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New drug shows promise as powerful anticancer agent

Research published in the March issue of the journal Cancer Cell describes a small molecule inhibitor of polo-like kinase1 (Plk1) that could lead to a new avenue for targeted cancer therapy. The compound, ON01910, is a potent inhibitor of human tumors in a mouse model system and has low toxicity. The results of this study have led to clinical evaluation of this compound in phase I clinical trials.

Plk1 is a molecule that plays a key role in driving cell division. High levels of Plk1 have been observed in many human tumors, and studies using various laboratory techniques have shown that inhibition of Plk1activity leads to cell death. "Because all signaling pathways that have gone awry in a cancer cell ultimately affect cell proliferation, a reasonable approach to cancer therapy is to develop inhibitors that block the function of a critical molecule that is required by a tumor cell to complete cell division," explains lead author Dr. E. Premkumar Reddy from Temple University School of Medicine. "One such molecule appears to be Plk1."

Dr. Reddy and colleagues examined the effects of Plk1 inhibitor ON01910 on tumor growth in several animal models. The researchers found that ON01910 arrests cell division in a variety of human cancer cells, including cells that are notoriously resistant to commonly used chemotherapeutic agents. The compound significantly inhibited a wide variety of human tumors, including liver, breast, and pancreatic cancers that were grown in mice. ON01910 was also highly effective and, in many cases, strongly synergistic when tested in combination with other chemotherapeutic agents. Studies examining normal human cells show that, in contrast to tumor cells, they are not influenced by ON01910.

The authors suggest that because ON01910 is highly effective in combination with other chemotherapies and appears to be nontoxic, it may be beneficial for treatment of some advanced cancers that are resistant to conventional therapies. "Clin ical studies, which are currently in progress, should reveal the best way to utilize ON01910 in human cancer therapy," writes Dr. Reddy.

The other members of the research team include Kiranmai Gumireddy, M.V. Ramana Reddy, Stephen C. Cosenza, R. Boomi Nathan, Stacey J. Baker, Nabisa Papathi, and E. Premkumar Reddy of Temple University School of Medicine; and Jiandong Jiang and James Holland of Mount Sinai School of Medicine. This work was supported by grants from Onconova Therapeutics Inc. and the Fels Foundation. This work was supported by a grant from Onconova Therapeutics Inc. drug discovery program, and E.P.R. and M.V.R.R. are stockholders of Onconova Therapeutics Inc. E.P.R., S.C.C., and M.V.R.R. are consultants to Onconova Therapeutics Inc.

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Kiranmai Gumireddy, M.V. Ramana Reddy, Stephen C. Cosenza, R. Boomi Nathan, Stacey J. Baker, Nabisa Papathi, Jiandong Jiang, James Holland, and E. Premkumar Reddy: "ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent"

Publishing in Cancer Cell, Volume 7, Number 3, March 2005, pages 275-286. http://www.cancercell.org


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Source:Cell Press


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