High Antitumor Activity Research Articles

Characterization and In Vitro Evaluation of Cytotoxicity, Antimicrobial and Antioxidant Activities of Chitosans Extracted from Three Different Marine Sources.

Chitins in the α and β isomorphs were extracted from three Tunisian marine sources shrimp (Penaeus kerathurus) waste, crab (Carcinus mediterraneus) shells and cuttlefish (Sepia officinalis) bones. The obtained chitins were transformed into chitosans, the acid-soluble form of chitin. Chitosans were characterized and their biological activities were compared. Chitosan samples were then characterized by Fourier transform infrared spectroscopy (FTIR). The results showed that all chitosans presented identical spectra. Antimicrobial, antioxidant, and antitumor activities of the extracted chitosans were investigated. In fact, cuttlefish chitosan showed the highest DPPH radical-scavenging activity (83 %, 5 mg/ml), whereas it was 79 % and 76 % for shrimp and crab chitosans, respectively. However, in linoleate-β-carotene system, cuttlefish and crab chitosans exerted higher antioxidant activity (82 % and 70 %, respectively), than shrimp chitosan (49 %). Chitosans were tested for their antimicrobial activities against three Gram-negative and four Gram-positive bacteria and five fungi. Chitosans markedly inhibited growth of most bacteria and fungi tested, although the antimicrobial activity depends on the type of microorganism and on the source of chitin. In addition, chitosans showed high antitumor activity which seemed to be dependent on the chitosan characteristics such as acetylation degree and especially the molecular weight.

Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse.

Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable mechanism of antitumor activity and hematological toxicity. The objective of this study was to examine the TFT incorporation into tumor- and white blood cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT effect on the colony formation of mouse bone marrow cells was also investigated. Pharmacokinetics of TFT was determined in nude mice after single oral administration of TAS-102, while the antitumor activity and body weight change were evaluated in the tumor-bearing nude mice after multiple oral administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay. TFT systemic exposure in plasma increased dose-dependently. The tumor growth rate and body weight gain decreased dose-dependently, but TFT concentrations in the DNA of tumor tissues and white blood cells increased dose-dependently. TFT inhibited colony formation of bone marrow cells in a concentration-dependent manner. A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy.

Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL.

7010 Background: Adult patients (pts) with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) have dismal prognosis. We previously reported high anti-tumor activity of autologous T cel...

Facile construction of dual-bioresponsive biodegradable micelles with superior extracellular stability and activated intracellular drug release

It is still a major challenge for targeted cancer chemotherapy to design stable biodegradable micellar drug delivery systems which show a rapid and complete intracellular drug release. Here, reversibly core-crosslinked pH-responsive biodegradable micelles were developed based on poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate-co-pyridyl disulfide carbonate) [PEG-P(TMBPEC-co-PDSC)] copolymers and investigated for intracellular doxorubicin (DOX) release. PEG-P(TMBPEC-co-PDSC) copolymers formed micelles with a small size of 58.6nm were readily crosslinked by the addition of dithiothreitol (DTT). Notably, in vitro release studies showed that under physiological conditions only ca. 19.9% of DOX was released from the reversibly crosslinked micelles in 24h at a low micelle concentration of 40μg/mL. The release of DOX was accelerated at pH5.0 or in the presence of 10mM glutathione (GSH) at pH7.4, in which 64.2% and 44.1% of DOX was released, respectively, in 24h. The drug release was further boosted at pH5.0 and 10mM GSH, with 98.8% of DOX released in 12h. Moreover, DOX release was also facilitated by a 4h incubation at pH5.0 followed by incubation at pH7.4 with 10mM GSH. Confocal microscopy indicated that DOX was delivered and released into the nuclei of RAW 264.7 cells following a 12h incubation with DOX-loaded reversibly crosslinked micelles. MTT assays revealed that DOX-loaded reversibly crosslinked micelles had much higher antitumor activity than irreversibly crosslinked controls, with low IC50 values of 1.65 and 1.14μg/mL for HeLa and RAW 264.7 cells, respectively, following a 48h incubation. The blank crosslinked micelles had a low cytotoxicity of up to a concentration of 0.8mg/mL. These reversibly crosslinked pH-sensitive biodegradable micelles with superior extracellular stability but activated intracellular drug release provide a novel platform for tumor-targeting drug delivery.

IL-33/ST2 activation of IL-9-secreting T cells alters the balance of fatal immunity and tumor immunity (TRAN1P.926)

Abstract Allogeneic hematopoietic cell transplantation (HCT) is the most potent curative therapy for cancers of the bone marrow; however, graft-versus-host disease (GVHD) continues to be the major limitation to successful HCT, with mortality rates around 50%. Current strategies to suppress GVHD also compromise the beneficial graft-versus-tumor (GVT) activity. We have shown that elevated IL-33-sequestering soluble ST2 in the plasma is a risk factor for severe GVHD. In addition, the IL-9-secreting Th9 and Tc9 cell subsets have higher antitumor activity than Th1 and Tc1. We hypothesized that induction of the ST2/IL-33 pathway will both alleviate GVHD and increase GVT activity. Differentiation of Th9 with IL-33 increased expression of membrane ST2 (ST2L) and PU.1, a transcription factor that promotes IL-9 production. Adoptive transfer of IL-33-treated Th9 cells with bone marrow cells in HCT murine models showed less severe GVHD compared to Th9 without IL-33, or Th2 cells that are protective of GVHD. Polarization of total T cells with IL-33 to IL-9 secreting cells showed that IL-9 was also increased in Tc9 cells via Th9 help. Transcriptome analysis of IL-33-T9 cells showed increased expression of genes with anti-tumor activity. Higher GVT activity with IL-33-T9 cells was demonstrated in models of GFP+MLL-AF9 acute myeloid leukemia. Human IL-33-T9 cells also showed a strong anti-leukemia cytolytic activity. Thus, IL-33-T9 cells represent a promising curative cellular therapy following HCT.

475. Phase I Clinical Trial of Autologous CD19-Targeted 19-28z CAR T Cells in Adult Patients With Relapsed or Refractory B-ALL

Adult patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) have a dismal prognosis with a median overall survival (OS) < 6 months. Salvage chemotherapy is ineffective and often induces only a transient remission. We previously reported high anti-tumor activity of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (CAR) targeting CD19 antigen in adult patients with ALL (Davila M et al. Sci Transl Med 2014). Herein, we report updated results and long-term outcome from our phase I clinical trial of 19-28z CAR T cells in adult patients with R/R ALL (NCT01044069). Adult patients with R/R B-ALL were enrolled, and underwent leukapheresis. T cells were transduced with a gamma-retroviral vector encoding a CAR construct composed of anti-CD19 scFv linked to CD28 and CD3ζ signaling domains (19-28z). All patients received lymphodepleting chemotherapy followed 2 days later by 1-3 x106 CAR T cells/kg. Bone marrow (BM) biopsy was performed immediately prior to T cell infusion for disease status assessment. 28 patients (pts) have been treated to date. The median age was 55 years (range, 23-74). 9 pts (32%) had Ph+ B-ALL (T315I mutation in 3 pts), 8 pts (29%) had prior allogeneic stem cell transplant (allo-SCT), and 22 pts (78%) had either primary refractory disease or CR1 duration of <12 months. Of the 28 pts, 27 pts were evaluable for response. At the time of 19-28z CAR T cell infusion, 14 of 27 evaluable pts had morphologic disease (>5% blasts in BM) and 13 pts had minimal residual disease (MRD). 24 of 27 pts (89%) were in complete remission (CR) following the 19-28z CAR T cell infusion; 11 of these pts had morphologic disease at the time of T cell infusion, and 13 pts had MRD. 21 of 24 CR (88%) was MRD negative. A median time to CR was 22.5 days (range, 9-33). 10 pts successfully underwent allo-HSCT following the 19-28z CAR T cell therapy. The median follow-up is 6 months (range, 1-38 months) with 15 pts having at least 6 months of follow-up. Responses appear durable with 12 pts remaining disease-free, including 7 pts without subsequent allo-SCT. Median OS of all pts is 8.5 months. While none of the 13 pts with MRD at the time of T cell infusion developed significant cytokine release syndrome (CRS), 5 of 15 pts with morphologic disease developed severe CRS that required either vasopressors or mechanical ventilation for hypoxia, successfully managed with corticosteroid and/or IL-6R inhibitor. Treatment with 19-28z CAR T cells can induce a high CR rate of 89% in these heavily pretreated adult pts with R/R ALL regardless of the disease risk characteristics including Ph+ status, age, pre-T cell disease burden, prior allo-SCT, and CR1 duration. While CRS can develop following T cell infusion, the risk of CRS predictably correlates with the disease burden and can successfully be managed with corticosteroid and/or IL-6R inhibitor. These findings support the use of 19-28z CAR T cells in adult pts with R/R ALL and warrant a further investigation in a larger phase 2 trial.

Study of the use possibility of the chemical-biological adduct of the 1,1-bis-[5-bromopyrimidine-2’,4’-diono-1’-il]-2-bromo-2’-chloroethylene and bacterial lectin for the treatment of the Pliss’ lymphosarcoma

Aim. Study of the pyrimidine metabolism antimetabolites that can be preformed compounds in the link of biosynthetic processes and can brake tumour’s growth is a more successful, perspective finding direction of new antitumor medications. New original chemical-biological adduct was studied as potential antitumor agent.Methods and results. It was obtained on the base of 1,1-bis-[5-bromopyrimidine-2’,4’-diono-1’-il]-2-bromo-2’-chloroethylene and antitumour bacterial lectin from Bacillus polymyxa. It was found that new chemical-biological adduct of bis-derivative of pyrimidine and bacterial lectin has little toxic preparation (LD50=635 mg/kg) and demonstrates considerable antitumour effect upon to 65.5% on Pliss Limphosarcoma tumour.Conclusion. It confirms that new chemical-biological adduct is perspective for the future investigation as substance with a little toxicity and high antitumour activity on the Pliss Limphosarcoma.

Eribulin synergizes with Polo-like kinase 1 inhibitors to induce apoptosis in rhabdomyosarcoma

Eribulin, a novel microtubule-interfering drug, was recently shown to exhibit high antitumor activity in vivo against various pediatric cancers. Here, we identify a novel synthetic lethal interaction of Eribulin together with Polo-like kinase 1 (PLK1) inhibitors against rhabdomyosarcoma (RMS) in vitro and in vivo. Eribulin and the PLK1 inhibitor BI 2536 at subtoxic concentrations synergize to induce apoptosis in RMS cells as confirmed by calculation of combination index (CI). Also, Eribulin/BI 2536 co-treatment is significantly more effective than monotherapy to reduce cell viability and inhibit colony formation of RMS cells. Similarly, Eribulin and BI 2536 act in concert to trigger apoptosis in a primary, patient-derived ARMS culture, underscoring the clinical relevance of this combination. Importantly, Eribulin and BI 2536 cooperate to suppress tumor growth in an in vivo model of RMS. On molecular grounds, Eribulin/BI 2536 co-treatment causes profound mitotic arrest, which is critically required for synergism, since inhibition of mitotic arrest by CDK1 inhibitor RO-3306 abolishes Eribulin/BI 2536-mediated apoptosis. Eribulin and BI 2536 cooperate to activate caspase-9, -3 and -8, which is necessary for apoptosis induction, since the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) reduces Eribulin/BI 2536-induced apoptosis significantly, yet partially. Intriguingly, knockdown of endonuclease G (ENDOG) also significantly inhibits Eribulin/BI 2536-triggered apoptosis, demonstrating the involvement of both caspase-dependent and -independent effector pathways. Synergistic induction of apoptosis is similarly found for Eribulin/BI 2536 co-treatment in neuroblastoma cells and for the combination of vincristine (another antimicrotubule chemotherapeutic) with Poloxin (another PLK1 inhibitor), thus pointing to a broader significance of this concomitant microtubule- and PLK1-targeting strategy for pediatric oncology. In conclusion, the identification of a novel synthetic lethality by dual targeting of mitosis using microtubule-interfering and PLK1-targeted drugs, i.e. Eribulin and BI 2536, has important implications for the development of more effective treatment strategies for RMS.

New Member of Organic Ligand Functionalized TMSP: Synthesis, Characterized and Properties of Na15[(MnII(COOH))3(AsW9O33)2]·15H2O

Reaction of [Mn12(CH3COO)16(H2O)4O12]·2CH3COOH·4H2O and Na9[AsW9O33]·19.5H2O in aqueous solution leads to the isolation of a new carboxy group decorated TMSP, Na15[(MnII(COOH))3(AsW9O33)2]·15H2O (1). The structure of 1 was characterized by elemental analysis, thermometric analysis and single crystal X-ray diffraction (Crystal data for 1: Trigonal, P-3, a = 12.8804(4) A, b = 12.8804(4) A, c = 30.3501(19) A, V = 4360.6(3) A3, Z = 2). Structural analysis reveals that 1 represents the first example of carboxy group decorated arsenotungstate. Antitumor study indicates that compound 1 possesses high antitumor activity against Hela cells. In addition, the magnetic properties of 1 were also investigated.

A novel peptide for efficient siRNA delivery in vitro and therapeutics in vivo

Small interfering RNA (siRNA) shows great therapeutic potential due to its ability to regulate gene expression in a highly selective manner. However, its application has been limited by ineffective cellular uptake of siRNAs. To achieve successful gene-silencing efficiency, a safe and effective delivery vector is generally required. In this study, we designed a series of amphipathic peptides that comprised a variant of a nuclear localization sequence, 0–6 histidine residues and an optional stearic acid group. Among these candidates, STR-HK exhibited good characteristics as a safe and efficient siRNA delivery vector, facilitating efficient siRNA delivery to mammalian cells without causing cytotoxicity. Moreover, the intratumoral injection of STR-HK/siRNA complexes achieved high anti-tumor activity through the downregulation of the Bcl-2 protein in mice, with an inhibition rate of 62.8%. Our data demonstrate that STR-HK is a highly promising siRNA delivery vector for therapeutic applications.

FRI-10 MITOMYCIN-C: HISTORICAL ASPECTS OF THE DISCOVERY OF MOST COMMONLY USED CHEMOTHERAPY AGENT IN UROLOGY

You have accessJournal of UrologyHistory of Urology Forum I1 Apr 2015FRI-10 MITOMYCIN-C: HISTORICAL ASPECTS OF THE DISCOVERY OF MOST COMMONLY USED CHEMOTHERAPY AGENT IN UROLOGY Hemant Nemade, Hussein Tukmatchy, and Peter Thompson Hemant NemadeHemant Nemade More articles by this author , Hussein TukmatchyHussein Tukmatchy More articles by this author , and Peter ThompsonPeter Thompson More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.488AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Although urology is primarily a surgical speciality, evolution of pharmacotherapy over time has revolutionised the treatment of certain disorders. Endoscopic resection was the only treatment that was available for superficial bladder tumours, till the development of intravesical instillation of chemotherapeutic agents. The discovery and introduction of mitomycin C into urological field is researched in this presentation. METHODS Material per taining to early treatment of bladder cancer was reviewed. Correspondences with Japanese companies where the discovery was made also contributed immensely to the research. RESULTS The mitomycins are a family of aziridine-containing products isolated from Streptomyces species. After discovery of penicillin by Fleming, there was an interest in isolating substances from microorganisms that were capable of killing other bacteria. Japan, after its defeat in the WWII, was keen to be a frontrunner in development of newer antibiotics. Dr. Kitasato founder of Kitasato Institute laid the foundation of early development of microbiology and pharmacology. Dr Toju Hata (1908-2004), after serving in the army during the War, joined Kitasato Institute to pursue his interest in microbiology. His hard work paid results as in 1953, he discovered the antibiotic Leucomycin. In 1956, Hata isolated mitomycin-A & mitomycin-B from Steptomyces caespitosus that had antibiotic & antitumour activities. Dr Hata along with Dr Shigetoshi Wakagi from Kyowa Hakko Kogyo company later reported the isolation of mitomycin-C from the same fermentation broth at a higher pH and that this compound had much higher antitumour activity. After the success of intravesical therapy using Thiotepa in 1961 by Jones and Swinney, Dr Shida and his colleagues reported in a Japanese journal the use of mitomycin C. Because of lesser side-effects and its efficacy, mitomycin-C became the most popular agent for intravesical therapy for superficial bladder cancer. CONCLUSIONS The discovery of mitomycin C is interesting as it was being isolated as an antibiotic but found to have antineoplastic properties. Its success in reducing the recurrence had made it the most commonly used chemotherapeutic agent in urology. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e585 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hemant Nemade More articles by this author Hussein Tukmatchy More articles by this author Peter Thompson More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PH-Responsive chimaeric pepsomes based on asymmetric poly(ethylene glycol)-b-poly(l-leucine)-b-poly(l-glutamic acid) triblock copolymer for efficient loading and active intracellular delivery of doxorubicin hydrochloride.

pH-Responsive chimaeric polypeptide-based polymersomes (refer to as pepsomes) were designed and developed from asymmetric poly(ethylene glycol)-b-poly(l-leucine)-b-poly(l-glutamic acid) (PEG-PLeu-PGA, PEG is longer than PGA) triblock copolymers for efficient encapsulation and triggered intracellular delivery of doxorubicin hydrochloride (DOX·HCl). PEG-PLeu-PGA was conveniently prepared by sequential ring-opening polymerization of l-leucine N-carboxyanhydride and γ-benzyl-l-glutamate N-carboxyanhydride using PEG-NH2 as an initiator followed by deprotection. Pepsomes formed from PEG-PLeu-PGA had unimodal distribution and small sizes of 64-71 nm depending on PLeu block lengths. Interestingly, these chimaeric pepsomes while stable at pH 7.4 were quickly disrupted at pH 5.0, likely due to alternation of ionization state of the carboxylic groups in PGA that shifts PGA blocks from hydrophilic and random coil structure into hydrophobic and α-helical structure. DOX·HCl could be actively loaded into the watery core of pepsomes with a high loading efficiency. Remarkably, the in vitro release studies revealed that release of DOX·HCl was highly dependent on pH, in which about 24.0% and 75.7% of drug was released at pH 7.4 and 5.0, respectively, at 37 °C in 24 h. MTT assays demonstrated that DOX·HCl-loaded pepsomes exhibited high antitumor activity, similar to free DOX·HCl in RAW 264.7 cells. Moreover, they were also potent toward drug-resistant MCF-7 cancer cells (MCF-7/ADR). Confocal microscopy studies showed that DOX·HCl-loaded pepsomes delivered and released drug into the cell nuclei of MCF-7/ADR cells in 4 h, while little DOX·HCl fluorescence was observed in MCF-7/ADR cells treated with free drug under otherwise the same conditions. These chimaeric pepsomes with facile synthesis, efficient drug loading, and pH-triggered drug release behavior are an attractive alternative to liposomes for targeted cancer chemotherapy.

Synthesis and Biological Activity of New 3-Ethyl-2-Thioxo-2,3-Dihydro-1H-Spiro[Benzo[h]-Quinazolin-5,1′-Cyclohexane]-4(6H)-One Derivatives

2-Sulfanyl-substituted 3-ethyl-3H-spiro[benzo[h]quinazolin-5,1-cyclohexane]-4(6H)-ones were synthesized by reacting 3-ethyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazolin-5,1-cyclohexane]-4(6H)-one with halides. 2-Hydrazino-3-ethyl-3H-spiro[benzo[h]quinazolin-5,1-cyclohexane]-4(6H)-one was prepared from 3-ethyl-2-methylthio-3H-spiro[benzo[h]quinazolin-5,1-cyclohexane]-4(6H)-one and transformed into 1-sulfanyl-substituted triazolobenzoquinazolines. Several of the synthesized compounds exhibited high anti-monoamine oxidase and antitumor activity.

Synthesis and evaluation of new salicylaldehyde-2-picolinylhydrazone Schiff base compounds of Ru(II), Rh(III) and Ir(III) as in vitro antitumor, antibacterial and fluorescence imaging agents.

Reaction of salicylaldehyde-2-picolinylhydrazone (HL) Schiff base ligand with precursor compounds [{(p-cymene)RuCl2}2] 1, [{(C6H6)RuCl2}2] 2, [{Cp*RhCl2}2] 3 and [{Cp*IrCl2}2] 4 yielded the corresponding neutral mononuclear compounds 5-8, respectively. The in vitro antitumor evaluation of the compounds 1-8 against Dalton's ascites lymphoma (DL) cells by fluorescence-based apoptosis study and by their half-maximal inhibitory concentration (IC50) values revealed the high antitumor activity of compounds 3, 4, 5 and 6. Compounds 1-8 render comparatively lower apoptotic effect than that of cisplatin on model non-tumor cells, i.e., peripheral blood mononuclear cells (PBMC). The antibacterial evaluation of compounds 5-8 by agar well-diffusion method revealed that compound 6 is significantly effective against all the eight bacterial species considered with zone of inhibition up to 35 mm. Fluorescence imaging study of compounds 5-8 with plasmid circular DNA (pcDNA) and HeLa RNA demonstrated their fluorescence imaging property upon binding with nucleic acids. The docking study with some key enzymes associated with the propagation of cancer such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II revealed strong interactions between proteins and compounds 5-8. Conformational analysis by density functional theory (DFT) study has corroborated our experimental observation of the N, N binding mode of ligand. Compounds 5-8 exhibited a HOMO (highest occupied molecular orbital)-LUMO (lowest unoccupied molecular orbital) energy gap 2.99-3.04 eV. Half-sandwich ruthenium, rhodium and iridium compounds were obtained by treatment of metal precursors with salicylaldehyde-2-picolinylhydrazone (HL) by in situ metal-mediated deprotonation of the ligand. Compounds under investigation have shown potential antitumor, antibacterial and fluorescence imaging properties. Arene ruthenium compounds exhibited higher activity compared to that of Cp*Rh/Cp*Ir in inhibiting the cancer cells growth and pathogenic bacteria. At a concentration 100 µg/mL, the apoptosis activity of arene ruthenium compounds, 5 and 6 (~30 %) is double to that of Cp*Rh/Cp*Ir compounds, 7 and 8 (~12 %). Among the four new compounds 5-8, the benzene ruthenium compound, i.e., compound 6 is significantly effective against the pathogenic bacteria under investigation.

Total syntheses and biological evaluation of miuraenamides.

The miuraenamides, relatively simple representatives of a class of cyclodepsipeptides with high antitumor activity, can be easily and flexibly obtained by the concept of peptide modification. A reaction sequence consisting of an aldol reaction, oxidation, and methylation of the glycine subunit of the cyclodepsipeptides allows the incorporation of the unusual α,β-unsaturated dehydroamino acid in one of the last steps of the synthesis.

Search for new antitumor compounds among n-glycoside indolo[2,3-a]carbazole derivatives

The study investigated antitumor activity of 10 new compounds in the series of N-glycosides of indolo[2,3-a] carbazoles. The results identified strong antitumor activity of compounds LCS-1208, LCS -1054, LCS -999 and LCS-1006 against lymphocytic leukemia P-388 (ILS=85 - 119%). Glycosides LCS-1208, LCS-999 and LCS-1006 exhibited high antitumor activity immediately after treatment for Lewis epidermoid lung carcinoma LLC (TGI =90%). In addition, the antitumor effect after LCS-999 and LCS-1006 treatment kept on for 10 days, and LCS-1208 - for 15 days. Glycoside LCS-1208 had a therapeutic efficiency on melanoma B-16 for 7 days (TGI=91 - 58%). Thus, the study of relation «structure-activity» in a series of derivatives of N-glycosides of indolo[2,3-a]carbazoles allowed to select highly effective compound LCS-1208 for preclinical studies.

Ginsenoside Rg3-induced EGFR/MAPK pathway deactivation inhibits melanoma cell proliferation by decreasing FUT4/LeY expression.

Malignant melanoma is a destructive and lethal form of skin cancer with poor prognosis. An effective treatment for melanoma is greatly needed. Ginsenoside Rg3 is a herbal medicine with high antitumor activity. It is reported that abnormal glycosylation is correlated with the tumor cell growth. However, the antitumor effect of Rg3 on melanoma and its mechanism on regulating glycosylation are unknown. We found that Rg3 did not only inhibit A375 melanoma cell proliferation in a dose-dependent manner, but also decreased the expression of fucosyltransferase IV (FUT4) and its synthetic product Lewis Y (LeY), a tumor-associated carbohydrate antigen (TACA). Knocking down FUT4 expression by siRNA dramatically reduced FUT4/LeY level and inhibited cell proliferation through preventing the activation of EGFR/MAPK pathway. Consistently, the inhibitory effect of the Rg3 and FUT4 knockdown on melanoma growth was also seen in a xenograft melanoma mouse model. In conclusion, Rg3 effectively inhibited melanoma cell growth by downregulating FUT4 both in vitro and in vivo. Targeting FUT4/LeY mediated fucosylation by Rg3 inhibited the activation of EGFR/MAPK pathway and prevented melanoma growth. Results from this study suggest Rg3 is a potential novel therapy agent for melanoma treatment.

Enzymatically and reductively degradable α-amino acid-based poly(ester amide)s: synthesis, cell compatibility, and intracellular anticancer drug delivery.

A novel and versatile family of enzymatically and reductively degradable α-amino acid-based poly(ester amide)s (SS-PEAs) were developed from solution polycondensation of disulfide-containing di-p-toluenesulfonic acid salts of bis-l-phenylalanine diesters (SS-Phe-2TsOH) with di-p-nitrophenyl adipate (NA) in N,N-dimethylformamide (DMF). SS-PEAs with Mn ranging from 16.6 to 23.6 kg/mol were obtained, depending on NA/SS-Phe-2TsOH molar ratios. The chemical structures of SS-PEAs were confirmed by (1)H NMR and FTIR spectra. Thermal analyses showed that the obtained SS-PEAs were amorphous with a glass transition temperature (Tg) in the range of 35.2-39.5 °C. The in vitro degradation studies of SS-PEA films revealed that SS-PEAs underwent surface erosion in the presence of 0.1 mg/mL α-chymotrypsin and bulk degradation under a reductive environment containing 10 mM dithiothreitol (DTT). The preliminary cell culture studies displayed that SS-PEA films could well support adhesion and proliferation of L929 fibroblast cells, indicating that SS-PEAs have excellent cell compatibility. The nanoparticles prepared from SS-PEA with PVA as a surfactant had an average size of 167 nm in phosphate buffer (PB, 10 mM, pH 7.4). SS-PEA nanoparticles while stable under physiological environment undergo rapid disintegration under an enzymatic or reductive condition. The in vitro drug release studies showed that DOX release was accelerated in the presence of 0.1 mg/mL α-chymotrypsin or 10 mM DTT. Confocal microscopy observation displayed that SS-PEA nanoparticles effectively transported DOX into both drug-sensitive and -resistant MCF-7 cells. MTT assays revealed that DOX-loaded SS-PEA nanoparticles had a high antitumor activity approaching that of free DOX in drug-sensitive MCF-7 cells, while more than 10 times higher than free DOX in drug-resistant MCF-7/ADR cells. These enzymatically and reductively degradable α-amino acid-based poly(ester amide)s have provided an appealing platform for biomedical technology in particular controlled drug delivery applications.

Isolation of novel indole diterpenes and dihydrodibenzofuran from the marine fungus &lt;i&gt;Aspergillus&lt;/i&gt; sp.

Twelve secondary metabolites were earlier isolated from two marine-derived fungal strains, Aspergillus sp. AF-119 and Aspergillus sp. JQG a-6f. The objectives of this investigation were to isolate and purify natural products produced in these fungi, and identify possible drug candidates. The chemical structures of these compounds were elucidated and characterized by the analysis of 1D and 2D NMR spectra, UV, optical rotation and massspectroscopy data. Three of the isolated compounds are novel derivatives of indole diterpenes (1&amp; 2), and dihydrodibenzofuran, namely, 9-hydroxy-7-methyl-2, 3-dihydrodibenzo [b, d] furan-1, 4-dione (3). The rest of the compounds were also determined from spectroscopy data to be known. These included three indole diterpenes – paspalinine (4), paspalicine (5) and paspaline (6); two ditetopiperazines –fumitremorgin B and lanosulin (7 &amp; 8); methyl 2,8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1 carboxylate (9); 1,3,8-trihydroxy-6-methylanthracene-9,10- dione (10); terphenyl (11) and 2-(3-chloro-2-hydroxyphenyl)-5-hydroxy-3,7,8-trimethoxy-4H-chromen-4-one (12). Paper disc diffusion assays showed that the novel compounds exhibit antibacterial activity on S. aureus, B. subtilis, and E. coli, but no activity on C. niger. MTT assays showed that the three novel compounds have antibacterial activity in vitro. These findings further enhanced the concept that natural products synthesized by marine-derived fungi possessed high structural diversity, antimicrobial and antitumor activities. Hence, they are a rich resource for drug discovery.Keywords: Marine Fungi; Natural product; Indole diterpenes; Cytotoxicity Assay

High-molecular weight star conjugates containing docetaxel with high anti-tumor activity and low systemic toxicity in vivo

The star polymer-docetaxel conjugates exert a much higher therapeutic activity and yet a lower systemic toxicity than free DTX.