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Sulindac and its derivatives: a novel class of anticancer agents
1University Medical Center Nijmegen, Consultant Medical Spectrum Twente, Enschede, The Netherlands. felixhaan@wxs.nl
Abstract:
It has been repeatedly observed that non-steroidal anti-inflammatory drugs, in particular sulindac and derivatives, may effectively prevent colorectal cancer. It has become apparent that exisulind (sulindac sulfone) induces apoptosis in tumor cells. Cell biological studies provided circumstantial evidence that the mechanism by which these agents exert their antitumor effect should be attributed to inhibition of cyclic-GMP phosphodiesterase (cGMP-PDE). The secondary increase of cGMP activates protein kinase G (PKG) and induces transcription of caspase genes, resulting in apoptosis. cGMP-PDEs comprise 11 gene families. Each family of PDEs is characterized by their ability to bind and degrade cAMP and cGMP but differs in physical and kinetic properties. Any single type of cell expresses a limited number of PDE-isoforms in order to regulate cGMP or cAMP levels. The majority of PDE inhibitors that have been investigated until now, except exisulind and a number of its analogs, do not induce apoptosis in tumor cells. Sulindac has a preventive effect on tumorigenesis in patients with polyposis of the colon. The anticancer effect of the novel sulindac derivatives has been demonstrated in over 50 different tumor cell lines, as well as in animal models of a variety of human cancers, such as mammary, prostate, lung and pancreatic carcinomas. Selective apoptotic antineoplastic drugs (SAANDs), as developed by Cell Pathways Inc, represent a novel class of anticancer agents that target a novel form of cGMP-PDE. It is believed that this enzyme is selectively increased in precancerous and cancerous cells. By specifically inhibiting the action of this particular cGMP-PDE, SAANDs enable various tumor cells to process an apoptotic signal and to commit suicide without affecting normal cells. As a result, side effects normally associated with traditional chemotherapeutic agents are not observed. One of the new compounds, CP-461, appeared < or = 100-fold more potent than exisulind in vitro. Studies of human cancer cell lines in vitro and dose-ranging phase I/II studies, both oral and iv, are discussed. Combinations of CP-461 with other chemotherapeutic agents are well tolerated.
Insights
Non-steroidal anti-inflammatory drugs like sulindac derivatives can prevent colorectal cancer by inducing tumor cell apoptosis. Novel agents selectively inhibit cyclic-GMP phosphodiesterase (cGMP-PDE), leading to cancer cell death with minimal side effects.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Non-steroidal anti-inflammatory drugs (NSAIDs), particularly sulindac and its derivatives, show promise in preventing colorectal cancer.
- Exisulind (sulindac sulfone) and related compounds induce apoptosis in tumor cells.
- Evidence suggests the antitumor mechanism involves inhibition of cyclic-GMP phosphodiesterase (cGMP-PDE), leading to increased cyclic guanosine monophosphate (cGMP), protein kinase G (PKG) activation, and caspase gene transcription.
Purpose of the Study:
- To investigate the mechanism of action of sulindac derivatives as anticancer agents.
- To evaluate novel selective apoptotic antineoplastic drugs (SAANDs) targeting a specific cGMP-PDE isoform.
- To assess the efficacy and tolerability of CP-461, a potent SAAND, in preclinical and early clinical studies.
Main Methods:
- Cell biological studies to elucidate the apoptotic pathway.
- In vitro testing of sulindac derivatives against over 50 human cancer cell lines.
- In vivo studies using animal models of various human cancers (mammary, prostate, lung, pancreatic).
- In vitro and in vivo evaluation of CP-461, including dose-ranging Phase I/II clinical trials (oral and intravenous).
Main Results:
- Sulindac derivatives, including exisulind, induce apoptosis in tumor cells via cGMP-PDE inhibition.
- SAANDs selectively target a cGMP-PDE isoform upregulated in cancerous cells, inducing apoptosis without harming normal cells.
- CP-461 demonstrated significantly higher potency than exisulind in vitro (up to 100-fold).
- CP-461 was well-tolerated in combination with other chemotherapeutic agents in clinical trials.
Conclusions:
- Sulindac derivatives represent a novel class of anticancer agents (SAANDs) with a unique mechanism of action.
- Targeting the specific cGMP-PDE isoform in cancer cells offers a promising strategy for cancer treatment with reduced side effects.
- CP-461 shows potential as an effective and well-tolerated anticancer therapeutic, warranting further investigation.