Abstract:
:Clinically relevant resistance to the currently approved camptothecins, irinotecan and topotecan, is poorly understood but may involve increased expression of ATP-dependent drug transporters such as ABCG2 (breast cancer resistant protein, BCRP). Gimatecan (ST1481) is a lipophilic 7-substituted camptothecin derivative that exhibits potent anti-tumor activity in a variety of preclinical cancer models and is under investigation in the clinic. Previous studies reported that gimatecan cytotoxicity was not affected by expression of ABCG2. To confirm and extend this finding, we assessed the cytotoxicity of gimatecan in pairs of isogenic cell lines consisting of transfectants expressing either ABCG2 (including wild-type, R482T, or R482G mutants), ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2), or ABCC4 (MRP4). Expression of wild-type or mutant ABCG2 in human cell lines conferred resistance to topotecan but not to gimatecan. Similarly, intracellular accumulation of gimatecan was unaffected by expression of wild-type ABCG2. Furthermore, expression of P-glycoprotein or MRP2 did not alter gimatecan cytotoxicity. Whereas expression of MRP1 had a minor effect on gimatecan cytotoxicity, expression of ABCC4 was found to significantly reduce the anti-proliferative effects of this drug. Cells containing resistance-conferring mutations in topoisomerase I were also resistant to gimatecan. These results suggest that gimatecan may be more effective than irinotecan or topotecan in cancers that express ABCG2, but not in cancers that express high levels of ABCC4 or contain certain topoisomerase I (TOP1) mutations.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Gounder MK,Nazar AS,Saleem A,Pungaliya P,Kulkarni D,Versace R,Rubin EHdoi
10.1007/s10637-007-9093-0subject
Has Abstractpub_date
2008-06-01 00:00:00pages
205-13issue
3eissn
0167-6997issn
1573-0646journal_volume
26pub_type
杂志文章abstract::The combination of anti-cancer drugs with nutritional factors is a potential strategy for improving the efficacy of chemotherapy, particularly for hepatocellular carcinoma because its conventional therapies are mostly ineffective. Using a highly invasive hepatoma SK-Hep-1 cell line, we investigated the possible synerg...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9727-0
更新日期:2012-08-01 00:00:00
abstract::AZQ was given intravenously to 23 patients with mixed mesodermal sarcoma of the uterus refractory to conventional treatment at a dose of 22.5-30 mg/m2 q three weeks. There was one partial response lasting seven weeks and one drug-related death. Based upon the activity observed in this trial, there does not appear to b...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1007/BF00194555
更新日期:1991-02-01 00:00:00
abstract::A Phase II study of Didemnin-B, a marine cyclic depsipeptide, was undertaken in patients with progressive epithelial ovarian cancer. The starting dose was 2.6 mg/m2. Fifteen patients received the drug, of whom twelve were evaluable. There were no responses observed in the twelve patients. The two most frequent toxicit...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/BF01275473
更新日期:1992-04-01 00:00:00
abstract::Diflubenzuron (DFB) and Clanfenur (CFN) belong to a group of compounds called Benzoylphenyl Ureas (BPUs). Several BPUs regulate cell growth in insects and/or inhibit growth of B-16 murine melanomas. In view of potential clinical use for these compounds, DFB and CFN were selected as examples of BPUs and tested for effe...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00874426
更新日期:1993-11-01 00:00:00
abstract:PURPOSE:A phase I study of intraperitoneal paclitaxel (ip PTX) combined with gemcitabine (GEM) plus nab-paclitaxel (nab-PTX) (GnP) was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in pancreatic cancer patients with peritoneal metastasis in first-line setting. METHODS:Based on t...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-00982-7
更新日期:2020-08-08 00:00:00
abstract:BACKGROUND:Gemcitabine (G) has shown activity in mantle cell lymphoma (MCL) as a single agent. The combination of mitoxantrone (M) and rituximab (R) is also active in MCL. The primary objective of this study was to determine the efficacy of G+M+R in relapsed or refractory MCL. PATIENTS AND METHODS:Sixteen patients wer...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-008-9191-7
更新日期:2009-10-01 00:00:00
abstract::This study sought to measure the degree of synergy induced by specific small molecule inhibitors of DNA-PK [NU7026 and IC486241 (ICC)], a major component of the non-homologous end-joining (NHEJ) pathway, with SN38 or oxaliplatin. Synergy between the DNA damaging drugs and the DNA-PK inhibitors was assessed using the s...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9626-9
更新日期:2012-06-01 00:00:00
abstract::Background It would be useful to have criteria for predicting long-term treatment responses to immune checkpoint inhibitors (ICIs). Maximum depth of response correlates with treatment outcomes among patients receiving programmed death protein 1 axis inhibitors for non-small cell lung cancer (NSCLC). We investigated as...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-019-00770-y
更新日期:2019-12-01 00:00:00
abstract:BACKGROUND:We evaluated the efficacy and safety of cetuximab in combination with XELOX [XELoda® (capecitabine) and OXaliplatin] in advanced gastric cancer (AGC) patients. The objectives were to evaluate overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of cetuximab plus XEL...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-009-9363-0
更新日期:2011-04-01 00:00:00
abstract::Epidermal growth factor receptor (EGFR) gene mutations activate the KRAS-RAF-MEK-ERK pathway in lung cancer cells. EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib induce apoptosis of cancer cells, but prolonged treatment is often associated with acquired resistance. Here, we identified a novel MEK1/2 inhibito...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-013-0030-0
更新日期:2013-12-01 00:00:00
abstract::Ninhydrin (2,2-dihydroxy-1,3-indane dione) was evaluated for its antitumor and cytotoxic properties in Ehrlich ascites carcinoma cell (EAC Cell)-bearing mice. The rationale behind this study has been mainly the literature reports of its characteristic interference with DNA synthesis and calcium homeostasis. Antitumor ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1023/a:1006465504723
更新日期:2000-08-01 00:00:00
abstract:PURPOSE:Epidermal growth factor receptor (EGFR) inhibition may overcome chemotherapy resistance by inhibiting important anti-apoptotic signals that are constitutively activated by an overstimulated EGFR pathway. METHODS:This phase I dose escalation trial assessed the safety and efficacy of vinflunine, a novel vinca al...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9427-1
更新日期:2011-10-01 00:00:00
abstract:OBJECTIVE:The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has received considerable attention as a first-line treatment of advanced colorectal cancers. Difficulties associated with effectively monitoring the activity of this drug have prompted us to seek a pharmacodynamic marker suitable for def...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9817-7
更新日期:2013-02-01 00:00:00
abstract::Nafazatrom, a synthetic pyrazolinone derivative, has been shown to have substantial antitumor activity in vitro and antitumor and antimetastatic activity in experimental animal systems. The drug has produced no substantial toxicity in preclinical studies and during limited human trials. A phase I clinical trial with t...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00179592
更新日期:1986-01-01 00:00:00
abstract::Background Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We conducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally ac...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-01044-8
更新日期:2021-01-06 00:00:00
abstract::Based on the high response rates seen among patients with colon cancer receiving high dose Melphalan with autologous marrow infusion, the Southwest Oncology Group conducted a Phase II trial of the compound at a conventional dose. The initial starting dose of 40 mg/m2 was reduced to 30 mg/m2 after severe myelotoxicity ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00171991
更新日期:1990-01-01 00:00:00
abstract::There is no effective systemic therapy for disseminated metastatic melanoma. Data suggest that endothelin may play a role in pathophysiology of melanoma and that the dual endothelin receptor antagonist bosentan may have anti-tumor activity. This multicenter, open-label, single-arm, prospective, proof-of-concept study ...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-006-9014-7
更新日期:2007-06-01 00:00:00
abstract::Glioblastoma is a fast-growing primary brain tumor observed in adults with the worst prognosis. Preclinical studies have demonstrated the encouraging anticancer activity of statins. This study evaluated the efficacy of atorvastatin in combination with standard therapy in patients with glioblastoma. In this prospective...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-00992-5
更新日期:2020-08-27 00:00:00
abstract::Background Older non-small cell lung cancer (NSCLC) patients under erlotinib are reported to experience more acute toxicity. We hypothesized that modifications in erlotinib pharmacokinetics might explain this observation. Methods A monocentric prospective clinico-pharmacological study included stage IIIb/IV NSCLC cons...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/s10637-016-0400-5
更新日期:2017-04-01 00:00:00
abstract::We studied the effect of riccardin D, a macrocyclic bisbibenzyl, which was isolated from the Chinese liverwort plant, on human leukemia cells and the underlying molecular mechanism. Riccardin D had a significant antiproliferative effect on human leukemia cell lines HL-60, K562 and its multidrug resistant (MDR) counter...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9554-8
更新日期:2012-02-01 00:00:00
abstract::Twenty-four patients with a variety of solid tumors entered a Phase I trial with 4-demethoxydaunorubicin, a new analogue of daunorubicin. The drug was given as a single oral dose of 10-60 mg/m2 repeated every 3-4 weeks. Leukopenia was the dose-limiting toxicity. Other toxic effects included mild to moderate nausea and...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00175378
更新日期:1984-01-01 00:00:00
abstract::3-Deazaguanine (Dezaguanine), a purine antimetabolite, was evaluated in a phase I trial in 42 patients with advanced solid tumors. Dezaguanine was given as a weekly intravenous infusion for three consecutive weeks of a four-week cycle. The dose ranged from 30 to 2000 mg/m2; no consistent dose-limiting hematologic or g...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/BF00198593
更新日期:1990-11-01 00:00:00
abstract::Background DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-016-0420-1
更新日期:2017-06-01 00:00:00
abstract:BACKGROUND:TAS-102 is a nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). We investigated the recommended dose (RD) of TAS-102 plus irinotecan for metastatic colorectal cancer refractory to 5-fluorouracil (5-FU) and oxaliplatin. METHODS:This study was used a escalated dose ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0271-1
更新日期:2015-10-01 00:00:00
abstract::The novel oral antiangiogenic agent TSU-68 was investigated in patients with metastatic breast cancer. Patients with anthracycline-pretreated metastatic breast cancer were randomly assigned to receive either TSU-68 400 mg twice daily on days 1-21 plus docetaxel 60 mg/m(2) on day 1 every 3 weeks, or docetaxel 60 mg/m(2...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s10637-014-0093-6
更新日期:2014-08-01 00:00:00
abstract:PURPOSE:This study investigated the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic (PK) profiles of DHP107, a novel oral paclitaxel containing neither Cremophor EL nor P-glycoprotein (P-gp) inhibitor. PATIENTS AND METHODS:Patients with advanced solid tumors refractory to all standard t...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9841-7
更新日期:2013-06-01 00:00:00
abstract:BACKGROUND:Docetaxel-prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC ...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-014-0199-x
更新日期:2015-04-01 00:00:00
abstract::Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lea...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9720-7
更新日期:2012-08-01 00:00:00
abstract::The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (INNO-206) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that is being assessed clinically. The prodrug binds rapidly to circulating serum albumin and releases doxorubicin selectively at the tumor site. This novel mechanism may p...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9208-2
更新日期:2010-02-01 00:00:00
abstract::Menogarol is a new anthracycline undergoing phase I clinical trial. We report here the lethality after 2 hr exposure to 2 drug combinations of menogarol and several antitumor agents. A new statistical procedure was used to identify synergistic combinations. Most of these combinations were additive, except for menogaro...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00179427
更新日期:1985-01-01 00:00:00