title: Methotrexate-gelonin conjugate - an inhibitor of MCF-7 cells expressing the dihydrofolate receptor.
abstract: An immunotoxin composed of gelonin, a basic ribosome-inactivating protein, type I of 30 kDa, isolated from the seeds of the Indian plant Gelonium multiflorum and methotrexate (MTX) has been studied as a potential tool of gelonin delivery into the cytoplasm of MTX-responsive cells. On the average, about five molecules of methotrexate were chemically coupled to gelonin via an N-hydroxysuccinimide ester of the drug. The MTX-gelonin conjugate was able to reduce the viability of MCF-7 cells in a dose-dependent manner with ID50 of 10 nm, whereas gelonin or MTX alone showed none or very little effects. Besides its ribosome-inactivating activity, which is about ten-fold lower in an in vitro translation assay (IC50 of 50.5 ng/ml as compared to 4.6 ng/ml), the conjugate also significantly induced direct and oxidative DNA damage as shown by the alkaline comet assay. Hence, MTX-gelonin conjugates are promising candidates for the treatment of MTX-responsive cancers.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Badr
authors.forename: Christian
authors.initials: C
authors.lastname: Kopp
authors.forename: Sandra
authors.initials: S
authors.lastname: Theison
authors.forename: Jennifer
authors.initials: J
authors.lastname: Meyer
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Trommer
mesh_terms: D000595:Amino Acid Sequence; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000032:analysis; D005492:Folic Acid / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis / Q000187:drug effects; D054789:Ribosome Inactivating Proteins, Type 1 / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D058973:Folate Receptors, GPI-Anchored; D005493:Folic Acid Antagonists; D000922:Immunotoxins; D054789:Ribosome Inactivating Proteins, Type 1; C010920:dihydrofolate; C025674:GEL protein, Gelonium multiflorum; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate