Selective Apoptotic Antineoplastic Drugs

May 11th, 2011 | Author: Pharmacist

Overview

OSI Pharmaceuticals is pioneering a new approach to the prevention and treatment of cancer with the development of agents termed selective apoptotic antineoplastic drugs. These drugs aim to selectively induce apoptosis in precancerous and cancerous cells.

Mechanism Of Action

Selective apoptotic antineoplastic drugs exert their apoptotic effect by inhibiting cyclic GMP phosphodiesterase (cGMP PDE), an enzyme know to be overex-pressed in precancerous and cancerous cells. Inhibition results in an increase in cellular cGMP, a second messenger molecule that can induce apoptosis through a series of steps involving the activation of protein kinase G, reduction in β-catenin, and activation of caspases.

OSI-461

OSI-461 is a more potent analogue of OSI Pharmaceuticals’ first-generation Selective apoptotic antineoplastic drugs exisulind (Aptosyn), which is in Phase III trials for non-small-cell lung cancer. In 2001, the company initiated three Phase Ha trials of OSI-461 for chronic lymphocytic leukemia, renal cell carcinoma, and hormone-refractory prostate cancer.

Fifteen previously untreated chronic lymphocytic leukemia patients received 400 mg OSI-461 daily for up to 30 weeks. Four of the 15 patients experienced a decline in absolute lymphocyte count (ALC) of more than 50%, and 3 achieved a 25-50% decline in ALC. Responses were observed two to six weeks after initiating treatment. Six patients maintained stable disease and two experienced disease progression. Six additional patients were enrolled in this study at the higher dosage of 800 mg daily. No further clinical data are available at this time.

In February 2004, OSI Pharmaceuticals announced that it had expanded an ongoing Phase I dose-escalating and pharmacokinetic trial of OSI-461 in patients with advanced solid tumors. The company reported that preclinical data demonstrated that administering OSI-461 with food increased the drug exposure levels. The ongoing Phase I study was amended to allow OSI Pharmaceuticals to explore these data. The company stated that although initial antitumor activity was demonstrated in chronic lymphocytic leukemia, it does not believe OSI-461′s optimal dose has been determined.

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Posted in Antineoplastic agents | Tags: ALC

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