Histone deacetylase inhibtors
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I wonder if anyone has fabricated a drug of HDAC called MS-275. It showed powerful impact on cholangiocarcinoma cell lines in vitro back in 2006.
Sorry guys, Spelled the drug wrong: Here some info:
FDA-Approved Drugs: Vorinostat (Zolinza, suberoylanilide hydroxamic acid [SAHA])
Investigational Drugs: CRA-024781 (Celera Genomics), depsipeptide (Romidepsin)
Mechanism of Action
DNA coils around histones, which are proteins that help push the DNA strands into tightly coiled chromatin in the nucleus of the cell. Histones play an important role in turning genes on and off. When the chromatin is loose and uncoiled, the gene is turned on and DNA transcription can occur. If there is too much deacetylation of the histones (caused by an overexpression of histone deacetylase), such as may occur in cancer, the chromatin is tightly coiled and closed, so that the gene is turned off (cannot be transcribed). Deacetylation is the removal of acetyl groups from proteins or transcription factors. For example, if the gene that is silenced is a tumor suppressor gene, then without the “brakes” on cell division, cancer cells may proliferate. Another gene that may be silenced is a cyclin kinase inhibitor, which regulates the cell cycle. Again, the tumor would be able to continue to divide and make more tumor cells. Imagine a Slinky toy as a DNA coiled helix. When you move it so that the rings are open, you see that the portion of DNA that codes for the gene is exposed. When the rings are open, the gene can be activated and transcribed. When the Slinky moves down a step, it closes in on itself, and there is no way that the gene can be exposed for transcription. Vorinostat is a histone deacetylase (HDAC) inhibitor, which blocks the deacetylase enzyme and allows the acetyl groups to accumulate on the histones. This uncoils the DNA within the chromatin so that genes are exposed; they become activated and are then transcribed. This causes cancer cells to stop dividing (cell cycle arrest) and to die (apoptosis).
Vorinostat Metabolism
The drug is well absorbed, and if taken with a high-fat meal had a 33% higher extent of absorption and a slightly slower rate of absorption (not clinically significant). The drug is primarily metabolized by glucuronidation and hydrolysis, followed by oxidation into two inactive metabolites. Less than 1% of the drug is recoverable in the urine.
Indications
Vorinostat is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent, or recurrent disease during or after two systemic therapies.
Patient Education
Educate the patient about the correct oral administration of vorinostat: swallow the prescribed capsules (400 mg) whole (do not chew or break), once a day with food. Drink at least eight 8-ounce glasses of liquid a day.Hi Chrissy, Good going girl ! Love your positve and persistent approach. I wrote it down on my research sheet but hadn’t got to it. It will be interesting to hear what chucks Oncologist has to say.
Wishing only the best!
Jeff G.Chucks and I had an appointment with our oncologist yesterday. I did some research on the histone deacetylase inhibitors and found an fda approved drug called Vonistat. I took the research to our oncologist and he was very interested especially since this is fairly new and the drug is fda approved so he can prescribe it. He said that he was going to do some research on the drug and find out what effects it might have on the liver and other organs and get back to us. He said that he is more than happy to try anything that might show promise and is safe for chucks to use. I will let you guys know what he says about this drug.
Wayne,
Thanks for posting your correspondence with Dr. Alberts. It’s great to know and personally I feel just knowing, supports the reason for hope that I have and will always remain positive to the best of my ability; Despite whatever or however my own personal results may be. The wheels are turning even though slowly,there turning.
Jeff G.I sent the abstract of the German research to Dr. Steven Alberts MD, one of the top oncologists on cholangiocarcinoma (in his early years as an oncologist he worked with native American populations who suffer higher incidence of bile duct cancer – and Mayo has historically dealt with more BDC patients than any other center) and here is his response:
Dear Mr. Parsons,
Thank you for your e-mail. I hope you are doing well.
In regard to your e-mail, there is actually quite a bit of work going on with HDAC inhibitors in oncology with several agents in clinical trials. I am not currently aware of any work in pancreatic cancer or cholangiocarcinoma. However, I expect that this will occur at some point.
Best wishes,
Steven R. Alberts, MDWayne …. Thank You for this research information. It is of great interest and I also believe the input of studies outside of the cancer research arena is extrememly valuable and could one day, very well be the bullet we are all searching. What’s that saying ” don’t leave any stone unturned” Wayne , just wanted to say how sorry I am for the lost of Valerie. May God give you the strenght during this grieving time.
God Bless,
Jeff G.
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