Vascular smooth muscle has four major types of PDE: PDE1 which mainly hydrolyzes cyclic GMP
and is activated by calcium/calmodulin, PDE3 which mainly hydrolyzes cyclic AMP but can also hydrolyze cyclic GMP
(since it has a higher affinity for cyclic GMP
than for cyclic AMP, and cyclic AMP hydrolysis is competitively inhibited by cyclic GMP
), PDE4 which specifically hydrolyzes cyclic AMP, and PDE5 which specifically hydrolyzes cyclic GMP
Then the researchers used isolated fat cells and treated the cells directly with cyclic GMP
and identified a "browning" effect as well.
1990, Purification and chemical characterization of peptide GI, an invertebrate neuropeptide that stimulates cyclic GMP
The recent direct evidence that the internal messenger is cyclic GMP
rather than calcium ions comes out of experiments with a powerful, relatively new technique called "patch clamping" (SN: 11/7/81, p.
The same concentrations of Aptosyn(R), CP461, and CP248 that cause an increase in cyclic GMP
and induce death by apoptosis in human colon cancer cells also lead to phosphorylation of VASP," said W.
It achieves this selective activity by inhibiting certain cyclic GMP
phosphodiesterases that are expressed at high levels in the abnormal cells, thus freeing those damaged cells to die through normal cellular processes.
CP461 and Cell Pathways' other selective apoptotic antineoplastic drugs (SAANDs) inhibit cyclic GMP
(cGMP) phosphodiesterases 2 and 5, resulting in the activation of protein kinase G and the triggering of downstream cellular pathways leading to apoptosis (programmed cell death).
SAANDs selectively trigger apoptosis in cancerous and precancerous cells by inhibiting certain cyclic GMP
phosphodiesterases that company scientists and collaborators have shown to be over-expressed in a variety of tumor types.
The results of this study continue to support clinical proof-of-principle for exisulind, a cyclic GMP
phosphodiesterase inhibitor, in the prevention of growth of precancerous adenomatous polyps of the colon," said Rifat Pamukcu, MD, chief scientific officer of Cell Pathways, Inc.
In studies of diseased canine and human tissues, high levels of cyclic GMP
phosphodiesterases (cGMP PDE) of the PDE2 and PDE5 gene families have been detected (both molecular targets for CP461) in activated macrophages associated with IBD.
In previous research, we have shown that exisulind, CP461, and CP248 selectively inhibit cell growth and trigger apoptosis in a number of human cancer types, through inhibition of cyclic GMP
phosphodiesterases 2 and 5," said lead author I.
Cell Pathways scientists and their collaborators have demonstrated that SAANDs exert their apoptotic effects by inhibiting certain cyclic GMP
phosphodiesterases that are over-expressed in a variety of tumor types.