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1,2-Bis(Methylsulfonyl)-1-(2-Chloroethyl)-2-[[1-(4-Nitrophenyl)Ethoxy]Carbonyl]Hydrazine: An Anticancer Agent Targeting Hypoxic Cells

Seow, Helen A. ; Penketh, Philip G. ; Shyam, Krishnamurthy ; Rockwell, Sara ; Sartorelli, Alan C. ; Cerami, Anthony

Proceedings of the National Academy of Sciences - PNAS, 2005-06, Vol.102 (26), p.9282-9287 [Periódico revisado por pares]

United States: National Academy of Sciences

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1,2-Bis(Methylsulfonyl)-1-(2-Chloroethyl)-2-[[1-(4-Nitrophenyl)Ethoxy]Carbonyl]Hydrazine: An Anticancer Agent Targeting Hypoxic Cells
Autor: Seow, Helen A. ; Penketh, Philip G. ; Shyam, Krishnamurthy ; Rockwell, Sara ; Sartorelli, Alan C. ; Cerami, Anthony
Assuntos: Aerobic conditions ; Anaerobic conditions ; Animals ; Antineoplastic Agents - pharmacology ; Biological Sciences ; Cancer ; Cell lines ; Cell Survival ; Cells ; CHO Cells ; Chromatography, High Pressure Liquid ; Cricetinae ; Cross-Linking Reagents - pharmacology ; Cytochrome-B Reductase - metabolism ; Cytotoxicity ; DNA - chemistry ; Dose-Response Relationship, Drug ; Drug therapy ; Edetic Acid - chemistry ; Enzymes ; Glutathione - metabolism ; Glutathione Transferase - metabolism ; Hydrazines - pharmacology ; Hypoxia ; Hypoxia - metabolism ; Mice ; Mice, Inbred BALB C ; Models, Chemical ; NAD(P)H Dehydrogenase (Quinone) - metabolism ; NADPH-Ferrihemoprotein Reductase - metabolism ; Neoplasm Transplantation ; Neoplasms - drug therapy ; Neoplasms - pathology ; Nitrogen - metabolism ; Oxygen - metabolism ; Prodrugs ; Sulfhydryl Compounds ; Sulfonamides - pharmacology ; Time Factors ; Treatment Outcome ; Tumor cell line ; Tumors ; Xanthine Oxidase - metabolism ; Zinc - chemistry
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2005-06, Vol.102 (26), p.9282-9287
Notas: ObjectType-Article-2
SourceType-Scholarly Journals-1
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content type line 23
Edited by Anthony Cerami, Kenneth S. Warren Institute, Kitchawan, NY, and approved May 16, 2005
To whom correspondence should be addressed at: Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208066, New Haven, CT 06520. E-mail: alan.sartorelli@yale.edu.
Author contributions: H.A.S., P.G.P., K.S., S.R., and A.C.S. designed research, analyzed data, and wrote the paper; H.A.S., P.G.P., and S.R. performed research; and H.A.S., P.G.P., and K.S. contributed new reagents/analytic tools.
Abbreviations: 90CE, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine; KS119, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine; NBR, NADH:cytochrome b5 reductase; NPR, NADPH:cytochrome P450 reductase; NQO1, NAD(P)H:quinone oxidoreductase 1; PNBC, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-nitrobenzyloxy)carbonyl]hydrazine; XO, xanthine oxidase; GSH, glutathione.
This paper was submitted directly (Track II) to the PNAS office.
The agent described in this article has been licensed by Yale University to Vion Pharmaceuticals, Inc. A.C.S. is a Director and Chairman of the Scientific Advisory Board of Vion Pharmaceuticals. Vion has provided A.C.S.'s laboratory with a relatively small gift; none of these monies were used to support the research described here. Additionally, A.C.S., P.G.P., and K.S. are stockholders in Vion Pharmaceuticals.
Descrição: 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 μM 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 NAD(P)H: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.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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1,2-Bis(Methylsulfonyl)-1-(2-Chloroethyl)-2-[[1-(4-Nitrophenyl)Ethoxy]Carbonyl]Hydrazine: An Anticancer Agent Targeting Hypoxic Cells

Seow, Helen A. ; Penketh, Philip G. ; Shyam, Krishnamurthy ; Rockwell, Sara ; Sartorelli, Alan C. ; Cerami, Anthony

United States: National Academy of Sciences

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