Abstract:
:Any approach applied to drug discovery and development by the medical community and pharmaceutical industry has a direct impact on the future availability of improved, novel, and curative therapies for patients with cancer. By definition, drug discovery is a complex learning process whereby research efforts are directed toward uncovering and assimilating new knowledge to create and develop a drug for the purpose of providing benefit to a defined patient population. Accordingly, a highly desirable technology or approach to drug discovery should facilitate both effective learning and the application of newly discovered observations that can be exploited for therapeutic benefit. However, some believe that drug discovery is largely accomplished by serendipity and therefore appropriately addressed by screening a large number of compounds. Clearly, this approach has not generated an abundance of new drugs for cancer patients and suggests that a tangibly different approach in drug discovery is warranted. We employ an alternative approach to drug discovery, which is based on the elucidation and exploitation of biological, pharmacological, and biochemical mechanisms that have not been previously recognized or fully understood. Mechanism-based drug discovery involves the combined application of physics-based computer simulations and laboratory experimentation. There is increasing evidence that agreement between simulations based on the laws of physics and experimental observations results in a higher probability that such observations are more accurate and better understood as compared with either approach used alone. Physics-based computer simulation applied to drug discovery is now considered by experts in the field to be one of the ultimate methodologies for drug discovery. However, the ability to perform truly comprehensive physics-based molecular simulations remains limited by several factors, including the enormous computer-processing power that is required to perform the formidable mathematical operations and data processing (e.g. memory bandwidth, data storage and retrieval). Another major consideration is the development of software that can generate an appropriate and increasingly complex physical representation of the atomic arrangements of biological systems. During the past 17 years, we have made tremendous progress in addressing some of these obstacles by developing and optimizing physics-based computer programs for the purpose of obtaining increasingly accurate and precise information and by improving the speed of computation. To perform physics-based simulations that involve complex systems of biological and pharmaceutical interest, we have developed methods that enable us to exceed Moore's law. This has been accomplished by parallel processing as well as other methods that have enabled us to study more complex and relevant molecular systems of interest. This paper provides an overview of our approach to drug discovery and describes a novel drug, currently in clinical development, which has directly resulted from the application of this approach.
journal_name
Cancer Chemother Pharmacoljournal_title
Cancer chemotherapy and pharmacologyauthors
Hausheer FH,Kochat H,Parker AR,Ding D,Yao S,Hamilton SE,Petluru PN,Leverett BD,Bain SH,Saxe JDdoi
10.1007/s00280-003-0653-5keywords:
subject
Has Abstractpub_date
2003-07-01 00:00:00pages
S3-15eissn
0344-5704issn
1432-0843journal_volume
52 Suppl 1pub_type
杂志文章,评审abstract:PURPOSE:To evaluate the antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a vascular disrupting agent currently under phase II clinical trials in combination with cancer chemotherapy, in rats bearing chemically induced primary mammary tumours. METHODS:Tumours were induced in female Wistar rats by in...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-006-0321-7
更新日期:2007-04-01 00:00:00
abstract:PURPOSE:Thymidylate synthase (TS) is one of the target molecules for the antitumor effects of fluoropyrimidine drugs. The cellular thymidylate synthase level is one of the determining factors for the antitumor activity of fluoropyrimidines. TYMS, which encodes TS, has been reported to possess 28-bp tandem repeat sequen...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-005-1018-z
更新日期:2005-11-01 00:00:00
abstract:PURPOSE:Previous studies have shown that angiotensin peptides stimulate the proliferation of hematopoietic progenitors in vitro, promote survival after exposure to lethal irradiation as well as accelerate the recovery of white blood cells (WBC), i.e., lymphocytes, monocytes and neutrophils, and platelets. These changes...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-002-0509-4
更新日期:2003-02-01 00:00:00
abstract:PURPOSE:Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. METHODS:Part 1 used an open-label, two-...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-017-3471-x
更新日期:2017-12-01 00:00:00
abstract:PURPOSE:SU5416 is a novel small organic molecule that non-competitively inhibits the phosphorylation of the VEGF tyrosine kinase receptor, Flk-1. This phase IB study was performed to determine the safety, pharmacokinetics, and preliminary efficacy of the combination of SU5416 and paclitaxel in recurrent or metastatic c...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s00280-004-0871-5
更新日期:2005-03-01 00:00:00
abstract:PURPOSE:This study evaluated the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine in pre-treated metastatic colorectal cancer patients. METHODS:Five dose level combinations with irinotecan (from 180 to 240 mg/m(2), day 1, q21), capecitabine (1,...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-008-0852-1
更新日期:2009-06-01 00:00:00
abstract::A randomized controlled clinical trial was conducted to compare the use of farmorubicin (FARM) and adriamycin (ADR) in Lipiodol transcatheter arterial chemoembolization (L-TAE) as a treatment of hepatocellular carcinoma. In all, 192 hospitals participated, and 415 patients were enrolled in the study during the period ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1007/BF00686677
更新日期:1994-01-01 00:00:00
abstract::In order to determine if any inherent sensitivity differences may exist between VP16-213 and VM26 individual human tumors were grown in vitro and drug sensitivities were determined using the soft agar clonogenic assay method. Only nine of the 34 tumors tested so far showed a differing sensitivity to VP16-213 and VM26 ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00254531
更新日期:1982-01-01 00:00:00
abstract:PURPOSE:The aromatase inhibitor, letrozole, is being investigated in experimental animal models as a novel treatment for high-grade gliomas (HGGs). To facilitate optimal dosing for such studies, we evaluated the plasma and brain pharmacokinetics (PK) of letrozole in NOD-scid gamma (NSG) mice, which are frequently emplo...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-018-3705-6
更新日期:2019-01-01 00:00:00
abstract::DDMP, a diaminopyrimidine folate antagonist, was given to 26 tumor patients in a dosage of 50 mg/m2 per week orally, simultaneously with 3 mg CF i.m. or i.v. The CF dose was increased to 30 mg in patients showing evidence of toxicity, and withdrawn in the absence of toxicity. The dose-limiting toxicity was seen in mye...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00254043
更新日期:1978-01-01 00:00:00
abstract:PURPOSE:Streptozocin (STZ) is a key agent for treating advanced pancreatic neuroendocrine tumors (pNET). Most STZ regimens for pNET are daily and also include 5-fluorouracil (5FU), whereas STZ monotherapy and weekly regimens have also been applied in daily practice in Japan. The present study aimed to evaluate response...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-018-3656-y
更新日期:2018-10-01 00:00:00
abstract::We propose a mathematical model that takes into account a classical maximum tolerated dose (MTD) chemotherapy regimen (whose primary targets are the tumor cells) as well as a metronomic chemotherapy regimen (whose primary targets are the tumor endothelial cells) for the administration of temozolomide (Temodal(®)) in o...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-013-2095-z
更新日期:2013-04-01 00:00:00
abstract::A series of in vitro cytotoxicity studies were performed to achieve pharmacologic reversal of resistance to the alkylating agent mitomycin (MMC) in L-1210 leukemia cells. A multidrug-resistant (MDR), P-glycoprotein-positive cell line, RL-1210/.1 [11], was exposed to potential MDR modulators in the absence or presence ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00685114
更新日期:1991-01-01 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:PURPOSE:The intra-tumour distribution of anticancer drugs remains an important, but often under-estimated, influence on drug efficacy. Tumour acidity and the presence of efflux pumps were examined for their influence on the distribution of doxorubicin in a solid tumour model. METHODS:Anticancer drug distribution and o...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-011-1598-8
更新日期:2011-11-01 00:00:00
abstract:PURPOSE:To assess the effect of elotuzumab on corrected QT (QTc) intervals and cardiac safety. METHODS:Patients with high-risk smoldering multiple myeloma who had been treated with elotuzumab monotherapy (10 or 20 mg/kg) in Study CA204011 (NCT01441973) underwent electrocardiogram (ECG) examination over 8-10 weeks (tre...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-016-3182-8
更新日期:2016-12-01 00:00:00
abstract:PURPOSE:Multi-drug resistance and cumulative cardiotoxicity are major limitations for the clinical use of anthracyclines. Here, we evaluated and compared the cross-resistance of amrubicin, a third-generation synthetic anthracycline and potent topoisomerase (topo)-II inhibitor with little or no observed cardiotoxicity t...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-011-1782-x
更新日期:2012-04-01 00:00:00
abstract::Peripheral blood stem and progenitor cells (PBSC and PBPC), which circulate at very low levels during steady-state hematopoiesis, show a transient but marked increase during hematologic recovery from marrow-suppressive chemotherapy. To ensure rapid and sustained hematologic engraftment after autologous PBSC transplant...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800051051
更新日期:1996-01-01 00:00:00
abstract::Forty-three previously untreated patients, all of whom had poor-prognosis small cell lung cancer and/or were greater than 65 years old, received treatment with vindesine and VP16-213. Thirteen patients had limited disease and 30 extensive disease. Response rates (CR + PR) of 86% (CR 29%) and 66% (CR 17%) were seen in ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00257124
更新日期:1984-01-01 00:00:00
abstract:PURPOSE:To report population pharmacokinetic (PK) analysis of the phase 1 study (FPA144-001, NCT02318329) and to select a clinical dose and schedule that will achieve an empirical target trough concentration (Ctrough) for an anti-fibroblast growth factor receptor 2b antibody, bemarituzumab. METHODS:Nonlinear mixed-eff...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-020-04139-4
更新日期:2020-11-01 00:00:00
abstract:OBJECTIVES:Concurrent chemoradiotherapy (CRT) is the current standard of treatment for anal squamous carcinoma. However, local or metastatic recurrences remain significant after CRT with 5-fluorouracil (5-FU) and mitomycin C (MMC). Therefore, the present study evaluated the feasibility and efficacy of adding cisplatin ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-016-3185-5
更新日期:2016-12-01 00:00:00
abstract:BACKGROUND:Statins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safet...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s00280-013-2328-1
更新日期:2014-01-01 00:00:00
abstract:PURPOSE:Although chemotherapeutic protocols that include chloroethylnitrosoureas (CENUs), such as 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), have been a mainstay of treatment for glioblastomas, the clinical outcomes ha...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800050023
更新日期:2000-01-01 00:00:00
abstract:PURPOSE:Curcumin, a major constituent of the spice turmeric, suppresses expression of the enzyme cyclooxygenase 2 (Cox-2) and has cancer chemopreventive properties in rodents. It possesses poor systemic availability. We explored whether formulation with phosphatidylcholine increases the oral bioavailability or affects ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-006-0355-x
更新日期:2007-07-01 00:00:00
abstract::We evaluated the antiproliferative and the proapoptotic ability of gemcitabine in three non-small-cell lung cancer (NSCLC) cell lines. NCI-H292 (mucoepidermoid carcinoma), NCI-CorL23 (large-cell carcinoma) and NCI-Colo699 (adenocarcinoma) cells were cultured with and without 0.5, 0.05 and 0.005 microM gemcitabine for ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800000183
更新日期:2000-01-01 00:00:00
abstract::We studied the release of histamine elicited by some antineoplastic drugs in rat pleural and peritoneal mast cells. The drugs tested included the antibiotic mitomycin; the anthracyclines daunorubicin, doxorubicin, and epirubicin; the glycopeptide bleomycin; the chromopeptide dactinomycin; the platinum coordination com...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00685603
更新日期:1992-01-01 00:00:00
abstract:PURPOSE:The survival benefit of chemotherapy (CTx) compared with best supportive care (BSC) is unclear in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M-ESCC) previously treated with fluorouracil (FU), platinum (PT), and taxane (TAX). PATIENTS AND METHODS:The data of 283 consecutive pati...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-016-3179-3
更新日期:2016-12-01 00:00:00
abstract::Fifty-four patients whose disease had been staged as extensive small cell carcinoma of the bronchus were randomised to receive either CAV1 (cyclophosphamide 600 mg m-2 i.v., adriamycin 50 mg m-2 i.v., given on day 1, and etoposide 500 mg m-2 p.o. given on day 3) or CAV5 (cyclophosphamide and adriamycin given as for CA...
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/BF00254574
更新日期:1987-01-01 00:00:00
abstract:PURPOSE:We evaluated the efficacy and safety of capecitabine and temozolomide (CAPTEM) in patients with metastatic neuroendocrine tumors (NETs) to the liver. This regimen was based on our studies with carcinoid cell lines that showed synergistic cytotoxicity with sequence-specific dosing of 5-fluorouracil preceding tem...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-012-2055-z
更新日期:2013-03-01 00:00:00
abstract:PURPOSE:To further improve the prognosis of esophageal cancer patients, it is necessary to investigate new treatment strategies. The purposes of this study were to retrospectively assess the safety and efficacy of neoadjuvant chemoradiotherapy (CRT) with docetaxel/cisplatin/5-fluorouracil (DCF) (DCF-RT) in patients wit...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-018-03764-4
更新日期:2019-03-01 00:00:00