Abstract:
:Matrix metalloproteinases (MMPs) are a class of structurally related enzymes that function in the degradation of extracellular matrix proteins that constitute the pericellular connective tissue and play an important role in both normal and pathological tissue remodelling. Increased MMP activity is detected in a wide range of cancers and seems correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic and therapeutic purposes. Several synthetic matrix metalloproteinase inhibitors (MMPIs) are currently being developed. Preclinical studies are promising as they suggest inhibition of several steps in the metastatic process. Marimastat is the first MMPI to enter comparative phase III trials after early clinical trials established the safety profile. Clinical trials will need to be specifically designed to optimally evaluate the therapeutic potential of this novel class of cytostatic drugs. Safety studies should consider the markedly different toxicity profile and determine the range of biologically active dosage, while efficacy studies should be performed in selected clinical settings with appropriate end-points. We review the present achievements in preclinical and clinical studies with MMPIs, discuss specific considerations for appropriate study design and reflect on the future prospects of this novel class of agents.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Denis LJ,Verweij Jdoi
10.1023/a:1005855905442subject
Has Abstractpub_date
1997-01-01 00:00:00pages
175-85issue
3eissn
0167-6997issn
1573-0646journal_volume
15pub_type
杂志文章,评审abstract::Antiproliferative factor (APF) is a potent frizzled protein 8-related sialoglycopeptide inhibitor of bladder epithelial cell proliferation that mediates its activity by binding to cytoskeletal associated protein 4 in the cell membrane. Synthetic asialylated APF (as-APF) (Galβ1-3GalNAcα-O-TVPAAVVVA) was previously show...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9746-x
更新日期:2012-10-01 00:00:00
abstract::Peloruside A is a microtubule-stabilizing agent that is currently under investigation as a potential anticancer agent. Peloruside A binds to a site on β-tubulin that is distinct to that of the taxanes (paclitaxel and docetaxel) and the epothilones. An attractive clinical quality of microtubule-stabilizing agents is th...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0232-8
更新日期:2015-06-01 00:00:00
abstract::Background This open-label, first-in-human, phase 1 study evaluated AMG 232, an oral selective MDM2 inhibitor in patients with TP53 wild-type (P53WT), advanced solid tumors or multiple myeloma (MM). Methods In the dose escalation (n = 39), patients with P53WT refractory solid tumors enrolled to receive once-daily AMG ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-019-00840-1
更新日期:2020-06-01 00:00:00
abstract::Background C-Met, which is frequently activated in multiple cancers, has been implicated in tumor formation, progression, metastasis, angiogenesis, and resistance to multiple therapies. MK-8033 is a small-molecule inhibitor of c-Met that binds preferentially to the activated conformation, and has demonstrated anti-tum...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-018-0567-z
更新日期:2018-10-01 00:00:00
abstract:BACKGROUND:Although its efficacy is unproven, 5-fluorouracil plus cisplatin (FP) is used to prevent postoperative relapse in gastric cancer. We investigated the safety and feasibility of S-1 plus cisplatin (SP) vs. FP for stage IIIB-IV (M0) gastric cancer. METHODS:Following curative resection, 41 stage IIIB-IV (M0) ga...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9515-2
更新日期:2012-02-01 00:00:00
abstract::Cancer is one of the major causes of death for non-transmissible chronic diseases worldwide. Conventional treatments including surgery, chemotherapy and external beam radiotherapy are generally far from curative. Complementary therapies are attempted for achieving more successful treatment response. Systemic targeted ...
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1007/s10637-011-9758-6
更新日期:2012-10-01 00:00:00
abstract:BACKGROUND:To evaluate the safety and tolerability of two different weekly doses of the fully humanized epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab combined with high-dose 5-fluorouracil, leucovorin and cisplatin (PLF) in the first-line treatment of patients with EGFR-positive advanc...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9848-0
更新日期:2013-06-01 00:00:00
abstract:PURPOSE:Preclinical data indicate that combination HER2-directed and anti-VEGF therapy may bypass resistance to trastuzumab. A phase I trial was performed to assess safety, activity, and correlates. EXPERIMENTAL DESIGN:Patients with advanced, refractory malignancy were enrolled (modified 3 + 3 design with expansions f...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-014-0173-7
更新日期:2015-02-01 00:00:00
abstract::Gemcitabine is a deoxycytidine (dCyd) analog with activity in leukemia and solid tumors, which requires phosphorylation by deoxycytidine kinase (dCK). Decreased membrane transport is a mechanism of resistance to gemcitabine. In order to facilitate gemcitabine uptake and prolong retention in the cell, a lipophilic pro-...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9377-7
更新日期:2011-06-01 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::Bryostatin 1 (Bryo) is a naturally occurring macrocyclic lactone with antineoplastic activity. Like the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) it directly activates the calcium- and phospholipid-dependent protein kinase C (PKC), thus generating a number of different cellular responses. We investigat...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00873230
更新日期:1994-01-01 00:00:00
abstract::The matrix metalloproteinases (MMPs) are a family of at least fifteen secreted and membrane-bound zinc-endopeptidases. Collectively, these enzymes can degrade all of the components of the extracellular matrix, including fibrallar and non-fibrallar collagens, fibronectin, laminin and basement membrane glycoproteins. MM...
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1023/a:1005722729132
更新日期:1997-01-01 00:00:00
abstract::Fluorouracil (5-FU) plus irinotecan combined with bevacizumab has significant activity in metastatic colorectal cancer (mCRC), but S-1 has become a substitute for continuous infusion of 5-FU and has a very low incidence of hand-foot syndrome. With the S-1 plus irinotecan regimen (SIR), the response rate was 62.5%, and...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9743-0
更新日期:2012-08-01 00:00:00
abstract:PURPOSE:Erlotinib (Tarceva®, OSI-774) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. As high-grade gliomas frequently show amplification, overexpression and/or mutation of EGFR, this drug has been tested in several clinical trials with glioblastoma patients, but unfortunat...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9569-1
更新日期:2012-04-01 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::SHetA2 is a small molecule flexible heteroarotinoid (Flex-Het) with promising cancer prevention and therapeutic activity. Extensive preclinical testing documented lack of SHetA2 toxicity at doses 25 to 150 fold above effective doses. Knowledge of the SHetA2 molecular target(s) that mediate(s) the mechanism of SHetA2 a...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-013-0041-x
更新日期:2014-06-01 00:00:00
abstract::Objective The aim of the current study was to examine the anticancer activity and the detailed mechanism of novel diisoquinoline derivatives in human gastric cancer cells (AGS). Methods The viability of AGS cells was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cell cycle analy...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-018-0584-y
更新日期:2018-12-01 00:00:00
abstract::The modulation of intracellular nuclear factor-kappaB (NF-κB) signaling pathway involved in the deregulated expression of cell proliferation and cell cycle regulatory molecules is a pragmatic approach for chemoprevention. Eugenol (4-allyl-1-hydroxy-2-methoxybenzene), a natural phenolic constituent of oils of cloves is...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9345-2
更新日期:2011-02-01 00:00:00
abstract:AIM:To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib under these conditions in patients with advanced solid tumours. METHODS:This was a three-treatment, randomised, three-sequence c...
journal_title:Investigational new drugs
pub_type: 杂志文章,随机对照试验
doi:10.1007/s10637-013-0055-4
更新日期:2014-06-01 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::The purpose of this study was to assess the efficacy and safety of bevacizumab plus cetuximab with or without gemcitabine in patients with advanced pancreatic adenocarcinoma. Patients with locally advanced or metastatic pancreatic adenocarcinoma, previously untreated, were randomized to bevacizumab (10 mg/kg q2w) plus...
journal_title:Investigational new drugs
pub_type: 杂志文章,随机对照试验
doi:10.1007/s10637-011-9691-8
更新日期:2012-08-01 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::The Eastern Cooperative Oncology Group undertook a limited institution phase II study of PCNU in advanced, metastatic breast cancer. The study was limited to patients treated with 1 to 2 prior chemotherapy regimens. Accrual goals were 30 patients but the study was terminated after 10 patients had no response, with a r...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00170866
更新日期:1989-07-01 00:00:00
abstract:PURPOSE:Vincristine sulfate liposomes injection (VSLI, Marqibo®) is an FDA approved encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical pharmacokinetics show VSLI to be a long-circulating, slow release formulation that is confined to plasma, and prior data on cerebrospinal ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0311-x
更新日期:2016-02-01 00:00:00
abstract::Mitoxantrone (Novantrone) and prednimustine (Sterecyt) are both active as single agents in the treatment of unfavorable non-Hodgkin lymphoma (UNHL). The efficacy and toxicity of the combination of these agents (NOSTE) was evaluated in 28 patients with advanced histopathologically proven UNHL who were not eligible for ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00195368
更新日期:1988-06-01 00:00:00
abstract::Tea (Camellia sinensis) is one of the most widely used beverages worldwide and tea consumption has been shown to have an inverse correlation to the incidence of human cancers in epidemiological and experimental studies. In the present study, the protective effects of green tea polyphenols (GTP) and black tea polypheno...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9204-6
更新日期:2009-12-01 00:00:00
abstract::Cribrostatin 6 is a quinone-containing natural product that induces the death of cancer cell lines in culture, and its mechanism of action and scope of activity are unknown. Here we show that cribrostatin 6 has broad anticancer activity, potently inducing apoptotic cell death that is not preceded by any defined cell c...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9390-x
更新日期:2011-08-01 00:00:00
abstract:PURPOSE:To summarize the safety experience obtained from phase II clinical trials conducted with trabectedin as single-agent therapy in patients with advanced solid tumors. METHODS:This retrospective analysis includes 1,132 patients exposed to trabectedin in 19 phase II trials carried out between February 1999 and Apr...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-011-9662-0
更新日期:2012-06-01 00:00:00
abstract::Background PF-06650808 is a novel anti-Notch3 antibody-drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-ag...
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/s10637-019-00754-y
更新日期:2020-02-01 00:00:00
abstract::A series of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-dione derivatives 6 (a-d) and 7 (a-g) were synthesized with different substituted aromatic sulfonyl chlorides (R-SO(2)-Cl) and alkyl halides (R-X) and were characterized by (1)H NMR, LC/MS, FTIR and elemental analyses. All the compounds synthesised were evalu...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-008-9130-7
更新日期:2008-10-01 00:00:00