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PubMed1995

Vinca site agents induce structural changes in tubulin different from and antagonistic to changes induced by colchicine site agents.

Vinca site agents are antimicrotubule compounds that bind to the same site on tubulin as do the vinca alkaloids. These include agents that induce the formation of nonmicrotubule oligomers of tubulin (vinblastine and vincristine) and agents that do not (maytansine and rhizoxin). All of these quench the fluorescence of tubulin upon binding. Quenching preferentially affects the red side of tubulin emission, likely affecting more than one solvent-exposed tryptophan. Similar quenching is observed upon binding to either tubulin or tubulin-colchicine. None of these agents induces the local unfolding of the amphipathic helix in the carboxyl terminal region of beta-tubulin that colchicine and other colchicine site ligands do. All four vinca site agents inhibit this unfolding in tubulin-colchicine complexes without displacing colchicine. Both groups of vinca site agents enhance the chymotryptic cleavage of beta-tubulin after Tyr-281. Both groups of vinca site agents increase the beta-tubulin specificity of photolabeling with colchicine, and both groups inhibit colchicine-stimulated GTP hydrolysis. All of these effects common to both groups of vinca site agents are interpreted as due to vinca site occupancy alone. The vinca alkaloids differ from maytansine and rhizoxin by causing a large enhancement of chymotryptic cleavage of beta and a large inhibition of typtic cleavage of alpha, after Arg-339. These effects are interpreted as due to vinca induced oligomerization of tubulin. It is argued that the common binding site for the vinca site agents is located on beta-tubulin, close to the helix that is disrupted by colchicine.

Animals↗

PubMed1989

A novel replicating agent isolated from the human intestinal tract having characteristics shared with Creutzfeldt-Jakob and related agents.

A novel replicating agent (IFDO) was isolated from ileal fluid. Growth occurred in vitro under aerobic and anaerobic conditions, and was faster at 37 degrees C than at room temperature. The doubling time was 15.8 min. Colonies were dark brown in colour and occurred beneath the surface of agar after conventional surface inoculation. Provisional data indicate that the agent may be a normal intestinal commensal. The agent was remarkably resistant to inactivation by steam at 134 degrees C, formaldehyde and glutaraldehyde; it was relatively resistant to ionising radiation, and it was filterable through membranes with a nominal pore diameter of 10 nm. Such properties, with the exception of growth in cell-free medium, are shared by "unconventional agents" such as those of Creutzfeldt-Jakob disease and scrapie. Further comparison of the properties of the intestinal agent and of slow viruses revealed additional shared characteristics, including resistance to proteinase K and trypsin, and inactivation by guanidine thiocyanate, diethyl pyrocarbonate, phenol and sodium hydroxide. The agent differs from that of scrapie in being inactivated by ethidium bromide, zinc nitrate, EDTA, hydroxylamine in the presence Sarkosyl, and, under certain circumstances, by ribonuclease. Broth cultures of the agent contained particles possessing considerable size heterogeneity. The smaller filterable particles were generally more susceptible to inactivation, did not survive autoclaving, and were inactivated by papaya protease and lipase. It is possible that the replicating agent may be formed by crystallisation from constituents of the medium, and not by a biological process. This does not exclude the postulated relationship to slow viruses.

Anti-Bacterial Agents↗

PubMedDate not supplied

National survey of the use of sedating drugs, neuromuscular blocking agents, and reversal agents in the intensive care unit.

The objectives of this study were to describe the sedative, neuromuscular blocking agents (NMBA) and reversal agents utilized in adult intensive care units across the United States and determine the adherence to American College of Critical Care Medicine and Society of Critical Care Medicine (SCCM) guidelines. In addition, the authors assessed the use of written protocols, criteria used for selecting these agents, and monitoring practices. Questionnaires were mailed to attending physician members of SCCM in the spring of 1998. A cover letter was enclosed that explained the purpose of the survey asking the respondent to forward the questionnaire to a colleague if unable to complete. Four-hundred fifty-seven questionnaires were returned representing 393 different institutions for a response rate of 50.4% (393/780). Respondents were physicians (91.2%) practicing in a community (49.7%) or university teaching hospital (38.3%). The sedative agents used most often were opioids and benzodiazepines for >72 hours, and NMBA utilized were vecuronium and pancuronium for >24 hours. The most often cited indications for sedatives were agitation, anxiety/fear, and facilitation of intubation and maintenance of mechanical ventilation for NMBA. Only 32.6% used written protocols for sedatives and 46.8% for NMBA. Decisions regarding agent selection were based on clinician preference and experience and agent duration of action. Seventy-eight percent monitored sedative use primarily with the Glasgow Coma Scale and the modified Ramsay score. Monitoring of NMBA was used more frequently (91.3%) with peripheral nerve stimulation. The most common reversal agents used were naloxone and flumazenil for adverse drug effects. While many of the respondents indicated they used morphine and lorazepam for long-term sedation, the majority utilized midazolam and propofol for >24 hours despite the recommendation of SCCM. Vecuronium was prescribed more routinely than pancuronium. The number of institutions utilizing protocols for any of these agents was low; instead, decisions were based on clinician preference.

Adult↗

PubMed2000

Liquid and fluid agents for preventing adhesions after surgery for subfertility.

BACKGROUND: Pelvic surgery is associated with high rates of both de novo adhesion formation and adhesion reformation. Although the role of pelvic and/or tubal surgery in the management of infertility is more limited since the development of in-vitro fertilisation such surgery remains indicated for a number of selected patients. Other forms of pelvic surgery will remain prevalent in women of reproductive age (e.g. endometriosis surgery, ovarian cystectomy, myomectomy). Since subsequent fertility is reduced with increasing severity of periadnexal adhesions, pelvic adhesions will remain a clinical problem in infertility patients. Adjuvant therapy has been promoted for many years to prevent adhesion formation. Numerous substances have been used experimentally in animal models, many have been advocated for use during human surgery, and some are widely used in clinical practice. Steroids and antihistamines are given in the belief that they will promote fibrinolysis during healing without preventing healing. OBJECTIVES: To investigate whether pharmacological and liquid agents used as adjuvants during pelvic surgery in infertility patients lead to a reduction in the incidence or severity of postoperative adhesion (re-)formation, and/or an improvement in subsequent pregnancy rates. SEARCH STRATEGY: The specialised database of the Menstrual Disorders and Subfertility Group. SELECTION CRITERIA: Randomised controlled trials investigating the use of pharmacological and liquid agents to prevent adhesion formation after pelvic surgery for infertility. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the first 2 authors. Differences of opinion were registered and resolved by consensus with the senior author (RJL). Two by two tables were generated for each trial for the dichotomous outcome of pregnancy and the effects on pregnancy rate of each study is expressed as an odds ratio with 95% confidence intervals. MAIN RESULTS: None of the pharmacological or liquid agents investigated in a randomised controlled fashion was shown to improve postoperative pregnancy rates. There was some evidence that steroids reduced the incidence and severity of postoperative adhesion formation. Dextran appeared to neither reduce the incidence or severity of adhesions. REVIEWER'S CONCLUSIONS: The routine use of pharmacological agents to prevent post-operative adhesions after infertility surgery cannot be recommended on the basis of the available evidence derived from RCTs. In connection with adhesion prevention, the evidence with regard to steroids is far from perfect but tentatively suggests that they may be beneficial. Further randomised studies should be conducted to investigate this further.

Anticoagulants↗

PubMed1986

The effect of anesthetic agents on human immune system function. I. Design of a system to deliver inhalational anesthetic agents to leukocyte cultures in vitro.

A novel system for exposing purified human mononuclear leukocyte subsets or any cultured cell to inhalational anesthetic agents has been devised. Monocytes and lymphocytes are purified by counter-current centrifugal elutriation and put into culture vessels with and without appropriate functional activators. The culture vessels are placed into one of four anesthetic agent exposure chambers, each containing a different concentration of the anesthetic agent to be tested. The system that delivers the anesthetic agent to the culture vessels is essentially the same as the one used in the operating room; the actual levels of anesthetic agent delivered are monitored. In this report, we present evidence that halothane can be successfully tested using the above-cited experimental design; this agent substantially inhibits the secretion of interferon by human mononuclear cells. The ability of monocytes to secrete alpha interferon in response to polyinosinic: polycytidylic acid (poly I:C) was significantly depressed following 4 h in vitro exposure to increasing concentrations of halothane; the secretion of gamma interferon by lymphocytes in response to phytohemagglutinin (PHA) was also depressed, although to a lesser degree. The system presented should allow for the in vitro exploration of the effects of inhalational agents on purified human leukocyte subset functions as well as for the analysis of the effect of these agents on monocyte/lymphocyte interactions.

Halothane↗

PubMed2004

Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--an update.

Development of effective antiemetic therapy depends upon an understanding of both the antiemetic agents and the emetogenic challenges these agents are designed to address. New potential antiemetic agents should be studied in an orderly manner, proceeding from phase I to phase II open-label trials and then to randomized double-blind phase III trials comparing new agents and regimens to best standard therapy. Use of placebos in place of antiemetic therapy against highly or moderately emetogenic chemotherapy is unacceptable. Nausea and vomiting should be evaluated separately and for both the acute and delayed periods. Defining the emetogenicity of new antineoplastic agents is a challenge, since such data are often not reliably recorded during early drug development. A four-level classification system is proposed for emetogenicity of intravenous antineoplastic agents. A separate four-level classification system for emetogenicity of oral antineoplastic agents, which are often given over an extended period of time, is also proposed.

Antiemetics↗

PubMed1989

In vitro activities of a dual-action antibacterial agent, Ro 23-9424, and comparative agents.

The in vitro activity of the dual-action antibacterial agent Ro 23-9424 was compared with those of cefotaxime, ceftazidime, ciprofloxacin, fleroxacin, imipenem, and amikacin against 358 aerobes and anaerobes. The MIC ranges, MICs for 50 and 90% of the strains (MIC50s and MIC90s), and percentage of strains susceptible for each agent at the recommended susceptible MIC breakpoint were determined for each genus. The MIC90s (micrograms per milliliter) of the agents against members of the family Enterobacteriaceae were as follows: ciprofloxacin, 0.063; Ro 23-9424, fleroxacin, and imipenem, 0.5; ceftazidime, 2; amikacin, 4; and cefotaxime, 16. The MIC90s (micrograms per milliliter) against Pseudomonas and Acinetobacter spp. were as follows: ciprofloxacin, 2; ceftazidime and imipenem, 8; Ro 23-9424, 16; fleroxacin, 32; amikacin, 64; and cefotaxime, 128. Against gram-positive bacteria, excluding the enterococci, the MIC90s (micrograms per milliliter) were as follows: ciprofloxacin, 1; imipenem, 4; Ro 23-9424 and fleroxacin, 8; amikacin, 64; and ceftazidime and cefotaxime, greater than 128. Against gram-positive bacteria, including the enterococci, the MIC90s changed only for the following agents: Ro 23-9424, 16 micrograms/ml; and amikacin, 128 micrograms/ml. Strains of Branhamella catarrhalis, Haemophilus influenzae, and Neisseria gonorrhoeae were 100% susceptible to Ro 23-9424, cefotaxime, ciprofloxacin, and fleroxacin, while the other three agents showed somewhat less activity only against N. gonorrhoeae. Against anaerobes, imipenem was the most effective agent, while the activities of the other six agents were variable.

Anti-Bacterial Agents↗

PubMed1999

Safety and efficacy of using a single agent or a phase II agent before instituting standard combination chemotherapy in previously untreated metastatic breast cancer patients: report of a randomized study--Cancer and Leukemia Group B 8642.

PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF. RESULTS: The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm. CONCLUSION: The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.

Adenine↗

PubMed1998

Economic outcomes of antipsychotic agents in a Medicaid population: traditional agents vs. risperidone.

Clinical trials reveal that the newer atypical antipsychotic agents are more effective and have fewer side effects than traditional agents. However, these newer agents have a higher acquisition cost than traditional agents. This study assessed the differential impact of risperidone and traditional agents on the total schizophrenia-related cost of care for Medicaid patients suffering from schizophrenia. This was a retrospective longitudinal pretest-posttest analysis of Medicaid claims data covering January 1992 to August 1996. Continuously eligible patients (n = 150) with a documented diagnosis of schizophrenia were evaluated. Medical claims were analyzed for patients treated with traditional antipsychotics for at least 12 months and then switched to risperidone and followed for at least 12 months. Patients who failed on at least one traditional agent and who remained on other traditional agents throughout the study timeframe served as a control group. Monthly costs per patient were estimated using mixed model linear regression with age and gender serving as covariates. The total monthly costs per patient for the risperidone and traditional cohorts were similar ($1,050.52 and $946.24, respectively; p = .5438) during the pretest phase of the study. For patients treated with risperidone, drug costs were $177.35 higher (CL0.95 +/- $7.64; p = .0001) per patient per month in the posttest period compared with the pretest period. However inpatient hospital costs were $312.04 lower (CL0.95 +/- $146.76; p = .001) per patient per month in the posttest period compared with the pretest period. In addition, physician costs were $9.55 lower (CL0.95 +/- $5.31; p = .0004) per patient per month in the posttest period. The difference from the pretest to posttest period for outpatient mental health clinic costs was statistically similar. For those in the risperidone cohort, total estimated costs decreased by $204.87 per patient per month during treatment with risperidone (CL0.95 +/- $161.01; p = .0127). Over the same time-frame, total costs increased $160.68 per patient per month (CL0.95 +/- $196.04; n.s.; p = .1082) in the control cohort. While the mean monthly drug cost was significantly higher during treatment with risperidone, this increase was offset by cost reductions elsewhere in the system.

Adult↗

PubMed2004

Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis.

CONTEXT: Randomized trials have demonstrated that adding a drug to a single-agent or to a 2-agent regimen increased the tumor response rate in patients with advanced non-small-cell lung cancer (NSCLC), although its impact on survival remains controversial. OBJECTIVE: To evaluate the clinical benefit of adding a drug to a single-agent or 2-agent chemotherapy regimen in terms of tumor response rate, survival, and toxicity in patients with advanced NSCLC. DATA SOURCES AND STUDY SELECTION: Data from all randomized controlled trials performed between 1980 and 2001 (published between January 1980 and October 2003) comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC. There were no language restrictions. Searches of MEDLINE and EMBASE were performed using the search terms non-small-cell lung carcinoma/drug therapy, adenocarcinoma, large-cell carcinoma, squamous-cell carcinoma, lung, neoplasms, clinical trial phase III, and randomized trial. Manual searches were also performed to find conference proceedings published between January 1982 and October 2003. DATA EXTRACTION: Two independent investigators reviewed the publications and extracted the data. Pooled odds ratios (ORs) for the objective tumor response rate, 1-year survival rate, and toxicity rate were calculated using the fixed-effect model. Pooled median ratios (MRs) for median survival also were calculated using the fixed-effect model. ORs and MRs lower than unity (<1.0) indicate a benefit of a doublet regimen compared with a single-agent regimen (or a triplet regimen compared with a doublet regimen). DATA SYNTHESIS: Sixty-five trials (13 601 patients) were eligible. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (OR, 0.42; 95% confidence interval [CI], 0.37-0.47; P<.001) and 1-year survival (OR, 0.80; 95% CI, 0.70-0.91; P<.001) in favor of the doublet regimen. The median survival ratio was 0.83 (95% CI, 0.79-0.89; P<.001). An increase also was observed in the tumor response rate (OR, 0.66; 95% CI, 0.58-0.75; P<.001) in favor of the triplet regimen, but not for 1-year survival (OR, 1.01; 95% CI, 0.85-1.21; P =.88). The median survival ratio was 1.00 (95% CI, 0.94-1.06; P =.97). CONCLUSION: Adding a second drug improved tumor response and survival rate. Adding a third drug had a weaker effect on tumor response and no effect on survival.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1974

Effect of chelating agents on the susceptibility of some strains of gram-negative bacteria to some antibacterial agents.

The effects of ethylenediaminetetraacetic acid and related chelating agents on the susceptibility of Pseudomonas aeruginosa and other strains of gram-negative bacteria to some beta-lactam antibiotics and some non-antibiotic antibacterial agents have been studied by two methods: (i) the determination of minimal inhibitory concentrations in the presence and absence of a chelating agent; and (ii) pretreatment with a chelating agent, followed by exposure for up to 120 min at 37 C to a beta-lactam drug in a nutrient medium or to the other type of antibacterial agent in a non-nutrient environment. The pretreatment technique gave the more significant results, especially with chlorhexidine, cetrimide, and benzalkonium chloride. Chelating agents that had previously been found to give a low order of activity as measured by effects on bacterial viability nevertheless appeared to induce some changes in the surface layers of the treated organisms, rendering them susceptible to sub-inhibitory concentrations of non-antibiotic drugs.

Anti-Bacterial Agents↗

PubMed1993

Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent.

NAD(P)H dependent cytochrome P450's and other haemoproteins under hypoxia, mediate two-electron reduction of a wide range of structurally dissimilar N-oxides to their respective tertiary amines. Metabolic reduction can be utilised, in acute and chronic hypoxia, to convert N-oxides of DNA affinic agents to potent and persistent cytotoxins. In this respect a knowledge of N-oxide bioreduction and the importance of the cationic nature of agents that bind to DNA by intercalation can be combined to rationalise N-oxides as prodrugs of DNA binding agents. The concept is illustrated using the alkylaminoanthraquinones which are a group of cytotoxic agents with DNA binding affinity that is dependent on the cationic nature of these compounds. The actions of the alkylaminoanthraquinones involve drug intercalation into DNA (and double stranded RNA) and inhibition of both DNA and RNA polymerases and topoisomerase Type I and II. A di-N-oxide analogue of mitoxantrone, 1,4-bis([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxyanthracene -9,10- dione (AQ4N) has been shown to possess no intrinsic binding affinity for DNA and has low toxicity. Yet in the absence of air AQ4N can be reduced in vitro to a DNA affinic agent with up to 1000-fold increase in cytotoxic potency. Importantly the reduction product, AQ4, is stable under oxic conditions. Studies in vivo indicate that antitumour activity of AQ4N is manifest under conditions that promote transient hypoxia and/or diminish the oxic tumour fraction. The advantage of utilising the reductive environment of hypoxic tumours to reduce N-oxides is that, unlike conventional bioreductive agents, the resulting products will remain active even if the hypoxia that led to bioactivation is transient or the active compounds, once formed, diffuse away from the hypoxic tumour regions. Furthermore, the DNA affinic nature of the active compounds should ensure their localisation in tumour tissue.

Animals↗

PubMed1993

Induction of cholinergic and adrenergic differentiation in N-18 cells by differentiation agents and DNA demethylating agents.

Effects of various differentiating agents and DNA demethylating agents on the expression of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH), marker enzymes for cholinergic and adrenergic differentiation, respectively, were examined in N-18 neuroblastoma cells. Retinoic acid (RA) and a medium conditioned over C6-glioma cells (GCM), which have been shown to enhance the ChAT activity of PC12 cells, NG108-15 cells and fetal rat brain cells, did not induce ChAT activity of N-18 cells. Treatment of the cells with the DNA demethylating agents alone also did not affect ChAT activity. But after pretreatment of the cells with the DNA demethylating agents, ChAT activity of N-18 cells was greatly increased by either RA or GCM. TH activity of N-18 cells was enhanced by forskolin, an activator of adenylate cyclase. The pretreatment of the cells with the DNA demethylating agents greatly enhanced the induction of TH activity by forskolin. Levels of ChAT and TH messenger RNA were altered in accordance with changes in ChAT and TH activities. Possible mechanisms of the actions of the demethylating agents on cholinergic and adrenergic differentiation are discussed.

Acetylcholine↗

PubMed1998

Mutation of the p53 gene in human astrocytic tumours correlates with increased resistance to DNA-damaging agents but not to anti-microtubule anti-cancer agents.

Astrocytic tumours often become resistant to a variety of chemotherapeutic agents in advanced stages and frequently possess mutations in the p53 tumour-suppressor gene. Previous studies using established cell lines to investigate the relation between mutated p53 genes and altered resistance to anti-cancer agents brought inconsistent results. In this report, we examined the status of the p53 gene in 56 astrocytic tumour specimens by single-strand conformation polymorphism and their in vitro chemosensitivity to 30 different kinds of anti-cancer agents. The chemosensitivity was determined by drug-induced cell death using flow cytometry. We found that the mutated p53 gene correlated with increased resistance to DNA-damaging agents but the sensitivity to anti-microtubule agents was independent of the mutation, suggesting a clinical significance of the status of p53 gene in astrocytic tumours and a rational application of anti-microtubule agents to the patients with p53-mutated astrocytic tumours.

Antineoplastic Agents↗

PubMed1995

Does the dopamine receptor subtype selectivity of antipsychotic agents provide useful leads for the development of novel therapeutic agents?

Antipsychotic agents share the ability to antagonize dopamine (DA) receptors, and correlation studies have indicated that the clinical efficacy of neuroleptic agents may be coupled to their affinity for D2 receptors. More recently, a family of DA D2-like receptors has been identified. These receptors include the D2A, D2B, D3 and D4 receptors. On the basis of in vitro receptor-binding studies, it has been suggested that the atypical profile of clozapine might be related to a selective effect on the D4 receptor subtype. We have studied the receptor-binding profiles of a series of antipsychotic agents and evaluated some of the compounds in behavioural assays in the rat. Most of the antipsychotic agents lack selectivity for DA-receptors as well as selectivity for the various DA-receptor subtypes. Because of this lack of selectivity, it is impossible to draw firm conclusions about the role of any particular receptor in the clinical profile of the neuroleptic agents. Furthermore, the pharmacology of potential human metabolites has to be taken into account in a proper analysis of the clinical profile. Consequently, most speculations on the key-target of clinically interesting antipsychotics (including clozapine) may be of little practical value. Clinical studies with receptor (subtype)-selective agents will be more informative.

Animals↗

PubMed1986

Effects of antimuscarinic agents and prostaglandin E2 on the gastric mucosal lesions induced by necrotizing agents and water-immersion stress in rats.

The role of antimuscarinic action in gastric mucosal protection against necrotizing agents and the role of such mucosal protection in antiulcerogenic action were studied in rats with i.v. administered antimuscarinic agents. Pirenzepine, as well as PGE2, prevented the gastric mucosal lesions induced by all necrotizing agents (99.5% ethanol, 0.6 N HCI, 0.15 N NaOH, 0.4 N HCI-50 mM taurocholate), but atropine did not prevent the HCI-induced lesions. Cimetidine inhibited only the ethanol-induced lesions even at the antisecretory dose. Higher doses of pirenzepine (5-fold) and atropine (10-fold) were required to inhibit the gastric secretion in Shay rats than in vagally stimulated rats. There was no difference between the antisecretory doses of cimetidine in Shay rats and vagally stimulated rats. PGE2 (0.03-0.1 mg/kg) did not affect gastric secretion. The protective doses of pirenzepine and atropine against mucosal lesions induced by necrotizing agents were similar to the dose in inhibiting vagally stimulated acid secretion and water-immersion stress-induced lesions. PGE2 (100 micrograms/kg) did not prevent the water-immersion stress induced gastric lesions. These results suggested that antimuscarinic agents protect the gastric mucosa from necrotizing agents via a blocking action on the activation of the intrinsic cholinergic nerve. However, antiulcerogenic action is more deeply concerned with antisecretory action than cytoprotection.

Animals↗

PubMed2001

Sensitivity of soft tissue sarcoma cell lines to chemotherapeutic agents: identification of ecteinascidin-743 as a potent cytotoxic agent.

The cytotoxic effects of ecteinascidin-743(ET-743), a novel marine natural product, were evaluated and compared with that of clinically used anticancer agents methotrexate, doxorubicin, etoposide, and paclitaxel in eight human soft tissue sarcoma (STS) cell lines. HT-1080, a fibrosarcoma cell line, and HS-42, a malignant mesodermal cell line, were the most sensitive of the cell lines to methotrexate, doxorubicin, etoposide, and paclitaxel. Other cell lines (IC50s) varied considerably and were more resistant to these agents. ET-743 was more potent than any of these agents, with IC50s in the pM range in all of the cell lines. Cytotoxicity of ET-743 was dose- and time-related (4-72 h exposure). Cytotoxic concentrations of ET-743 produced a S/G2 block in all of the cell lines tested. Three colon adenocarcinoma cell lines, HCT-8, HT-29, and HCT-116, and one breast cancer cell line, MCF-7, were 1-2 logs less sensitive to ET-743 than the STS cell lines. Cell lines were also characterized as to expression of oncogenes and tumor suppressor genes to attempt to correlate sensitivity of these cell lines to ET-743 and other chemotherapeutic agents. All of the cell lines except M8805, a malignant fibrous histiocytoma cell line, had mutations in p53 and/or overexpressed the MDM2 protein. Only HS-18, a liposarcoma cell line, lacked expression of the retinoblastoma protein. None of the cell lines had detectable expression of P-glycoprotein as measured by immunohistochemistry. ET-743 is an extremely potent cytotoxic agent against human STS cell lines and is being evaluated as an antitumor agent in this disease.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

[New anti-cancer agents--from cytotoxic systemic chemotherapy to target-based agents].

Lung cancer is the leading cause of cancer-related death throughout the world including Japan. During the 1990s, new cytotoxic agents such as irinotecan, paclitaxel, docetaxel, vinorelbine, gemcitabine, and amrubicin showed impressive single-agent activity in patients with lung cancer. To date, clinical research has defined the current standard chemotherapy for advanced non-small cell lung cancer (NSCLC) as modern platinum-based doublets considered more efficacious than any single regimen and with no added benefit to triplet therapies. However, we have reached an efficacy plateau with these agents. Rearrangement of the drug combination or change of the drug doses and schedules will not result in significant further progress. New, less toxic agents that improve survival and quality of life are clearly needed. In the last three decades, we have gained a growing understanding of the molecular biologic changes and the complex series of cellular signals that allow cancer cells to manifest behavior. This provides an opportunity to develop novel therapies aimed at inhibiting some of these changes and signals. Targeted agents, primarily the epidermal growth factor receptor inhibitors, have led to a new era in the treatment of NSCLC. This paper will review the current status of cytotoxic agents and molecular targeted therapy in lung cancer potential useful in the treatment of the patients.

Anthracyclines↗