Abstract
The synthesis, characterization, in vitro imaging, and cytotoxic properties of a new folate conjugate of rhenium(I) are reported. The conjugate [FA-PEG-BQAV-Re(CO)3]+ (gamma-4) was screened against an adriamycin- and cisplatin-resistant human ovarian cancer cell line (A2780/AD) that overexpresses the folate receptor (FR). Compound gamma-4 was internalized by a folate-receptor-mediated endocytotic pathway, which results in internal accumulation of gamma-4. This was contrasted with a FR-negative Chinese hamster ovary cell line in which no internalization of gamma-4 was observed. gamma-4 was found to be cytotoxic with IC(50) values of 189 and 78 microM at 6 and 24 h, respectively, toward the FR-positive cell line. This is in contrast to the IC(50) value of 502 microM at 6 h and 84 microM at 24 h for cisplatin in the same cell line, with a significantly greater toxicity at the earlier time point. The cytotoxicity of gamma-4 as explained by interactions that occur between the rhenium(I) complex moiety and DNA is described.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CHO Cells
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Carrier Proteins / biosynthesis*
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Carrier Proteins / drug effects*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cricetinae
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Cricetulus
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DNA / chemistry
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DNA / drug effects
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DNA Topoisomerases, Type I / chemistry
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Electrophoretic Mobility Shift Assay / methods
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Female
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Folate Receptors, GPI-Anchored
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Folic Acid / analogs & derivatives
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Folic Acid / chemical synthesis
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Folic Acid / chemistry*
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Humans
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Inhibitory Concentration 50
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Intercalating Agents / chemical synthesis
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Intercalating Agents / chemistry
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Intercalating Agents / pharmacology
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Microscopy, Confocal
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Molecular Structure
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Organometallic Compounds / chemical synthesis
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Organometallic Compounds / chemistry
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Organometallic Compounds / pharmacology*
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Receptors, Cell Surface / biosynthesis*
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Receptors, Cell Surface / drug effects*
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Reverse Transcriptase Polymerase Chain Reaction
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Rhenium / chemistry*
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Structure-Activity Relationship
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Topoisomerase I Inhibitors
Substances
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Carrier Proteins
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Folate Receptors, GPI-Anchored
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Intercalating Agents
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Organometallic Compounds
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Receptors, Cell Surface
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Topoisomerase I Inhibitors
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Rhenium
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DNA
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Folic Acid
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DNA Topoisomerases, Type I