A review on α-mangostin as a potential multi-target-directed ligand for Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive memory loss, declining language skills and other cognitive disorders. AD has brought great mental and economic burden to patients, families and society. However due to the complexity of AD's pathology, drugs developed for the treatment of AD often fail in clinical or experimental trials. The main problems of current anti-AD drugs are low efficacy due to mono-target method or side effects, especially high hepatotoxicity. To tackle these two main problems, multi-target-directed ligand (MTDL) based on "one molecule, multiple targets" has been studied. MTDLs can regulate multiple biological targets at the same time, so it has shown higher efficacy, better safety. As a natural active small molecule, α-mangostin (α-M) has shown potential multi-factor anti-AD activities in a series of studies, furthermore it also has a certain hepatoprotective effect. The good availability of α-M also provides support for its application in clinical research. In this work, multiple activities of α-M related to AD therapy were reviewed, which included anti-cholinesterase, anti-amyloid-cascade, anti-inflammation, anti-oxidative stress, low toxicity, hepatoprotective effects and drug formulation. It shows that α-M is a promising candidate for the treatment of AD.

Efficacy, Stability, and Safety Evaluation of New Polyphenolic Xanthones Towards Identification of Bioactive Compounds to Fight Skin Photoaging.

Antioxidants have long been used in the cosmetic industry to prevent skin photoaging, which is mediated by oxidative stress, making the search for new antioxidant compounds highly desirable in this field. Naturally occurring xanthones are polyphenolic compounds that can be found in microorganisms, fungi, lichens, and some higher plants. This class of polyphenols has a privileged scaffold that grants them several biological activities. We have previously identified simple oxygenated xanthones as promising antioxidants and disclosed as hit, 1,2-dihydroxyxanthone (1). Herein, we synthesized and studied the potential of xanthones with different polyoxygenated patterns as skin antiphotoaging ingredients. In the DPPH antioxidant assay, two newly synthesized derivatives showed IC50 values in the same range as ascorbic acid. The synthesized xanthones were discovered to be excellent tyrosinase inhibitors and weak to moderate collagenase and elastase inhibitors but no activity was revealed against hyaluronidase. Their metal-chelating effect (FeCl3 and CuCl2) as well as their stability at different pH values were characterized to understand their potential to be used as future cosmetic active agents. Among the synthesized polyoxygenated xanthones, 1,2-dihydroxyxanthone (1) was reinforced as the most promising, exhibiting a dual ability to protect the skin against UV damage by combining antioxidant/metal-chelating properties with UV-filter capacity and revealed to be more stable in the pH range that is close to the pH of the skin. Lastly, the phototoxicity of 1,2-dihydroxyxanthone (1) was evaluated in a human keratinocyte cell line and no phototoxicity was observed in the concentration range tested.

Virtual screening, Docking, ADMET and System Pharmacology studies on Garcinia caged Xanthone derivatives for Anticancer activity.

Caged xanthones are bioactive compounds mainly derived from the Garcinia genus. In this study, a structure-activity relationship (SAR) of caged xanthones and their derivatives for anticancer activity against different cancer cell lines such as A549, HepG2 and U251 were developed through quantitative (Q)-SAR modeling approach. The regression coefficient (r2), internal cross-validation regression coefficient (q2) and external cross-validation regression coefficient (pred_r2) of derived QSAR models were 0.87, 0.81 and 0.82, for A549, whereas, 0.87, 0.84 and 0.90, for HepG2, and 0.86, 0.83 and 0.83, for U251 respectively. These models were used to design and screened the potential caged xanthone derivatives. Further, the compounds were filtered through the rule of five, ADMET-risk and synthetic accessibility. Filtered compounds were then docked to identify the possible target binding pocket, to obtain a set of aligned ligand poses and to prioritize the predicted active compounds. The scrutinized compounds, as well as their metabolites, were evaluated for different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Finally, the top hit compound 1G was analyzed by system pharmacology approaches such as gene ontology, metabolic networks, process networks, drug target network, signaling pathway maps as well as identification of off-target proteins that may cause adverse reactions.

Antidiabetic potential of polyherbal formulation DB14201: Preclinical development, safety and efficacy studies.

ETHNOPHARMACOLOGICAL RELEVANCE: The poly-herbal formulation DB14201 is a new combination of ayurvedic ingredients for treatment of diabetes. The aim of present study was to investigate safety and in vivo efficacy of DB14201 extract. Further this work was aimed to develop, characterize and standardize DB14201 extract and develop it as a botanical drug. MATERIALS AND METHODS: The polyherbal extract was standardized using four chemical markers. The LC-MS/MS method was developed for identification and quantification of mangiferin, berberine, kaempferol and curcumin. The extract was standardized for heavy metal content, aflotoxins, and microbial tests. The mechanism of action of DB14201 extract was explored through glucose uptake by adipocytes, TNF-α production and free fatty acid release, in vitro, was studied using murine adipocytes (3T3-L1). The effect of extract on insulin release was evaluated using murine pancreatic beta cell (ß TC-6). The safety and in vivo efficacy of extract was studied using suitable animal model. Hematology and blood biochemistry parameters were also assessed. RESULTS: In vitro studies of DB14201 in murine adipocytes and murine pancreatic beta cells demonstrated the plausible mechanism of action of DB14201 could be through increase in glucose uptake and by stimulation of insulin release by RIN-5f cells. The microbial load, heavy metals were found to be within the AYUSH permissible limits and aflotoxins were absent. Preclinical efficacy studies in animal models proved the anti-diabetic potential of the extract. The preclinical acute dose toxicity study and 90-days repeated dose toxicity study of DB14201 extract in wistar rats by oral route indicated that the extract is safe up to 1000mg/kg dose. Hematology and blood biochemistry parameters were within the normal range. CONCLUSIONS: The data presented herein demonstrated anti-diabetic potential of developed DB14201 extract and this study will serve as the benchmark for the further research on this polyherbal formulation.

Anticarcinogenic Effects of α-Mangostin: A Review.

Cancer chemoprevention is a promising strategy taken to block, reverse, or retard carcinogenesis. α-Mangostin, a natural xanthone isolated from the pericarps of mangosteen, represents one of the most studied chemopreventive agents. This compound has been reported to interfere with all the major stages of carcinogenesis: initiation, promotion, and progression. A number of mechanisms have been proposed for its anticarcinogenic activities. This review summarizes the current knowledge on the mechanisms that contribute to the observed activity of α-mangostin related to (i) modulation of carcinogenic biotransformation and mitigation of oxidative damage, (ii) induction of growth arrest and apoptosis, (iii) suppression of angiogenesis and metastasis, and (iv) combination with clinical chemotherapy drugs enhancing their efficacy and decreasing the toxic side effects. In addition, pharmacokinetic and toxicological studies of α-mangostin have also been highlighted in this review. Despite an overwhelming amount of knowledge in preclinical studies, there was almost no translation of α-mangostin into the clinic. It is hoped that continuous extensive and profound research will lead to the application of α-mangostin from experimental studies to evidence-based, clinically applicable pharmacotherapy.

Rhodomyrtone as a potential anti-proliferative and apoptosis inducing agent in HaCaT keratinocyte cells.

Psoriasis is a skin disease associated with hyperproliferation and abnormal differentiation of keratinocytes. Available approaches using synthetic drugs for the treatment of severe psoriasis may cause side effects. Alternatively, plant-derived compounds are now receiving much attention as alternative candidates for the treatment of psoriasis. In this study, the effects of rhodomyrtone, a bioactive plant extract isolated from Rhodomyrtus tomentosa leaves on the proliferation, growth arrest, and apoptosis of HaCaT keratinocytes were investigated. Percentage anti-proliferative activity of rhodomyrtone on HaCaT cells at concentrations of 2-32µg/ml after 24, 48, and 72h ranged from 13.62-61.61%, 50.59-80.16%, and 61.82-85.34%, respectively. In a scratch assay, rhodomyrtone at 2 and 4µg/ml significantly delayed closure of a wound by up to 61.78%, and 71.65%, respectively, after 24h incubation. HaCaT keratinocytes treated with rhodomyrtone showed chromatin condensation and fragmentation of nuclei when stained with Hoechst 33342. This indicated that rhodomyrtone induced apoptosis in the keratinocytes. In addition, flow cytometric analysis demonstrated an increase in the percentage of apoptosis of keratinocytes after treatment with rhodomyrtone at 2-32µg/ml from 1.2-10%, 8.2-35.4%, and 21.0-77.8% after 24, 48, and 72h, respectively, compared with the control. To further develop the compound as a potential anti-psoriasis agent, a rhodomyrtone formulation was prepared and subjected to skin irritation tests in rabbits. The formulation caused no skin irritation including such as erythema and edema. The results indicated that rhodomyrtone had the potential as a promising candidate for further development as a natural anti-psoriasis agent.

Gambogic acid-loaded pH-sensitive mixed micelles for overcoming breast cancer resistance.

Multidrug resistance (MDR) is one of the major obstacles to the successful treatment of breast cancer. The overexpression of drug efflux transporters such as P-glycoprotein (P-gp) and of anti-apoptotic proteins like survivin are the major causes of MDR. Here, we developed a gambogic acid (GA)-loaded mixed micelle system made of poly(ethylene glycol)-poly(L-histidine)-poly(D,L-lactide-co-glycolide) (PEG-pHis-PLGA) and D-α-tocopheryl polyethylene glycol 1000 (TPGS) that is potentially useful for overcoming MDR by integrating the beneficial effects of pH-sensitive behavior, P-gp inhibition, and down-regulation of anti-apoptotic proteins. The therapeutic potential and mechanism of action of GA-loaded pH-sensitive mixed micelles were examined in drug-sensitive human breast MCF-7 and drug-resistant MCF-7/ADR cells. The resulting GA-loaded mixed micelles with an average size of 190.1 nm were stable at pH 7.4, but dissociated rapidly in a weakly acidic environment (pH 5.5). The GA-loaded mixed micelles increased the cell cytotoxicity against both MCF-7 and MCF-7/ADR cells, which was associated with enhanced apoptosis. In addition, the GA-loaded mixed micelles down-regulated the expression of the anti-apoptotic proteins survivin and Bcl-2, and inhibited the expression and activity of P-gp in MCF-7/ADR cells. Our results indicate that this system could overcome drug resistant in breast cancer by targeting distinct mechanisms, which may facilitate the translation of the GA-mediated effects into clinical benefits.

A review of the efficacy of dietary polyphenols in experimental models of inflammatory bowel diseases.

Crohn's disease and ulcerative colitis presently have no cure and are treated with anti-inflammatory drugs or monoclonal antibodies targeting pro-inflammatory cytokines. A variety of rodent models have been used to model chronic and acute colitis. Dietary polyphenols in foods and botanicals are of considerable interest for prevention and treatment of colitis. Many dietary polyphenols have been utilized for prevention of colitis in rodent models. Berries, green tea polyphenols, curcumin, and stilbenes have been the most extensively tested polyphenols in rodent models of colitis. The majority of polyphenols tested have inhibited colitis in rodents, but increasing doses of EGCG and green tea, isoflavones, flaxseed, and α-mangostin have exacerbated colitis. Few studies have examined combination of polyphenols or other bioactives for inhibition of colitis. Translating polyphenol doses used in rodent models of colitis to human equivalent doses reveals that supplemental doses are most likely required to inhibit colitis from a single polyphenol treatment. The ability to translate polyphenol treatments in rodent models is likely to be limited by species differences in xenobiotic metabolism and microbiota. Given these limitations, data from polyphenols in rodent models suggests merit for pursuing additional clinical studies for prevention of colitis.

Dietary α-mangostin, a xanthone from mangosteen fruit, exacerbates experimental colitis and promotes dysbiosis in mice.

SCOPE: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. α-Mangostin (α-MG), the most abundant xanthone in mangosteen fruit, exerts anti-inflammatory and antibacterial activities in vitro. We evaluated the impact of dietary α-MG on murine experimental colitis and on the gut microbiota of healthy mice. METHODS AND RESULTS: Colitis was induced in C57BL/6J mice by administration of dextran sulfate sodium (DSS). Mice were fed control diet or diet with α-MG (0.1%). α-MG exacerbated the pathology of DSS-induced colitis. Mice fed diet with α-MG had greater colonic inflammation and injury, as well as greater infiltration of CD3(+) and F4/80(+) cells, and colonic myeloperoxidase, than controls. Serum levels of granulocyte colony-stimulating factor, IL-6, and serum amyloid A were also greater in α-MG-fed animals than in controls. The colonic and cecal microbiota of healthy mice fed α-MG but no DSS shifted to an increased abundance of Proteobacteria and decreased abundance of Firmicutes and Bacteroidetes, a profile similar to that found in human UC. CONCLUSION: α-MG exacerbated colonic pathology during DSS-induced colitis. These effects may be associated with an induction of intestinal dysbiosis by α-MG. Our results suggest that the use of α-MG-containing supplements by patients with UC may have unintentional risk.

Absorption, tissue distribution, tissue metabolism and safety of α-mangostin in mangosteen extract using mouse models.

The commercially available herbal products as the form of extract were usually mixtures containing various compounds. In spite of the purported efficacy in each active constituent, the coexisting constituents in the herbal extract might interfere with the efficacy and safety and affect the pharmacokinetic properties of active constituents. To compare for the pharmacokinetic properties of α-mangostin, a major bioactive compound, in mangosteen extract and pure α-mangostin, the pharmacokinetics as well as tissue distribution, in vitro metabolism, plasma protein binding and safety evaluation were conducted in mice because a mouse model is required a small amount of compounds and useful to develop disease models. The absorption of α-mangostin was increased and hepatic metabolism of α-mangostin was decreased in mice treated with mangosteen extract. However, the intestinal metabolism α-mangostin is comparable and still extensive in mice treated with α-mangostin and mangosteen extract. Intraperitorial LC50 of α-mangostin and mangosteen extract was 150 and 231 mg/kg, respectively. These findings may be valuable to explain the different pharmacokinetics and safety of α-mangostin and mangosteen extract. Furthermore, these findings are useful to design the efficacy and safety investigation of α-mangostin or mangosteen extract in mice with disease models or combination therapies to extrapolate into the clinical levels.

An open-labeled, randomized, multicenter phase IIa study of gambogic acid injection for advanced malignant tumors.

BACKGROUND: Gambogic acid is a pure active compound isolated from the traditional Chinese medicinal plant gamboge (Garcinia morella Desv.). Based on the preliminary results of a phase I study, this phase IIa study compared the efficacy and safety of different dosage schedules of gambogic acid in patients with advanced malignant tumors. METHODS: Patients with advanced or metastases cancer who had not received any effective routine conventional treatment or who had failed to respond to the existing conventional treatment were randomly assigned to receive either 45 mg/m(2) gambogic acid intravenously from Days 1 to 5 of a 2-week cycle (Group A), or 45 mg/m(2) every other day for a total of five times during a 2-week cycle (Group B). The primary endpoint was objective response rate (ORR). RESULTS: Twenty-one patients assigned to Group A and 26 to Group B were included in the final analysis. The ORRs were 14.3% in Group A and 0% in Group B. It was not possible to analyze the significant difference because one of the values was zero. The disease control rates (DCRs) were 76.2% in Group A and 61.5% in Group B (P = 0.0456). The observed adverse reactions were mostly Grades I and II, and occurred in most patients after administration of the trial drug. There was no significant difference in the incidence of adverse reactions between the two arms. CONCLUSIONS: The preliminary results of this phase IIa exploratory study suggest that gambogic acid has a favorable safety profile when administered at 45 mg/m(2). The DCR was greater in patients receiving gambogic acid on Days 1 - 5 of a 2-week cycle, but the incidence of adverse reactions was similar irrespective of the administration schedule.

Reducing effect of mangiferin on serum uric acid levels in mice.

CONTEXT: Mangiferin, a natural bioactive xanthone C-glycoside, is widely present in medicinal plants like the leaf of Mangifera indica L. (Anacardiaceae). It has been reported that mangiferin possesses a variety of biological activities, including antidiabetic, hepatoprotective, anti-inflammatory, antioxidant, and anticarcinogenic. OBJECTIVE: The hypouricemic effect and xanthine oxidoreductase (XOR) inhibitory activity of mangiferin were investigated here for the first time. MATERIALS AND METHODS: The hypouricemic effect of mangiferin was investigated in normal and hyperuricemic mice induced by potassium oxonate. Mangiferin at a dose of 0.75-100.0 mg/kg was given intragastrically to mice. The serum urate levels were determined using the phosphotungstic acid method. The hepatic activities of xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) in hyperuricemic mice were assayed using commercially available kits. RESULTS: The results showed that mangiferin at a dose of 1.5, 3.0, and 6.0 mg/kg significantly reduced the serum urate levels (148.7 ± 37.8, 142.2 ± 44.5, 121.7 ± 21.7 µmmol/L) in hyperuricemic mice, compared with untreated hyperuricemic mice (201.8 ± 71.2 µmmol/L). However, mangiferin did not decrease the serum urate levels in normal mice until mangiferin was up to 100 mg/kg. In addition, the hepatic activities of XDH in hyperuricemic mice were significantly decreased by mangiferin, while no changes of XOD were observed. Acute toxicity study in mice showed that mangiferin was very safe at a dose of up to 25 g/kg. DISCUSSION AND CONCLUSION: These findings demonstrate that mangiferin has the potential to be developed as a new therapeutic agent for the treatment of hyperuricemia and gout.

The safety and tolerability of intravenous ASA404 when administered in combination with docetaxel (60 or 75 mg/m²) in Japanese patients with advanced or recurrent solid tumors.

OBJECTIVE: This Phase I study was carried out to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of the flavonoid tumor-vascular disrupting agent ASA404 (vadimezan) in combination with docetaxel in Japanese patients with advanced or recurrent solid tumors. METHODS: Nine Japanese patients were given ASA404 (1800 mg/m(2)) plus two doses of docetaxel, 60 or 75 mg/m(2), administered every 3 weeks. RESULTS: Dose-limiting toxicity of Grade 3 febrile neutropenia was observed in one patient during Cycle 1 at Level 2 of ASA404 (1800 mg/m(2)) and docetaxel (75 mg/m(2)) treatment. The most frequently reported adverse events were neutropenia, fatigue, alopecia, decreased appetite, constipation and injection site pain. These adverse events were mainly Grade 1 or 2 in severity and, with the exception of injection site pain, were typically associated with docetaxel therapy. A partial response was observed in one patient, and five patients (55.6%) exhibited stable disease. Overall, the study demonstrated that ASA404 has an acceptable tolerability profile when combined with docetaxel at doses up to 75 mg/m(2) in Japanese patients with advanced solid tumors. CONCLUSIONS: The study supports the enrollment of Japanese patients in the Phase III study (ATTRACT-2) of ASA404 in combination with docetaxel for the second-line treatment of advanced non-small cell lung cancer. Clinicaltrials.gov identifier: NCT01285453.

Cardiovascular toxicity profiles of vascular-disrupting agents.

BACKGROUND: Vascular-disrupting agents (VDAs) represent a new class of chemotherapeutic agent that targets the existing vasculature in solid tumors. Preclinical and early-phase trials have demonstrated the promising therapeutic benefits of VDAs but have also uncovered a distinctive toxicity profile highlighted by cardiovascular events. METHODS: We reviewed all preclinical and prospective phase I-III clinical trials published up to August 2010 in MEDLINE and the American Association of Cancer Research and American Society of Clinical Oncology meeting abstracts of small-molecule VDAs, including combretastatin A4 phosphate (CA4P), combretastatin A1 phosphate (CA1P), MPC-6827, ZD6126, AVE8062, and ASA404. RESULTS: Phase I and II studies of CA1P, ASA404, MPC-6827, and CA4P all reported cardiovascular toxicities, with the most common cardiac events being National Cancer Institute Common Toxicity Criteria (version 3) grade 1-3 hypertension, tachyarrhythmias and bradyarrhythmias, atrial fibrillation, and myocardial infarction. Cardiac events were dose-limiting toxicities in phase I trials with VDA monotherapy and combination therapy. CONCLUSIONS: Early-phase trials of VDAs have revealed a cardiovascular toxicity profile similar to that of their vascular-targeting counterparts, the angiogenesis inhibitors. As these agents are added to the mainstream chemotherapeutic arsenal, careful identification of baseline cardiovascular risk factors would seem to be a prudent strategy. Close collaboration with cardiology colleagues for early indicators of serious cardiac adverse events will likely minimize toxicity while optimizing the therapeutic potential of VDAs and ultimately enhancing patient outcomes.

Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer.

PURPOSE: This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 (vadimezan), when combined with first-line platinum-based chemotherapy, improves survival in patients with advanced non-small-cell lung cancer (NSCLC) versus chemotherapy alone. PATIENTS AND METHODS: Patients with advanced stage IIIB or IV NSCLC, stratified by sex and tumor histology, were randomly assigned 1:1 to paclitaxel (200 mg/m(2)) and carboplatin (area under the curve, 6.0) with or without ASA404 (1,800 mg m(2)), given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: One thousand two hundred ninety-nine patients were randomly assigned. The trial was stopped for futility at interim analysis. At final analysis, there was no difference in OS seen between ASA404 (n = 649) and placebo (n = 650) arms: median OS was 13.4 and 12.7 months respectively (hazard ratio [HR], 1.01; 95% CI, 0.85 to 1.19; P = .535). Similarly, no OS difference was seen in the histologic (squamous or nonsquamous) and sex (male or female) strata. Median PFS was 5.5 months in both arms (HR, 1.04; P = .727), while ORR was 25% in both arms (P = 1.0). Overall rate of adverse events (AEs) was comparable between the ASA404 and placebo arms. Grade 4 neutropenia (27% v 19%) and infusion site pain (10% v 0.5%) were reported more frequently in the ASA404 arm. CONCLUSION: The addition of ASA404 to carboplatin and paclitaxel, although generally well tolerated, failed to improve frontline efficacy in advanced NSCLC.

Clinical trials of vascular disrupting agents in advanced non--small-cell lung cancer.

Tumor vascular disrupting agents (VDAs), such as the flavonoid compound ASA404 and the tubulin-binding compound combretastatin, selectively disrupt established tumor blood vessels, inhibit tumor blood flow, and induce extensive necrosis at the core of solid tumors. A rationale for combining tumor VDAs with standard chemotherapy for treating advanced non-small-cell lung cancer (NSCLC) includes their complementary actions on different spatial regions of solid tumors and their additive or synergistic preclinical activity in animal models of lung cancer. A randomized, phase II, multicenter, open-label trial with a single-arm extension phase evaluated outcomes in a total of 104 patients (> 18 years of age) with histologically confirmed stage IIIb or stage IV, previously untreated NSCLC that in this trial was treated with ASA404 plus standard chemotherapy vs. standard chemotherapy alone. Adding ASA404 to standard chemotherapy numerically improved tumor response, time to disease progression, and overall survival in this phase II trial, without significantly increasing the incidence or severity of side effects. Other randomized phase II and phase III clinical trials of ASA404 and combretastatin combined with standard chemotherapy in advanced NSCLC are currently ongoing or will be reported shortly.

Phase II study on the addition of ASA404 (vadimezan; 5,6-dimethylxanthenone-4-acetic acid) to docetaxel in CRMPC.

PURPOSE: This randomized phase II study evaluated ASA404 (vadimezan; 5,6-dimethylxanthenone-4-acetic acid) in combination with docetaxel in castration-refractory metastatic prostate cancer (CRMPC). EXPERIMENTAL DESIGN: Seventy-four patients with histopathologically confirmed CRMPC previously untreated with chemotherapy were randomized to receive either

Phase II study of ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800mg/m(2) combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer.

This single-arm phase II study evaluated the tumor-vascular disrupting agent ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800mg/m(2) plus standard therapy of carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). This ASA404 dose is 50% higher than that used in previous phase II studies. Thirty patients with histologically confirmed stage IIIb or IV NSCLC previously untreated with chemotherapy received carboplatin AUC 6mg/mlmin plus paclitaxel 175mg/m(2) plus ASA404 1800mg/m(2) every 21 days for up to six cycles. The addition of ASA404 1800mg/m(2) to standard therapy produced little change in the systemic exposure of either total or free carboplatin or paclitaxel, and was generally well-tolerated, with no cardiac serious adverse events or clinically relevant ophthalmic abnormalities. The best overall tumor response was partial response, which was seen in 37.9% of patients by independent assessment and in 46.7% by investigator assessment. Stable disease was seen in 48.3% of patients by independent assessment and in 43.3% by investigator assessment. Median time to tumor progression was 5.5 months by investigator assessment and median survival was 14.9 months. The data from this trial corroborate findings from a recent randomized phase II trial, which suggested improvements in efficacy variables, including survival, when ASA404 1200mg/m(2) was added to standard therapy for advanced NSCLC. The manageable safety profile, lack of adverse pharmacokinetic interactions and efficacy outcomes seen in this single-arm study suggest that ASA404 1800mg/m(2) is a viable dose for future combination studies.

Transient retinal effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA, ASA404), an antitumor vascular-disrupting agent in phase I clinical trials.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an anticancer vascular-disrupting agent, has induced transient visual symptoms in some patients. Exploratory investigations were undertaken to characterize the visual disturbances in two consecutive phase I trials. METHODS: Assessments were made in 21 patients before and immediately after a 20-minute IV infusion of DMXAA, including visual acuity, funduscopy, color discrimination, pattern electroretinography (PERG), pattern visual-evoked potentials (VEP), and full-field electroretinography (ERG). Evaluation of late effects was undertaken subsequently in 12 patients before and after 6 weeks of IV DMXAA at one dose per week. RESULTS: Frequency and intensity of transient visual disturbance increased with DMXAA dose, occurring in two thirds of patients at 3000 mg x m(-2). Symptoms included blurring, flickering, fragmentation, alteration of colors, and contrast and mild photosensitivity, starting during the infusion and resolving completely, usually within 60 minutes. Visual acuity was unchanged but color discrimination was perturbed. Dose-dependent increases in PERG P50 implicit time by up to 23 ms returned toward baseline values within 90 minutes. Prominent transient changes on ERG included prolonged scotopic rod and 30-Hz flicker implicit times and reduced 30-Hz flicker amplitude. In the second trial, no clinically significant sustained effects were detected, although an increase in bright flash a-wave implicit time (P = 0.022) was seen on whole-group analysis. In vitro studies showed nonspecific phosphodiesterase inhibition by DMXAA. CONCLUSIONS: DMXAA induced acute, transient disturbance of retinal activity consistent with phosphodiesterase inhibition. No clinically significant cumulative effects were noted and most effects occurred at doses higher than those used in ongoing clinical trials (ClinicalTrials.gov numbers, NCT00856336, NCT00863733, and NCT00003697).