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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Sartorelli, Alan C. Rockwell, Sara Penketh, Philip G. Shyam, Krishnamurthy Seow, Helen A. |
| Description | Author Affiliation: Seow HA ( Department of Pharmacology and Therapeutic Radiology, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.); |
| Abstract | To target malignant cells residing in hypoxic regions of solid tumors, we have designed and synthesized prodrugs generating the cytotoxic alkylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE) after bioreductive activation. We postulate that one of these agents, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119), requires enzymatic nitro reduction to produce 90CE, whereas another agent, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-nitrobenzyloxy)carbonyl]hydrazine (PNBC), can also be activated by nucleophilic attack by thiols such as glutathione (GSH)/GST. We demonstrated that these agents selectively kill hypoxic EMT6 mouse mammary carcinoma and CHO cells. In hypoxia, 50 microM KS119 produced 5 logs of kill of EMT6 cells without discernable cytotoxicity in air; similar effects were observed with CHO cells. PNBC was less efficacious against hypoxic tumor cells and also had some toxicity to aerobic cells, presumably because of GST/thiol activation, making PNBC less interesting as a selective hypoxic-cell cytotoxin. BALB/c mice with established EMT6 solid tumors were used to demonstrate that KS119 could reach and kill hypoxic cells in solid tumors. To gain information on bioreductive enzymes involved in the activation of KS119, cytotoxicity was measured in CHO cell lines overexpressing NADH:cytochrome b5 reductase (NBR), NADPH:cytochrome P450 reductase (NPR), or NADPH: quinone oxidoreductase 1 (NQO1). Increased cytotoxicity occurred in cells overexpressing NBR and NPR, whereas overexpressed NQO1 had no effect. These findings were supported by enzymatic studies using purified NPR and xanthine oxidase to activate KS119. KS119 has significant potential as a hypoxia-selective tumor-cell cytotoxin and is unlikely to cause major toxicity to well oxygenated normal tissues. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 26 |
| Volume Number | 102 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2005-06-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antineoplastic Agents Pharmacology Hydrazines Anoxia Neoplasms Drug Therapy Pathology Sulfonamides Animals CHO Cells Cell Survival Chromatography, High Pressure Liquid Cricetinae Cross-Linking Reagents Cytochrome-B(5) Reductase Metabolism DNA Chemistry Dose-Response Relationship, Drug Edetic Acid Glutathione Glutathione Transferase Mice Mice, Inbred BALB C Models, Chemical NAD(P)H Dehydrogenase (Quinone) NADPH-Ferrihemoprotein Reductase Neoplasm Transplantation Nitrogen Oxygen Sulfhydryl Compounds Time Factors Xanthine Oxidase Zinc Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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