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¹ Lady Davis Institute for Medical Research, SMBD Jewish General Hospital, Montreal, Quebec, Canada; ² Division of Experimental Medicine, Department of Medicine, ³ Department of Pharmacology and Therapeutics, ⁴ Departments of Medicine and Oncology, McGill University, Montreal, Quebec, Canada; and ⁵ Montreal Centre for Experimental Therapeutics in Cancer, Montreal, Quebec, Canada

Requests for reprints:Moulay A. Alaoui-Jamali, Lady Davis Institute for Medical Research, Room 523, Jewish General Hospital, 3755 chemin cote Ste Catherine, Montreal, P.Q., H3T 1E2 Canada. Phone: (514) 340-8222 ext. 3438; Fax: (514) 340-7576. E-mail: malaou{at}po-box.mcgill.ca

Bisperoxovanadium (bpV) compounds are irreversible protein tyrosine phosphatase (PTP) inhibitors with a spectrum of activity distinct from that of vanadium salts. We studied the efficacy of a panel of bpVs as antineoplastic agents in vitro and in vivo with a view to investigating phosphatases as potential antineoplastic targets. The Cdc25A dual-specificity phosphatase is an oncoprotein required for progression through G₁-S. It cooperates with oncogenic Ras to transform cells and is overexpressed in several cancers. Cdc25A is therefore an attractive candidate phosphatase target for the antineoplastic activity of bpV compounds. Cytotoxicity was examined in 28 cancer cell lines and in vivo efficacy was examined in a DA3 murine mammary carcinoma model. In vitro phosphatase assays were used to directly measure phosphatase inhibition, comparing Cdc25A to hVH2/DSP4, leukocyte antigen related/receptor type PTPF catalytic domain (LAR), Yersinia pestis phosphatase (YOPH), and T-cell PTPase/non-receptor type PTP2 (TCPTP). CDK2 activity and Rb phosphorylation were examined by immunocomplex kinase assays and Western blot. Cdc25A is at least 20-fold more sensitive to bpV inhibition than hVH2/DSP4, and 3- to 10- fold more sensitive than TCPTP and LAR. bpV inhibition of Cdc25A in cells leads to CDK2 inactivation and hypophosphorylation Rb, resulting in G₁-S arrest and induction of p53-independent apoptosis. The most cytotoxic analogue, bpV[4,7-dimethyl-1,10-phenanthroline-bisperoxo-oxo-vanadium (Me2Phen)], shows submicromolar IC₅₀s against a panel of cell lines and inhibited tumor growth by 80% in mice. These results demonstrate that bpVs may have significant antineoplastic activity. In addition, they are in vitro and in vivo inhibitors of phosphatases including Cdc25A, suggesting that phosphatases may be appropriate targets for novel antineoplastic agents and that further development of these agents, targeting them to specific phosphatases such as CDC25A, may lead to novel agents with enhanced antineoplastic activity.

Key Words: bisperoxovanadate • vanadate • PTPase • dual-specificity phosphatase • Cdc25

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Grant support:Canadian Institutes of Health Research and the Canadian Breast Cancer Research Initiative. P.J.S. is the recipient of a BCRP Predoctoral Fellowship #DAMD17-02-1-0478 sponsored by the Department of the Army. The U.S. Army Medical Research Acquisition Activity 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office.

Note: The content of this article does not necessarily reflect the position or the policy of the Government of the United States, and no official endorsement should be inferred. Research was conducted in compliance with the Animal Welfare Act Regulations and other Federal statutes relating to animals and experiments involving animals and adheres to the principles set forth in the Guide for Care and Use of Laboratory Animals, National Research Council, 1996.

² P. J. Scrivens, unpublished data.

Received 12/ 2/02; revised 3/25/03; accepted 7/22/03.

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