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At least 145 records · Page 8Linked to original sources

PubMed2006

NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent.

The diketopiperazine NPI-2358 is a synthetic analog of NPI-2350, a natural product isolated from Aspergillus sp., which depolymerizes microtubules in A549 human lung carcinoma cells. Although structurally different from the colchicine-binding site agents reported to date, NPI-2358 binds to the colchicine-binding site of tubulin. NPI-2358 has potent in-vitro anti-tumor activity against various human tumor cell lines and maintains activity against tumor cell lines with various multidrug-resistant (MDR) profiles. In addition, when evaluated in proliferating human umbilical vein endothelial cells (HUVECs), concentrations as low as 10 nmol/l NPI-2358 induced tubulin depolymerization within 30 min. Furthermore, NPI-2358 dose dependently increases HUVEC monolayer permeability--an in-vitro model of tumor vascular collapse. NPI-2358 was compared with three tubulin-depolymerizing agents with vascular-disrupting activity: colchicine, vincristine and combretastatin A-4 (CA4). Results showed that the activity of NPI-2358 in HUVECs was more potent than either colchicine or vincristine; the profile of CA4 approached that of NPI-2358. Altogether, our data show that NPI-2358 is a potent anti-tumor agent which is active in MDR tumor cell lines, and is able to rapidly induce tubulin depolymerization and monolayer permeability in HUVECs. These data warrant further evaluation of NPI-2358 as a vascular-disrupting agent in vivo. Currently, NPI-2358 is in preclinical development for the treatment of cancer.

Angiogenesis Inhibitors↗

PubMed1987

In vitro activity of two new aryl-fluoroquinolone antimicrobial agents, difloxacin (A-56619) and A-56620 compared to that of other antimicrobial agents.

The in vitro activity of difloxacin (A-56619) and A-56620, two new aryl-difluoroquinolones, was compared to that of other new quinolones and several parenteral and oral antimicrobial agents. A-56620 inhibited 90% of Enterobacteriaceae at less than or equal to 1 microgram/ml, Staphylococcus aureus 0.25 micrograms/ml, hemolytic streptococci 2 micrograms/ml, Pseudomonas aeruginosa 2 micrograms/ml, Bacteroides sp. and Clostridium at 8 micrograms/ml. A-56620 was equal or 2-fold more active than norfloxacin and ofloxacin, and 2-8-fold less active than ciprofloxacin. Difloxacin had similar in vitro activity with many isolates but usually was 2-8-fold less active than A-56620. Both agents inhibited beta-lactamase positive Haemophilus influenzae (MIC 0.015 micrograms/ml) and Neisseria gonorrhoeae (MK less than or equal to 0.008 micrograms/ml). Both agents were more active against streptococci and Streptococcus pneumoniae than norfloxacin, ofloxacin and enoxacin, but not more active than ciprofloxacin. They inhibited Enterobacter cloacae, Citrobacter freundii and Serratia marcescens resistant to cephalosporins and methicillin-resistant S. aureus and Staphylococcus epidermidis. Spontaneously resistant mutants were seen with Enterobacteriaceae, P. aeruginosa and S. aureus at a frequency similar to that found for other new quinolones. These agents show overall in vitro activity comparable to other quinolones in clinical trial or recently approved for clinical use.

Anti-Bacterial Agents↗

PubMed2005

Oral antihyperglycemic agents and renal disease: new agents, new concepts.

The results of the Diabetes Control and Complications Trial (DCCT) and UK Prospective Diabetes Study trials in type 1 and type 2 diabetes, respectively, have proved the importance of intensive glucose management in the prevention of microvascular complications (retinopathy, nephropathy, and neuropathy). Both trials showed encouraging trends for a decrease in macrovascular complications, and this is being pursued in new studies. These findings have led to more strict goals for glucose control. As glucose levels are aimed to be closer to the normal range, the risk for hypoglycemia also increases dramatically. The choice of the agent therefore is more influenced currently by the risk for hypoglycemia. There are presently four classes of oral antihyperglycemic agents. These agents differ greatly in terms of mechanisms of action, efficacy, side effect profiles, and cost. Except for Acarbose, all classes decrease the glycosylated hemoglobin by a similar magnitude: 1.0 to 1.5%. In chronic renal failure, the oral agents that can be used therefore include the insulin secretagogues repaglinide and nateglinide and the thiazolidinediones (rosiglitazone and pioglitazone) with caution. Insulin also can be used safely in renal failure.

Administration, Oral↗

PubMed1985

Cytoprotective agents and ulcer relapse.

This study establishes that real differences between relapse rates exist, and confirmed previous observations by Pounder et al. that relapse rates influence clinical outcomes in ulcer populations. The results make it clear that the way in which a drug influences relapse is an important determinant of therapeutic efficiency, additional to the requirement for healing efficiency. Cytoprotective agents as a group appear to be associated with lower relapse rates than cimetidine. It is not known whether the differences are peculiar to cimetidine, specific to the blockade of H2-histamine receptors, or whether they relate to the process of inhibition of secretory processes generally. Clearly, further comparisons are needed; however, conventional clinical trials are not designed to provide the necessary information. For the healing of peptic ulcers, lower relapse rates appear to provide therapeutic advantage to members of the cytoprotective group when compared with agents acting via anti-secretory mechanisms, in addition to that associated with the local (non-systemic) mode of action where applicable.

Aluminum↗

PubMed2001

[Developments in chemotherapy; cytostatic agents with an increased specificity and other forms of administering cytotoxic antineoplastic agents].

In recent years developments in molecular biology have greatly increased our knowledge about the cellular processes which govern the development of cancer. This has led to the development of anticancer agents that specifically target one of these cellular processes, for example, farnesyl transferase inhibitors, receptor tyrosine kinase inhibitors, matrix metalloproteinase inhibitors and anti-angiogenic agents. In addition to this, new chemotherapeutic agents with increased target specificity have been developed. Finally, in recent years there has been an emphasis on developing new forms of administration so that optimal use can be made of existing chemotherapeutic agents.

Alkyl and Aryl Transferases↗

PubMedDate not supplied

A new drug-delivery-system of anticancer agents: activated carbon particles adsorbing anticancer agents.

A new drug delivery system comprizing activated carbon particles adsorbing anticancer agents has been developed in order to enhance anticancer efficacy on local lesions and to reduce systemic toxicity. The system is designed to release the adsorbed anticancer agent slowly at a designated concentration level at the local site, and to allow the agent to remain for a long time at the local site, with affinity for the lymphatic system and the surface of cancer cells. Through this process, anticancer efficacy is enhanced at the local lesion and systemic toxicity decreases. Because the size of the particles influences the distribution of the agent, size is selected according to both targeted organs, i.e. lymphatic metastases, carcinomatous peritonitis, and administration methods, i.e. intramural, intracavitary, intrabronchial, or intratumoral administration.

Adsorption↗

PubMed1985

Dynamic analysis of changing features of tumor cells incubated with antitumor agents in vitro and its application for predictive activity assay of antitumor agents.

Continuous observation of living malignant cells (L1210) in a specially devised glass observation chamber with an inverted microscope made it possible to classify various cellular morphological features induced by antitumor agents into the following four stages: 1) an initial stage consisting of cytoplasmic granulation and coloring, 2) an intermediate stage of shrinkage of nuclei, increases of vacuoles and cytoplasmic budding, 3) a determinate stage of cell ballooning and 4) the terminal stage (cell ghost). Both the initial and intermediate stages are characterized by cellular changes that appear at an early phase and remain opportunistic in terms of viability. Emergence of these cellular changes is largely dependent on the specific mode of action of antitumor agents. In contrast, definite irreversibility in the changes found in both the terminal and determinate stages was confirmed by continuous observation until the cells showed lytic or ghost features, using a video-recording system. A plot of the number of cells counted in both the determinate and terminal stages versus the time-dose schedule is designated as the "time-dose-response" plot, and this proved useful for estimating the characteristics of the antitumor agents tested and the actions of new antitumor agents on malignant cells (predictive activity assay graph).

Animals↗

PubMed1981

Susceptibility of Haemophilus equigenitalis, the causal agent of contagious equine metritis, to 31 antimicrobial agents.

The minimal inhibitory concentrations of 31 antimicrobial agents were determined for 99 isolates of Haemophilus equigenitalis by the agar dilution method. All the isolates showed good susceptibility to 26 antimicrobial agents tests, minimal inhibitory concentrations of which were less than 3.13 micrograms/ml for more than 90% of the isolates. Of these agents, 4 macrolides (erythromycin, oleandomycin, kitasamycin, tylosin), 3 tetracyclines (tetracycline, chlortetracycline, oxytetracycline), 1 peptide (colistin), 1 penicillin (ampicillin) and 1 pleuromutilin (tiamulin) were the most active agents, showing a minimal inhibitory concentration of less than 0.39 micrograms/ml for more than 90% of the isolates. The growth of more than 90% of the isolates was not inhibited by 800 micrograms/ml of streptomycin.

Animals↗

PubMed1998

Cancer chemoprevention. Part 2: Hormones, nonclassic antioxidant natural agents, NSAIDs, and other agents.

This two-part series provides an up-to-date summary of the various chemopreventive agents currently in development and testing. Part 1, published in last month's issue, focused on the retinoids, such as all-trans-retinoic acid (ATRA [Vesanoid]), 9-cis-retinoic acid (9cRA), and isotretinoin (Accutane), and the carotenoids, such as beta-carotene and lycopene, and other "classic" antioxidants, such as vitamins E and C and selenium. This second part centers on hormonally mediated chemopreventives, such as tamoxifen (Nolvadex), finasteride (Proscar), oral contraceptives, and dehydroepiandrosterone (DHEA). A number of these agents have site-specific mechanisms of action and will be discussed as such. Also discussed in part 2 are various nonclassic antioxidant natural agents, including calcium, the polyphenols, the isothiocyanates, and genistein; nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin and sulindac; difluoromethylornithine (DFMO [Eflornithine]); oltipraz; and N-acetylcysteine.

Animals↗

PubMed2001

Micro-MR angiography of normal and intratumoral vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: reference to pharmacokinetic properties of dendrimer-based MR contrast agents.

Pharmacokinetic characteristics of intravascular macromolecular magnetic resonance imaging (MRI) contrast agents with polyamidoamine dendrimer cores smaller than generation-7 were previously studied in the literature. To evaluate the effects of greater hepatic uptake on the pharmacokinetics of the larger generation dendrimers, the MRI contrast agents GxD-(1B4M-Gd)(2(x+2)) were synthesized with generation-7, -8, and -9 polyamidoamine dendrimers and 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M). Their pharmacokinetic characteristics in mice were compared with that of G6D-(1B4M-Gd)(256). In biodistribution and dynamic micro-MRI studies, significantly less renal accumulation of G7D-(1B4M-Gd)(512), G8D-(1B4M-Gd)(1024), and G9D-(1B4M-Gd)(2048) was shown compared to G6D-(1B4M-Gd)(256) (P < 0.01). There was a significantly greater accumulation of G8D-(1B4M-Gd)(1024) and G9D-(1B4M-Gd)(2048) in the liver compared to G6D-(1B4M-Gd)(256) and G7D-(1B4M-Gd)(512) (P < 0.01). The highest blood retention of all dendrimer-based MRI contrast agents was exhibited by G7D-(1B4M-Gd)(512) (P < 0.01). The normal and intratumoral fine vessels of approximately 100 microm diameter were visualized in normal or tumor-bearing mice by high resolution three-dimensional-micro-MR angiographs with G7D-(1B4M-Gd)(512) and G8D-(1B4M-Gd)(1024) with good vessel-to-soft tissue contrast. In summary, increased accumulation in the liver with concomitant decreased uptake in the kidney was caused by increased molecular sizes of the dendrimer-based MRI contrast agents.

Analysis of Variance↗

PubMed2004

In vivo videomicroscopy reveals differential effects of the vascular-targeting agent ZD6126 and the anti-angiogenic agent ZD6474 on vascular function in a liver metastasis model.

Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on vascular development and function within metastases were compared in an experimental liver metastasis model. Ras-transformed PAP2 fibroblasts were injected into the mesenteric veins of SCID mice to produce a control liver metastasis burden of approximately 40% at 14 days. Mice given a single dose of ZD6126 (200 mg/kg, i.p.) on day 13 were examined 24 h later. Histology revealed a significant reduction in metastatic burden, associated with extensive tumor necrosis, increased tumor cell apoptosis and a reduction in tumor-associated vasculature. In vivo videomicroscopy (IVVM) revealed disrupted, non-functional vascular channels within metastases, with no blood flow. Mice given ZD6474 on days 4 to 10 (50 mg/kg daily, oral gavage) were examined on day 11. Histology revealed a lower metastatic burden, significant reductions in metastasis size and vasculature, and a significant increase in tumor cell apoptosis. IVVM revealed extensive reductions in vascularity and blood flow within metastases. Neither ZD6126 nor ZD6474 treatment affected surrounding normal liver tissue. This study shows that both agents can reduce experimental liver metastasis with no apparent effect on normal vasculature. However, these reductions were attained through distinct effects on the metastatic vasculature. Understanding differences in the modes of action of VTAs and anti-angiogenic agents will be important in optimizing their clinical application and in developing appropriate combination strategies.

Angiogenesis Inhibitors↗

PubMed1990

Studies of a novel agent possessing resistance to moist heat and disinfectants: parallels with Creutzfeldt-Jakob agent.

The resistance to sterilization and disinfection of a novel replicating agent (IFDO) with similarities to Creutzfeldt-Jakob agent (CJA) was investigated. Moist heat at 121 degrees C for 30 min did not kill the agent. Increasing the temperature to 140 degrees C, and the length of the autoclave cycle to 120 min also failed to guarantee sterilization, although some samples were sterilized after these treatments. Dry heat at 160 degrees C for 1 h sterilized 24 of 25 samples. Overnight disinfection with 10% Stericol or 1.2% chlorhexidine left few detectable survivors. Samples pretreated with these disinfectants and then autoclaved at 134 degrees C for 20 min were sterilized. Disinfection with hypochlorite (500 ppm available chlorine) was very effective if organic matter derived from spent culture medium was removed. We have adopted overnight Stericol disinfection, followed by autoclaving at 134 degrees C for 1 h for sterilization of glassware contaminated by IFDO. The agent may provide a valid model for sterilization of items contaminated with CJA and, if so, our data suggest that current disinfection guidelines for CJA by autoclaving at 134 degrees C for 1 h are inadequate.

Creutzfeldt-Jakob Syndrome↗

PubMed1999

Advantages of concurrent use of anabolic and antiresorptive agents over single use of these agents in increasing trabecular bone volume, connectivity, and biomechanical competence of rat vertebrae.

The purpose of this study was to evaluate the usefulness of a combination regimen of anabolic and antiresorptive agents in increasing skeletal quantity and quality in comparison to a single-drug regimen with these agents. We examined histomorphometrically and biomechanically the effects of separate and combined administration of intermittent parathyroid hormone (PTH) and estrogen or bisphosphonate on both axial and appendicular skeletons of male Wistar rats, which were 4 months old and weighed approximately 300 g at the beginning of the treatment. The animals were untreated or injected with vehicle, recombinant human PTH(1-84) (PTH; 100 microg/kg daily), 17beta-estradiol (E2, 500 microg/kg every other day), incadronate disodium (YM175, 80 microg/kg every other day), combined PTH and E2 (PTH + E2), or a combination of PTH and YM175 (PTH + YM175). After 1 month of treatment, the three groups in which PTH was administered (PTH, PTH + E2, and PTH + YM175) had significantly higher trabecular bone volume and connectivity in the proximal tibial metaphyses (PTMs) compared with the untreated and vehicle-treated groups, whereas only combination groups (PTH + E2 and PTH + YM175) showed significant increases in these indices in the lumbar vertebrae. This site-related discrepancy was attributed to the fact that PTH significantly elevated bone resorption not in the PTMs but in the vertebrae. This increased bone resorption in the vertebrae was suppressed by the addition of an antiresorptive agent. As a result, trabecular bone mass, connectivity, and mechanical strength of the vertebrae were significantly increased from control levels only in the concurrent treatment groups (PTH + E2 and PTH + YM175). The superior skeletal effects of PTH cotherapy over PTH monotherapy were not seen with regard to bone mass, but with increased connectivity and mechanical strength. The concurrent use of PTH and an antiresorptive agent has been shown to be superior to the single use of PTH for enhancing these properties of rat vertebrae, which encourages future research, especially in larger animals.

Animals↗

PubMed2006

Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin's lymphoma, with a mean survival of only 3-5 years and suboptimal therapeutic options. MCL is characterized by a balanced translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1, a G(1) cyclin regulated by the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. As improved therapy for MCL is required and the mTOR pathway may be involved in its pathophysiology, the antiproliferative effects of RAD001 (everolimus), an mTOR inhibitor, against three MCL cell lines were investigated. As a single agent, RAD001 inhibited proliferation in MCL cell lines (Jeko1, SP49 and NCEB1) approximately 40-65% compared to diluent control cells. This was associated with G(1) cell-cycle arrest and reduced phosphorylation of the mTOR downstream target, 4E-BP1. Furthermore, combination drug studies revealed predominantly synergistic cytotoxicity with RAD001 and several secondary agents, including doxorubicin, vincristine or rituximab (components of the standard MCL regimen), as well as paclitaxel, vorinostat and bortezomib. These data indicate that single agent RAD001 is effective in inhibiting growth of MCL cells in vitro and combination studies with secondary agents further demonstrate synergistic cytotoxicity. Thus, these findings support future clinical studies of RAD001 in the treatment of MCL.

Antibiotics, Antineoplastic↗

PubMed1985

An approach to the development of a short-term whole-animal bioassay to distinguish initiating agents (incomplete carcinogens), promoting agents, complete carcinogens, and noncarcinogens in rat liver.

With increased knowledge of the stages of initiation and promotion in the natural history of neoplastic development and the multiple observations that such stages are likely to be ubiquitous in the natural history of all histogenetic types of neoplasms, it is becoming increasingly important to distinguish chemical agents that act selectively during one or the other of these stages. Utilizing data obtained from the published literature as well as further observations, the experimental findings reported in this paper serve to indicate an approach to the development of a short-term whole-animal bioassay capable of distinguishing agents that act at one or the other or both of the stages of initiation and promotion in rat liver. Because of the tissue specificity for both complete carcinogens and promoting agents, this bioassay system is not likely to identify the initiating and promoting capabilities of all carcinogenic agents and thus at present is not designed to replace the standard chronic bioassay systems. However, in view of the diverse metabolic capabilities of hepatic tissue, the system proposed in this paper may represent a model capable of distinguishing the stages of carcinogenesis at which many, if not most, specific carcinogenic chemicals exert their primary action.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1986

An agent or agents produced by virus-transformed cells cause unregulated ruffling in untransformed cells.

KNRK cells (a normal rat kidney [NRK] cell line transformed by Kirsten murine sarcoma virus) in sparse culture exhibit a highly ruffled morphology, but the cause of this ruffling is unknown. In this study, we have demonstrated that the continuous, excess ruffling on KNRK cells is caused by one or more soluble agents secreted by the KNRK cells themselves. To do this study, an assay for ruffling responses in live cell cultures was defined, and its reproducibility was demonstrated. This assay permitted observation of the kinetics of ruffling responses (percentage of cells ruffled as a function of time after stimulation). This method was used to compare the kinetics of ruffling induced by insulin, epidermal growth factor, fibroblast growth factor, glucose, and KNRK cell conditioned medium (CM). Ruffling was elicited on NRK cells by each of the polypeptide mitogens and nutrients, but, in each case, this ruffling subsided spontaneously within an hour. CM from KNRK cells also caused ruffling movements on untransformed NRK cells, but this ruffling continued for at least 20 h. This response was largely blocked by premixing the KNRK cell CM with rabbit IgG against rat transforming growth factor, type alpha, (TGF-alpha). KNRK cells made quiescent (ruffle free) by a pH shift (from 7.4 to 8.4) responded to insulin, glucose, and KNRK cell CM with kinetics similar to those observed for each of these factors in NRK cells. The unusual feature for the ruffle-inducing agent(s) produced by KNRK cells was that this activity was not subject, in either NRK or KNRK cells, to the cellular off-regulation that limits the responses to insulin or glucose. Thus, the continuous ruffling of KNRK cells is caused by their own unregulated ruffle-inducing agent or agents, which appear to include TGF-alpha. This work also demonstrates that kinetic analysis of cellular responses to exogenous factors can provide new insights into the regulatory mechanisms involved in the normal limitation of these responses.

Animals↗

PubMed1978

Double-blind crossover comparison between a beta-adrenergic agent and a new anticholinergic agent by metered dose inhaler.

The recently developed anticholinergic agent Oxitropium bromide (OTB) by metered dose inhaler is compared in a double-blind crossover study with the beta-adrenergic agent Fenoterol (FEN). Total airway resistance and forced expiratory volume served as evaluation criteria for the bronchodilating effect. The maximum effect is reached more quickly with FEN, but the effect of OTB lasts longer. On the whole the results show that the intensity of action of the anticholinergic agent coincides to a large extent with that of the beta-adrenergic agent.

Adult↗

PubMed2003

Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer.

SU11248 is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities through targeting platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and FLT3, the first three of which are expressed in human breast cancer and/or its supporting tissues. The purpose of the present studies was to demonstrate the potent anticancer activity of SU11248 alone or in combination with conventional cytotoxic agents against several distinct preclinical models of breast cancer. SU11248 was administered as a monotherapy to (1) mouse mammary tumor virus-v-Ha-ras mice and 7,12-dimethylbenz(a)anthracene-treated rats bearing mammary tumors and (2) mice bearing human breast cancer xenografts of s.c. MX-1 tumors and osseous metastasis of a MDA-MB-435-derived cell line (435/HAL-Luc). SU11248 was also administered in combination with docetaxel both in xenograft models and in combination with 5-fluorouracil and doxorubicin in the MX-1 model. SU11248 treatment potently regressed growth of mammary cancers in mouse mammary tumor virus-v-Ha-ras transgenic mice (82% regression) and 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats (99% regression at the highest dose; P < 0.05 for both). This agent also inhibited MX-1 tumor growth by 52%, with markedly enhanced anticancer effects when administered in combination with docetaxel, 5-fluorouracil, or doxorubicin compared with either agent alone (P < 0.05). SU11248 treatment in combination with docetaxel effectively prolonged survival of mice, with 435/HAL-Luc cancer xenografts established in bone compared with either agent alone (P < 0.05). These results demonstrate that SU11248 is effective in preclinical breast cancer models and suggest that it may be useful in the treatment of breast cancer in the clinic.

Animals↗