HTB56 lung cancer cell lines, and this increased lactate production would have been expected to reduce the intracellular pH instead of raising it, it is possible that our alkaline-resistant cells have a higher Na+/H+ exchanger activity which would protect them from intracellular acidification.
journal_name
Cancer Chemother Pharmacoljournal_title
Cancer chemotherapy and pharmacologyauthors
Chau Q,Stewart DJdoi
10.1007/s002800050967keywords:
subject
Has Abstractpub_date
1999-01-01 00:00:00pages
193-202issue
3eissn
0344-5704issn
1432-0843journal_volume
44pub_type
杂志文章abstract:PURPOSE:Malignant rhabdoid tumors (MRT), although rare, are one of the most aggressive pediatric malignancies. Loss of INI1, a tumor suppressor gene and member of the SWI/SNF chromatin remodeling complex, is a recurrent genetic characteristic of these tumors and an important diagnostic marker. We have previously demons...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-008-0796-5
更新日期:2009-04-01 00:00:00
abstract:PURPOSE:The aim of this study was to determine the usefulness of receptor occupancy theory-based analysis using pharmacokinetic and pharmacodynamic parameters for predicting the average receptor occupancy (PhiB) in humans of each of five 5-HT3 antagonists administered at standard doses. METHODS:The relationship betwee...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-004-0798-x
更新日期:2004-08-01 00:00:00
abstract::The effects of intravesical chemoimmunotherapy with epirubicin and bacillus Calmette-Guérin (BCG) for prophylaxis of recurrence of superficial bladder cancer (pTa, pT1) were investigated in 29 patients aged a median of 70 years between January of 1991 and May of 1993. The patients received intravesical instillation of...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00686923
更新日期:1994-01-01 00:00:00
abstract:PURPOSE:Capecitabine is a prodrug that undergoes metabolism in three steps to form an active 5-fluorouracil (5-FU). The first step is primarily catalyzed by liver carboxylesterases (CES) 1. Here, we examined the effects of CES1 variants on pharmacokinetics and toxicity of capecitabine. METHODS:We enrolled postoperativ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-020-04087-z
更新日期:2020-06-01 00:00:00
abstract:PURPOSE:Gastric cancer is one of the leading cancerous diseases worldwide. It is diagnosed often at the advanced stage for which chemotherapy is the main treatment option. The prognosis remains poor for metastatic, especially the diffuse type, gastric cancers. We investigated the efficacy of intravenously administered ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-009-1222-3
更新日期:2010-09-01 00:00:00
abstract::To determine whether the morphometric indices of hepatocellular carcinoma (HCC) correlated with the prognoses, the microscopic morphometric values for 84 HCC cases treated by hepatic resection were studied using an image analyzer in relation to the survival rate and the gross classification. The mean survival time (MS...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00686663
更新日期:1994-01-01 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 aim of this study was to investigate typical population pharmacokinetic (PK) parameters, potential covariates, and interindividual and residual variabilities of PI-88, a heparanase endoglycosidase enzyme inhibitor being developed for the treatment of cancer. METHODS:A population PK model of PI-88 was devel...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-009-1080-z
更新日期:2010-03-01 00:00:00
abstract:PURPOSE:The platinum agent oxaliplatin could be useful in treatment of cancer in pregnant women, but it is fetotoxic in rats and its effect on the human fetus is unknown. METHODS:Oxaliplatin was administered to a 25-year-old pregnant woman with metastatic rectal cancer from 20 to 30 weeks gestational age as part of th...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-008-0731-9
更新日期:2009-01-01 00:00:00
abstract::Thirty-three patients with advanced transitional cell carcinoma of the urinary tract (23 bladder cases, 8 ureter cases, and 2 renal pelvis cases) were treated by three-drug combination chemotherapy using two protocols (protocol I: Adriamycin 50 mg/m2, cyclophosphamide 500 mg/m2, and 5-fluorouracil 500 mg/m2, protocol ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00256716
更新日期:1983-01-01 00:00:00
abstract:UNLABELLED:A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s002800050733
更新日期:1998-01-01 00:00:00
abstract:PURPOSE:Chemosensitizers such as cyclosporin A can increase intracellular accumulation of chemotherapeutic agents such as Adriamycin in certain multidrug-resistant (MDR) cell lines with overexpression of P-glycoprotein. It is likely that, when combined with cyclosporin A, hyperthermia could increase membrane permeabili...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800050033
更新日期:2000-01-01 00:00:00
abstract:PURPOSE:Cyclophosphamide is a cytotoxic chemotherapy drug that causes severe damages to hematopoietic and gastrointestinal systems. The aim of this study is to evaluate the protective effects of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on chemotherapy-induced mucositis (CIM) in a murine model of c...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-010-1439-1
更新日期:2011-06-01 00:00:00
abstract:BACKGROUND:The correlation of the oncological outcomes of docetaxel and cabazitaxel in Japanese metastatic castration-resistant prostate cancer (mCRPC) patients has not been unclear. MATERIALS AND METHODS:This study included a total of 47 consecutive Japanese mCRPC patients treated with cabazitaxel and assessed the pr...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-018-3698-1
更新日期:2018-12-01 00:00:00
abstract::A human stomach-adenocarcinoma cell line (MKN-45) was selected for resistance to Adriamycin by stepwise exposure to increasing concentrations of this agent. The resulting cell line (MKN/ADR) exhibited a high level of cross-resistance to topoisomerase II (topo II)-targeted drugs such as Adriamycin, mitoxantrone, and et...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800050751
更新日期:1998-01-01 00:00:00
abstract:PURPOSE:Topotecan is widely used for refractory solid tumors but multi-drug resistance may occur due to tumor expression of ATP-binding cassette (ABC) transporters. Since erlotinib, an inhibitor of the epidermal growth factor receptor, also inhibits several ABC transporters, we performed a phase I study to evaluate the...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-014-2385-0
更新日期:2014-03-01 00:00:00
abstract::The pharmakokinetic profiles of intraperitoneally infused platinum analogues were determined in 13 women exhibiting minimal residual disease following surgery and systemic chemotherapy for epithelial ovarian cancer or fallopian tube carcinoma by following the disposition of tracer doses of 195mPt radiolabel. Six patie...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00685543
更新日期:1991-01-01 00:00:00
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
pub_type: 杂志文章
doi:10.1007/s00280-008-0823-6
更新日期:2009-05-01 00:00:00
abstract::Bizelesin (U-77779) is a highly potent bis-alkylating antitumor agent that is effective against several tumor systems in vitro and in vivo. V79 cells that were 125- to 250-fold resistant to bizelesin developed after constant exposure to gradually increasing concentrations of the drug. Resistant cells exhibited a multi...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00686110
更新日期:1994-01-01 00:00:00
abstract:PURPOSE:The study mainly aimed to determine the biological function of a novelly synthesized phenanthroimidazole derivative, named L233, and to explore its potential mechanisms. METHODS:Cell survival was examined using the MTT assays, and the DNA-damaging role of L233 was explored using the comet assay. Moreover, the ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-015-2894-5
更新日期:2016-01-01 00:00:00
abstract::We reviewed 139 resected patients with hepatocellular carcinoma at our clinic between 1963 and 1987, and using the 118 cases for the period between 1963 and 1986, we analyzed the prognostic factors that influenced the long-term prognosis by comparing the survival curves. Significant differences in the survival pattern...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00647259
更新日期:1989-01-01 00:00:00
abstract::The purpose of this study was to examine the efficacy of a combination treatment of sequential irinotecan and doxifluridine, an intermediate of capecitabine, evaluated by the response rate and safety in patients with metastatic colorectal cancer. In all, 60 metastatic colorectal cancer patients with measurable disease...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,meta分析
doi:10.1007/s00280-007-0471-2
更新日期:2008-02-01 00:00:00
abstract:PURPOSE:This study evaluated the tolerability, pharmacokinetics, and preliminary antitumor activity of EZN-2208, a water-soluble poly(ethylene) glycol conjugate of SN38. METHODS:Patients with advanced malignancies were enrolled in dose-escalating cohorts (3 + 3 design). EZN-2208 was administered as a 1-h intravenous i...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-013-2149-2
更新日期:2013-06-01 00:00:00
abstract:PURPOSE:Decitabine is a nucleoside analog used in the treatment for myelodysplastic syndrome. The compound requires intracellular conversion to its triphosphate to become active. Decitabine triphosphate has, however, never been quantified in peripheral blood mononuclear cells (PBMCs) from patients. METHOD:This article...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-012-1850-x
更新日期:2012-06-01 00:00:00
abstract:BACKGROUND:The docetaxel/cisplatin (DC) combination is an active regimen against advanced/metastatic non-small-cell lung cancer (NSCLC), and bevacizumab (B) improves the efficacy of frontline chemotherapy. This phase II study was designed in order to explore the efficacy and safety of DCB regiment in this setting. MET...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-012-2037-1
更新日期:2013-03-01 00:00:00
abstract::Sodium cyanate (NaOCN) at a dose of 250 mg/kg was shown to decrease protein synthesis in P388 leukemia tumor cells to approximately 52% of control values at 2 h and 32% at 5 h after NaOCN administration, without a corresponding decrease in various normal tissues of the tumor-bearing CD2Fl mice. CD2Fl mice that had rec...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00254597
更新日期:1984-01-01 00:00:00
abstract:PURPOSE:In this exploratory study, the effect of postprocedural flushing with crystalloids after oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) on platinum concentrations in peritoneal tissue, blood, and drain fluid was studied. Interpatient variability in oxaliplatin pharmacokinetics and the relat...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-020-04107-y
更新日期:2020-07-01 00:00:00
abstract::To enable the treatment of hepatic metastasis with higher, theoretically more effective, doses of systemically toxic anticancer drugs, an isolated liver perfusion (ILP) technique was developed in WAG/Ola rats. First, in a toxicity study the maximally tolerated dose (MTD) of mitomycin C (MMC) was determined for a 25-mi...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00689698
更新日期:1991-01-01 00:00:00
abstract::In a phase II study we evaluated the effect and toxicity of a new alkylating agent, PTT-119, in 26 patients with non-Hodgkin's lymphomas (NHL) resistant to or relapsed after other chemotherapy. PTT was scheduled by escalating the dose from 2.0 to 3.3 mg/kg every 3 weeks. Among 21 evaluable patients with NHL, 12 (57%) ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00273532
更新日期:1989-01-01 00:00:00
abstract::Tumor angiogenesis is essential for tumor growth and metastasis formation. Luminex methodology was used to measure the levels of four angiogenic cytokines in cell culture medium and in the plasma of mice bearing human tumors. We obtained plasma and conditioned culture medium from 12 different human tumor cell lines. T...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-003-0572-5
更新日期:2003-04-01 00:00:00