ALL,
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Cell Pathways Confirms Method of Identifying Novel Compounds That Trigger Selective Apoptosis in Precancerous and Cancerous Cells
The Method Involves the Mechanism of Action of PREVATAC(tm) (Exisulind) and Other Cell Pathways' Compounds
HORSHAM, Penn.--(BW HealthWire)--Dec. 11, 1998-- In response to the publication of one of their European Patent Applications, Cell Pathways, Inc. (Nasdaq:CLPA - news) today confirmed the mechanism of action underlying its novel investigational drug, PREVATAC(tm) (exisulind), and other compounds under development at the company.
The published application states that compounds, like exisulind, which inhibit a cyclic GMP phosphodiesterase and cell growth, and induce apoptosis (programmed cell death), but do not inhibit COX pathways, are potentially useful for the treatment of precancerous and cancerous lesions.
This is also the subject of a corresponding patent which was allowed by and will issue very shortly from the U.S. patent office. Cell Pathways plans to provide full details on its scientific findings in a peer reviewed journal and at major scientific meetings in the first half of 1999.
''Exisulind acts via a mechanism we began to uncover several years ago. This mechanism involves a previously undescribed phosphodiesterase (PDE) that specifically degrades cyclic GMP (cGMP), similar to members of the PDE5 gene family. This new PDE, which is the subject of additional pending patent applications, is involved in regulating apoptosis in neoplastic (precancerous and cancerous) cells,'' said Rifat Pamukcu, M.D., chief scientific officer at Cell Pathways.
''This finding was exciting in that none of the known proteins regulating apoptosis, such as p53, bcl2 and bax, were involved. We found in a human colon cancer cell line that, when inhibited, this novel cGMP-PDE causes a rise in cellular cGMP levels and a subsequent drop in cyclic AMP (cAMP) levels resulting in apoptosis.
''In contrast, other inhibitors of PDE5, such as sildenifil (Viagra(tm)), do not inhibit the novel enzyme and do not induce apoptosis. Therefore, exisulind represents a new class of selective inhibitors of the novel cGMP-PDE. In fact, we recruited Dr. Joe Thompson, one of the original discoverers of cGMP-PDEs, as our vice president of research to develop further this important discovery.''
Dr. Thompson added, ''Targeting the new cGMP-PDE, our research group has discovered compounds that have up to 20,000 times the apoptotic potency of exisulind. Like exisulind, these new compounds affect neoplastic cells without inducing apoptosis in normal cells in cell culture.
Exisulind is in human clinical trials now, and has shown similar selectivity in such trials as it did in cell culture. One of our new compounds, CP461, which is up to 100 times more potent than exisulind in vitro, will be entering clinical trials in 1999.''
Cyclic GMP and cyclic AMP are key signaling molecules in cells. They mediate messages from the outside world to within the cell. Cell Pathways' scientists hypothesize that, in neoplastic cells, the novel cGMP-PDE interferes with the transmission of the message that signals apoptosis. The company's compounds selectively block the activity of the enzyme, allowing the apoptosis message to be processed.
Background
Since the 1980s, scientists have known that certain non-steroidal anti-inflammatory drugs (NSAIDs) could cause precancerous colon polyps to regress and prevent their recurrence.
Unfortunately, such drugs inhibit the synthesis of prostaglandin. With chronic use this causes significant gastrointestinal irritation and kidney toxicity, making their use in cancer prevention untenable. Since NSAIDs are known to inhibit COX I and/or COX II, which inhibit prostaglandin synthesis, it has been widely believed that the ability of NSAIDs to cause regression in precancerous or cancerous lesions is attributable to their known action of inhibiting COX I and/or COX II.
Previously reported discoveries by Cell Pathways' scientists and their collaborators have since shown that it is not necessary to inhibit COX I and/or COX II to treat precancerous and cancerous lesions. The company has identified compounds that lack COX inhibitory activity (and therefore are not NSAIDs or anti-inflammatory compounds), but inhibit the growth of and trigger apoptosis in a variety of premalignant and malignant cells without the side-effects associated with the NSAID class.
Cell Pathways is currently completing a Phase III trial with its lead compound, PREVATAC(tm) (exisulind), for the treatment of precancerous lesions in patients with adenomatous polyposis coli (APC), and expects to complete a New Drug Application filing for this indication in the first half of 1999. Cell Pathways is also conducting pivotal trials of PREVATAC(tm) (exisulind) for preventing the recurrence of prostate and breast cancer and for the treatment of sporadic precancerous colon polyps, as well as a pilot study in lung cancer.
Using the screening method described in the European Patent Application, Cell Pathways has identified over 500 additional compounds, in multiple chemical classes, many of which have significantly greater apoptotic activity than PREVATAC(tm) (exisulind). The selectivity of these compounds for neoplastic cells is expected to yield agents to treat precancerous and cancerous cells without the toxicities associated with conventional chemotherapeutic agents. The company plans to file an IND to begin human clinical testing of one compound, CP461, in a cancer indication by year-end.
Cell Pathways, Inc. is a pharmaceutical company focused on the development and commercialization of products to prevent and treat cancer. For additional information on Cell Pathways, Inc., visit the company's Web site at cellpathways.com.
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