Systematic discovery of multicomponent therapeutics

Multicomponent therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of medicine, including cancer, infectious diseases, and CNS disorders. We have developed a high-throughput screening method for identifying effective combinations of therapeutic compounds. We report here that systematic screening of combinations of small molecules reveals unexpected interactions between compounds, presumably due to interactions between the pathways on which they act. Through systematic screening of ≈120,000 different two-component combinations of reference-listed drugs, we identified potential multicomponent therapeutics, including (i) fungistatic and analgesic agents that together generate fungicidal activity in drug-resistant Candida albicans, yet do not significantly affect human cells, (ii) glucocorticoid and antiplatelet agents that together suppress the production of tumor necrosis factor-α in human primary peripheral blood mononu-clear cells, and (iii) antipsychotic and antiprotozoal agents that do not exhibit significant antitumor activity alone, yet together prevent the growth of tumors in mice. Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways and, when performed with reference-listed drugs, may result in the discovery of new combination drug regimens.

[1]  S. Loewe,et al.  Die quantitativen Probleme der Pharmakologie , 1928 .

[2]  L. Goodman,et al.  The Pharmacological Basis of Therapeutics , 1941 .

[3]  S. Loewe.  The problem of synergism and antagonism of combined drugs. , 1953, Arzneimittel-Forschung.

[4]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[5]  A. Chadli.  THE CANCER CELL , 1924, La Presse medicale.

[6]  Barry H. Smith,et al.  A continuous tumor‐cell line from a human lung carcinoma with properties of type II alveolar epithelial cells , 1976, International journal of cancer.

[7]  D. Spach.  Antimicrobial therapy. , 1977, JAMA.

[8]  A. J. Garrett,et al.  Characteristics of a serially propagated human diploid cell designated MRC-9. , 1979, Journal of biological standardization.

[9]  M C Berenbaum,et al.  Criteria for analyzing interactions between biologically active agents. , 1981, Advances in cancer research.

[10]  Paul Talalay,et al.  Analysis of combined drug effects: a new look at a very old problem , 1983 .

[11]  R. Ralph,et al.  Chlorpromazine: a potential anticancer agent? , 1984, Biochemical and biophysical research communications.

[12]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.

[13]  D. Marshak,et al.  Drug-protein interactions: binding of chlorpromazine to calmodulin, calmodulin fragments, and related calcium binding proteins. , 1985, Biochemistry.

[14]  J. Lazo,et al.  Increased lethality of calmodulin antagonists and bleomycin to human bone marrow and bleomycin-resistant malignant cells. , 1986, Cancer research.

[15]  J. Lazo,et al.  Antitumor and toxic effects of combination chemotherapy with bleomycin and a phenothiazine anticalmodulin agent. , 1988, Journal of the National Cancer Institute.

[16]  Berenbaum Mc.  What is synergy? , 1989, Pharmacological reviews.

[17]  Interferon response to dipyridamole in lupus erythematosus patients , 1989, The British journal of dermatology.

[18]  R. Tidwell,et al.  Structure and DNA binding activity of analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) , 1992, Journal of medicinal chemistry.

[19]  A. Pantazaki,et al.  Chlorpromazine-induced damage on nucleic acids: a combined cytogenetic and biochemical study. , 1992, Mutation research.

[20]  AC Tose.  Cell , 1993, Cell.

[21]  L. Chauvelot‐Moachon,et al.  Inhibition of human monocyte TNF production by adenosine receptor agonists. , 1993, Life sciences.

[22]  J. M. Requena,et al.  Binding of Pt-pentamidine to nucleosomal DNA. Studies of the antiproliferative activity of the drug against human cancer cells. , 1993, Chemico-biological interactions.

[23]  Z. S. Wang,et al.  Dexamethasone and cyclosporin A suppress mast cell-leukocyte cytokine cascades by multiple mechanisms. , 1995, International archives of allergy and immunology.

[24]  J. Rex,et al.  Resistance of Candida species to fluconazole , 1995, Antimicrobial agents and chemotherapy.

[25]  Y. Kitamura,et al.  Inhibition of constitutive nitric oxide synthase in the brain by pentamidine, a calmodulin antagonist. , 1995, European journal of pharmacology.

[26]  G. Zhanel,et al.  Phenazopyridine in Urinary Tract Infections , 1996, The Annals of pharmacotherapy.

[27]  K. E. Newhouse.  Goodman and Gilman's The Pharmacological Basis of Therapeutics , 1986, The Yale Journal of Biology and Medicine.

[28]  T. Greten,et al.  Endogenous Adenosine Curtails Lipopolysaccharide‐Stimulated Tumour Necrosis Factor Synthesis , 1997, Scandinavian journal of immunology.

[29]  J. Steer,et al.  Glucocorticoid modulation of human monocyte/macrophage function: Control of TNF-α secretion , 1997, Inflammation Research.

[30]  M. Badet-Denisot,et al.  Effects of pentamidine on polyamine level and biosynthesis in wild-type, pentamidine-treated, and pentamidine-resistant Leishmania. , 1997, Experimental parasitology.

[31]  M. Piccart,et al.  Paclitaxel activity, dose, and schedule: data from phase III trials in metastatic breast cancer. , 1999, Seminars in oncology.

[32]  M. Socinski.  The current status of adjuvant chemotherapy for resected non-small cell lung cancer. , 1999, Seminars in oncology.

[33]  Pumin Zhang,et al.  The cell cycle and development: redundant roles of cell cycle regulators. , 1999, Current opinion in cell biology.

[34]  Abraham Weizman,et al.  Effects of psychotropic drugs on cell proliferation and differentiation. , 1999, Biochemical pharmacology.

[35]  Lenz,et al.  Chemical ligands, genomics and drug discovery. , 2000, Drug discovery today.

[36]  E. Deitch,et al.  Adenosine inhibits IL-12 and TNF-a production via adenosine A 2 a receptor-dependent and independent mechanisms , 2000 .

[37]  L. Marnett,et al.  Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Gibbs.  Mechanism-based target identification and drug discovery in cancer research. , 2000, Science.

[39]  T. Hunter,et al.  Oncogenic kinase signalling , 2001, Nature.

[40]  K. Mokbel,et al.  From HER2 to Herceptin , 2001, Current medical research and opinion.

[41]  L. Ellis,et al.  Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. , 2001, Cancer research.

[42]  J. Steer,et al.  Targets of glucocorticoid action on TNF-α release by macrophages , 2001, Inflammation Research.

[43]  B. Druker,et al.  STI571 (Gleevec) as a paradigm for cancer therapy. , 2002, Trends in molecular medicine.

[44]  H. Kitano.  Systems Biology: A Brief Overview , 2002, Science.

[45]  Susumu Goto,et al.  The KEGG databases at GenomeNet , 2002, Nucleic Acids Res..

[46]  A. Ullrich,et al.  Smart drugs: tyrosine kinase inhibitors in cancer therapy. , 2002, Cancer cell.

[47]  Beat Ernst,et al.  Drug discovery today. , 2003, Current topics in medicinal chemistry.

[48]  S. Lehnert.  In vivo toxicity of phenothiazines to cells of a transplantable tumor , 2004, Cancer Chemotherapy and Pharmacology.