Current Issue : October - December Volume : 2015 Issue Number : 4 Articles : 6 Articles
Rhenium (I)-diselenother (Re-diselenoether) is a\nwater soluble metal-based compound, combining one atom of\nrhenium and two atoms of selenium. This compound has been\nreported to exhibit marked activities against several solid tumor\ncell lines.We now disclose an improved synthesis of this\ncomplex. The Re-diselenoether showed a potent inhibitory\neffect on MDA-MB231 cell division in vitro, which lasted\nwhen the complex was no longer present in the culture. Rediselenoether\ninduced a remarkable reduction of the volume\nof the primitive breast tumors and of the pulmonary metastases\nwithout clinical signs of toxicity, in mice-bearing a MDAMB231\nLuc+ tumor, orthotopically transplanted, after a daily\noral administration at the dose of 10 mg/kg/d. Interestingly, an\nantagonism was observed when cisplatin was administered as\na single i.p. injection 1 week after the end of the Rediselenoether\nadministration. In an effort to gain insight of\nthe mechanisms of action of Re-diselenoether complex, interaction\nwith 9-methylguanine as a nucleic acid base model was\nstudied. We have shown that Re-diselenoether gave both\nmono- and bis-guanine Re adducts, the species assumed to\nbe responsible for the DNA intrastrand lesions....
The phosphatidylinositol-3 kinase (PI3K) pathway is one of the\nmost frequently activated pathogenic signalling routes in\nhuman cancers, making it a rational and important target for\ninnovative anticancer drug development and precision\nmedicine. The three main classes of PI3K inhibitors currently in\nclinical testing comprise dual pan-Class I PI3K/mTOR inhibitors,\npan-Class I PI3K inhibitors lacking significant mTOR activity and\nisoform-selective PI3K inhibitors. A major step forward in recent\nyears is the progression of over 30 small molecule PI3K inhibitors\ninto clinical trials and the first regulatory approval of the PI3Kd\ninhibitor idelalisib for multiple B-cell malignancies. This review\narticle focuses on the progress made in the discovery and\ndevelopment of novel PI3K inhibitors, with an emphasis on\nantitumour activity and tolerability profiles for agents that have\nentered clinical trials. We also discuss the key issues of drug\nresistance, patient selection approaches and rational targeted\ncombinations. Finally, we envision the future development and\nuse of PI3K inhibitors for the treatment of patients with a range of\nmalignancies....
The healthy immune system protects against infection and\nmalignant transformation without causing significant damage\nto host tissues. Immune dysregulation results in diverse\npathologies including autoimmune disease, chronic\ninflammatory disorders, allergies as well as immune\ndeficiencies and cancer. Phosphoinositide 3-kinase (PI3K)\nsignalling has been shown to be a key pathway in the\nregulation of the immune response and continues to be the\nfocus of intense research. In recent years we have gained\ndetailed understanding of PI3K signalling, and saw the\ndevelopment of potent and highly selective small molecule\ninhibitors, of which several are currently in clinical trials for the\ntreatment of immune-related disorders and cancer. The role\nof PI3K signalling in the immune response has been the\nsubject of detailed reviews; here we focus on relevant recent\nprogress in pre-clinical and clinical development of PI3K\ninhibitors....
microRNAs (miRNA) are small regulatory RNAs exerting\npleiotropic functions in virtually any immune cell-type.\nDozens of miRNAs with a known function in the immune\nsystem constitute interesting drug targets for\nimmunomodulation. Chemical modifications of nucleic acidbased\nmiRNA mimics and inhibitors largely solved instability\nissues but delivery to immune cells remains a major\nchallenge. However, recent success targeting the acidic\ntumor microenvironment is very promising for inflammatory\ndiseases. Moreover, small molecules are being explored as\nan interesting alternative. Although RNA is often considered\nââ?¬Ë?undruggableââ?¬â?¢ by small molecules recent progress\nmodulating miRNA function through small molecules is\nencouraging. Computational approaches even allow\npredictions about specific small molecule/RNA interactions.\nFinally, recent clinical success demonstrates that drugs\ntargeting RNAs work in humans....
Background Although DNA-directed alkylating\nagents and related compounds have been a mainstay in chemotherapeutic\nprotocols due to their ability to readily interfere\nwith the rapid mitotic progression of malignant cells, their\nclinical utility is limited by DNA repair mechanisms and immunosuppression.\nHowever, the same destructive nature of\nalkylation can be reciprocated at the cell surface using novel\nplasma membrane alkylating agents. Results Plasma membrane\nalkylating agents have elicited long term survival in\nmammalian models challenged with carcinomas, sarcomas,\nand leukemias. Further, a specialized group of plasma membrane\nalkylating agents known as tetra-O-acetate\nhaloacetamido carbohydrate analogs (Tet-OAHCs) potentiates\na substantial leukocyte influx at the administration and\nprimary tumor site, indicative of a potent immune response.\nThe effects of plasma membrane alkylating agents may be\nfurther potentiated through the use of another novel class of\nchemotherapeutic agents, known as dihydroxyacetone phosphate\n(DHAP) inhibitors, since many cancer types are known\nto rely on the DHAP pathway for lipid synthesis. Conclusion\nDespite these compelling data, preliminary clinical trials for\nplasma membrane-directed agents have yet to be considered.\nTherefore, this review is intended for academics and clinicians\nto postulate a novel approach of chemotherapy; altering critical\nmalignant cell signaling at the plasma membrane surface\nthrough alkylation, thereby inducing irreversible changes to\nfunctions needed for cell survival....
Rationale Using the drinking-in-the-dark (DID) model, we\ncompared the effects of a novel mu-opioid receptor antagonist,\nGSK1521498, with naltrexone, a licensed treatment of alcohol\ndependence, on ethanol consumption in mice.\nObjective We test the ability of GSK1521498 to reduce alcohol\nconsumption and compare its intrinsic efficacy to that of\nnaltrexone by comparing the two drugs at doses matched for\nequivalent receptor occupancy.\nMethods Thirty-six C57BL/6J mice were tested in a DID procedure.\nIn 2-day cycles, animals experienced one baseline,\ninjection-free session, and one test session when they received\ntwo injections, one of test drug and one placebo. All animals\nreceived GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min\npre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c.\n10 min pre-treatment) in a cross-over design. Receptor\noccupancies following the same doses were determined\nex vivo in separate groups by autoradiography, using\n[3H]DAMGO. Binding in the region of interest was measured\nintegrally by computer-assisted microdensitometry and\ncorrected for non-specific binding.\nResults Both GSK1521498 and naltrexone dose-dependently\ndecreased ethanol consumption. When drug doses were\nmatched for 70ââ?¬â??75 % receptor occupancy, GSK1521498\n3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol\nconsumption than naltrexone 0.1 mg/kg, s.c. Both\nGSK1521498 and naltrexone significantly reduced sucrose\nconsumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test\nof conditioned taste aversion, GSK1521498 (3 mg/kg) reduced\nsucrose consumption 24 h following exposure to a conditioning\ninjection.\nConclusions Both opioid receptor antagonists reduced alcohol\nconsumption but GK1521498 has higher intrinsic efficacy\nthan naltrexone....
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