Abstract:
:Mezerein, the most active antitumor compound isolated from the daphne species of plants, has a structural similarity to phorbol myristate acetate (PMA), the major active compound isolated from croton oil. PMA is known to have tumor promoting activity and is a potent inflammatory agent. Mezerein has similarly been reported to have potent inflammatory properties but appears to be a weaker tumor promoter than PMA. While the effect of PMA on the function and metabolism of human blood cells has been extensively studied, there is little similar information concerning mezerein. Therefore, in these studies, we have compared the capacities of mezerein and PMA to activate the cytotoxic capacity and oxidative metabolism of human granulocyte (PMNs), monocyte, lymphocyte, and mononuclear cell (lymphocytes and monocytes) cultures in vitro. Mezerein stimulated the oxidative metabolism of PMNs in an identical manner to PMA as indicated by a burst in the activity of the HMPS pathway, the production of H2O2, hydroxyl radical and stable oxidants. Mezerein also stimulated the release of thromboxane B2 from PMNs. Both compounds activated the oxidative metabolism of monocytes but not the oxidative metabolism of lymphocytes. The enhanced oxidative metabolism of the phagocytic cells was associated with an increased cytotoxicity against human red cells which are sensitive to oxidant damage but not against the NK resistant Raji lymphoblast cell line or the SW1116 colon tumor cell line. Of interest is that mezerein did not augment significantly the minimal cytotoxic capacity (NK activity) of mononuclear cells, monocytes or freshly isolated lymphocyte cultures against the tumor cell targets used in our experiments. However, lymphocyte cultures preincubated for 15 hours with mezerein had a marked enhancement of cytotoxicity against the tumor targets. This activation was not observed in similarly treated mononuclear cell cultures suggesting a suppressor activity of the monocytes. Our data suggest that the potent inflammatory activity of mezerein similar to PMA, may be related to its capacity to activate the oxidative and arachidonic metabolism of phagocytic cells. In addition, the capacity of mezerein to activate the cytotoxic capacity of lymphocytes may relate to its reported in vivo antitumor activity.
journal_name
Invest New Drugsjournal_title
Investigational new drugsauthors
Barton K,Randall G,Sagone AL Jrdoi
10.1007/BF00170855subject
Has Abstractpub_date
1989-07-01 00:00:00pages
179-88issue
2-3eissn
0167-6997issn
1573-0646journal_volume
7pub_type
杂志文章abstract::Tyrosine kinase inhibitors (TKI) or monoclonal antibodies targeting EGFR, HER2 or VEGFR receptors have demonstrated substantial clinical benefit in patients with advanced breast cancer, colon cancer, head and neck cancer, non-small cell lung cancer, and renal cell carcinoma. Nevertheless, these drugs have some target ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-009-9252-6
更新日期:2010-06-01 00:00:00
abstract:PURPOSE:To assess the maximum well-tolerated dose (MWTD), dose limiting toxicity (DLT), pharmacokinetics (PK) and pharmacodynamics of zibotentan, a novel specific endothelin-A receptor antagonist, in patients with metastatic prostate cancer. METHODS:Patients with metastatic, castrate-resistant prostate cancer (CRPC) w...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-009-9318-5
更新日期:2011-02-01 00:00:00
abstract::The effect of administering increasing intravenous doses of difluoromethylornithine on human tumor cell polyamine levels was determined in patients with hematologic malignancies. Difluoromethylornithine from 5.5. to 64 gm/m2 per day was administered to nine patients with refractory acute leukemia or multiple myeloma. ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00195371
更新日期:1988-06-01 00:00:00
abstract::Drug lag, which delays patients' access to medicinal products, is typically associated with pharmaceutical regulations. To shorten drug lag, health authorities may establish new policies to liberalize the regulations, a step that is important in countries, such as Taiwan, with consumer demand for imported novel therap...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-018-00715-x
更新日期:2019-10-01 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::Therapies which target VEGF and mTOR are now available for patients with metastatic renal cell carcinoma, but there is a continued need to develop agents for patients who become refractory to these initial agents. Tandutinib is a relatively selective inhibitor of type III tyrosine kinase receptor kinases with promisin...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9516-1
更新日期:2012-02-01 00:00:00
abstract:BACKGROUND:Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was in...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1006102716920
更新日期:1998-01-01 00:00:00
abstract::Didemnin B is a depsipeptide derived from a Caribbean tunicate (sea squirt) that has demonstrated antineoplastic activity against a variety of murine tumor models, including the L1210 and P388 leukemia, the B16 melanoma, and M5076 sarcoma cell lines. Based on these data, we designed a phase II trial in which 15 patien...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/BF00877248
更新日期:1992-08-01 00:00:00
abstract::Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dos...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-016-0410-3
更新日期:2017-04-01 00:00:00
abstract::N-(phosphonacetyl)-disodium L-aspartic acid (PALA) demonstrates a synergistic antitumor effect when combined with 5-Fluorouracil (5-FU) in in vitro studies. In a Phase II trial, 23 eligible patients with unresectable or metastatic adenocarcinoma of the stomach were treated with weekly i.v. bolus PALA (250 mg/M2) follo...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1007/BF00180821
更新日期:1996-01-01 00:00:00
abstract:OBJECTIVE:To determine the recommended dose for phase II trials of elisidepsin (PM02734, Irvalec®) in combination with erlotinib in patients with advanced malignant solid tumors. METHODS:Open-label, dose-escalating, phase I study of intravenous elisidepsin administered weekly (days 1, 8 and 15) over 3 h as a flat dose...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-015-0305-8
更新日期:2016-02-01 00:00:00
abstract::The discovery of multiple putative therapeutic targets and multiple putative agents for these targets in prostate cancer in the coming years poses significant challenges for clinical trial design. This is especially true for cytostatic agents that are not expected to lead to frank tumor shrinkage or declines in the PS...
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1023/a:1015618108456
更新日期:2002-05-01 00:00:00
abstract::TNF-alpha may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the efficacy of NGR-TNF...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-005-4540-2
更新日期:2006-01-01 00:00:00
abstract:INTRODUCTION:The analysis of predictive factors of response may aid in predicting which patients with advanced renal cell carcinoma (RCC) would be good candidates for systemic treatments. MATERIALS AND METHODS:The expression of several biomarkers was retrospectively analyzed using immunohistochemistry (IHC), as well a...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9836-4
更新日期:2012-12-01 00:00:00
abstract:BACKGROUND:This Phase-I-study aimed to determine the recommended Phase-II-dosing-schedule of LY2334737, an oral gemcitabine prodrug, in patients with advanced/metastatic solid tumors. Pharmacokinetics, cytokeratin-18 (CK18) levels, genetic polymorphisms, and antitumor activity were additionally evaluated. METHODS:Pati...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0286-7
更新日期:2015-12-01 00:00:00
abstract::Cyclophosphamide (CPA) is widely used against leukemic and lymphoproliferative diseases, but in vitro studies on response to this agent so far have been limited to instable derivatives with poor galenic properties. ASTA Z 7557 is a newly synthesized "activated cyclophosphamide" that circumvents the need for hepatic ac...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/BF00232346
更新日期:1984-01-01 00:00:00
abstract::BMS-754807 is an inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor that also represses aurora kinase. Cancers that express high levels of IGF-1/IGF-1R are sensitive to BMS-754807; however, it shows limited efficacy in non-small cell lung cancer (NSCLC) in which IGF-1R-driven signals may ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-012-9874-y
更新日期:2013-06-01 00:00:00
abstract::Anthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to seconda...
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1007/s10637-017-0443-2
更新日期:2017-06-01 00:00:00
abstract:BACKGROUND:Foretinib is a small-molecule, oral multikinase inhibitor primarily targeting the mesenchymal epithelial transition (MET) factor receptor, and the vascular endothelial growth factor receptor 2. We conducted a phase II study to evaluate the single-agent activity and tolerability of foretinib in patients with ...
journal_title:Investigational new drugs
pub_type: 杂志文章,多中心研究
doi:10.1007/s10637-012-9861-3
更新日期:2013-04-01 00:00:00
abstract::Background We determined the safety, pharmacokinetics, pharmacodynamics, and antitumour activity of abexinostat in B-cell lymphoma or chronic lymphocytic leukaemia. Patients and methods Thirty-five patients received oral abexinostat 30, 45, or 60 mg/m(2) bid in a 3 + 3 design in three 21-day schedules: 14 days on trea...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-015-0206-x
更新日期:2015-04-01 00:00:00
abstract::Background Treatment of recurrent, unresectable granulosa cell tumor (GCT) of the ovary can be challenging. Given the rarity of the tumor, alternative therapies have been difficult to evaluate in large prospective clinical trials. Currently, to our knowledge, there are no reports of the use of immune checkpoint inhibi...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-020-01043-9
更新日期:2021-01-07 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::HDAC inhibitors (HDACI) are now emerging as one of the most promising new classes of drugs for the treatment of select forms of non-Hodgkin's lymphoma (NHL). They are particularly active in T-cell lymphomas, possibly hodgkin's lymphoma and indolent B cell lymphomas. Presently, two of these agents, vorinostat and romid...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9591-3
更新日期:2010-12-01 00:00:00
abstract::Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage ...
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/s10637-017-0450-3
更新日期:2017-06-01 00:00:00
abstract:UNLABELLED:Although UFT 300 mg/m2/day and leucovorin 90 mg/day administered orally in divided doses administered every 8 hours for 28 days repeated every 35 days could be administered safely to patients with advanced hepatomas and good performance status, this combination and schedule has limited activity in treating a...
journal_title:Investigational new drugs
pub_type: 临床试验,杂志文章
doi:10.1023/a:1006104217137
更新日期:1998-01-01 00:00:00
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 r...
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1023/a:1005855905442
更新日期:1997-01-01 00:00:00
abstract::Apoptin is a nonstructural protein encoded by one of the three open reading frames of the chicken anemia virus genome. It has attracted a great deal of interest due to its ability to induce apoptosis in multiple transformed and malignant mammalian cell lines without affecting primary and non-transformed cells. However...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-017-0431-6
更新日期:2017-06-01 00:00:00
abstract::Fluorinated pyrimidines, particularly 5-fluorouracil (FUra), have been the subject of intense and almost continuous basic and clinical study since development in the late 1950's by Dr. Charles Heidelberger. Despite this intensive effort, the most important mechanisms by which FUra influences tumor growth in individual...
journal_title:Investigational new drugs
pub_type: 杂志文章,评审
doi:10.1007/BF00178188
更新日期:1989-04-01 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::Sorafenib, an orally active multi-kinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC), is primarily metabolized both via cytochrome P450 3A4 isoform (CYP3A4) and UGT1A9. Due to the contribution of these two biotransformation pathways, sorafenib is considered to be less susceptible than other ...
journal_title:Investigational new drugs
pub_type: 杂志文章
doi:10.1007/s10637-010-9514-3
更新日期:2011-12-01 00:00:00