epigenetic dosing of decitabine

[Guest guest]

Greetings,

There are plenty of promising investigational fruit on the tree, so the

" failed " study - abstract copied below - is not a great concern. " Failed "

in quotes, because the study successfully identified, and published, a

dead-end, allowing researchers to focus on more promising directions.

The findings also show a fundamental difference between science-based

clinical research and alternative-opinion-based medical practices. The

former requires PK studies to measure dose concentrations in the blood as a

starting point - to see if the active dose can be achieved safely - the

so-called therapeutic window.

Science is not an issue for Alternative medicine practitioners who will

prescribe herbs without knowledge of its bioavailability - concentrations in

the blood at the dose provided, many times relying on cell culture studies

to justify the promotions of insignificant doses of this or that herb. By

definition, alternative medicine means untested.

Below, researchers explored lower doses of a cytotoxic drug, Decitabine, to

measure epigenetic effects - effects on the cells that re-program the

malignant behavior (such as to " wake up " silenced tumor suppressing genes),

instead of killing the cells outright (cytotoxic).

Copying some background: " The development of decitabine from its synthesis

in 1964 to the submission of a registration file has been described.

Although the unique DNA-demethylating capacity of decitabine is known for a

long time, its application is under continuing investigation. The use of

decitabine in MDS, AML, CML, stem cell transplant, sickle cell anemia and

thalassemia looks promising. The epigenetic dose seems lower than the

cytotoxic dose. Whereas most drugs have matured after 40 years, decitabine

is only at the beginning of a new development phase in epigenesis.

But theory needs to be clinically tested. The phase I results:

===

Abstract

Summary Targeting aberrant DNA hypermethylation in chronic lymphocytic

leukaemia (CLL) and non-Hodgkin lymphoma (NHL) with decitabine may reverse

epigenetic silencing in B-cell malignancies. Twenty patients were enrolled

in two phase I trials to determine the minimum effective pharmacological

dose of decitabine in patients with relapsed/refractory CLL (n = 16) and NHL

(n = 4). Patients received 1-3 cycles of decitabine. Dose-limiting toxicity

(DLT) was observed in 2 of 4 CLL and 2 of 2 NHL patients receiving

decitabine at 15 mg/m(2) per d days 1-10, consisting of grade 3-4

thrombocytopenia and hyperbilirubinaemia. Six patients with CLL received

decitabine at 10 mg/m(2) per d days 1-10 without DLT; however, re-expression

of methylated genes or changes in global DNA methylation were not observed.

Therefore, a 5-day decitabine schedule was examined. With 15 mg/m(2) per d

decitabine days 1-5, DLT occurred in 2 of 6 CLL and 2 of 2 NHL patients,

consisting of grade 3-4 neutropenia, thrombocytopenia, and febrile

neutropenia. Eight patients had stable disease. In 17 patients, there were

no significant changes in genome-wide methylation or in target gene

re-expression. In conclusion, dose-limiting myelosuppression and infectious

complications prevented dose escalation of decitabine to levels associated

with changes in global methylation or gene re-expression in CLL and NHL.

PMID: 20456354

Br J Haematol. <javascript:AL_get(this,%20'jour',%20'Br%20J%20Haematol.');>

2010 Apr 29. [Epub ahead of print]

Phase <http://www.ncbi.nlm.nih.gov/pubmed/20456354> I trial of low dose

decitabine targeting DNA hypermethylation in patients with chronic

lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting

myelosuppression without evidence of DNA hypomethylation.

Blum <http://www.ncbi.nlm.nih.gov/pubmed?term=%22Blum%20KA%22%5BAuthor%5D>

KA, Liu Z

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Liu%20Z%22%5BAuthor%5D> , Lucas

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lucas%20DM%22%5BAuthor%5D> DM,

Chen <http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chen%20P%22%5BAuthor%5D>

P, Xie Z <http://www.ncbi.nlm.nih.gov/pubmed?term=%22Xie%20Z%22%5BAuthor%5D>

, Baiocchi

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Baiocchi%20R%22%5BAuthor%5D> R,

Benson

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Benson%20DM%22%5BAuthor%5D> DM,

Devine

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Devine%20SM%22%5BAuthor%5D> SM,

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22%20J%22%5BAuthor%5D>

J, Andritsos

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Andritsos%20L%22%5BAuthor%5D>

L, Flynn

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Flynn%20J%22%5BAuthor%5D> J,

Plass <http://www.ncbi.nlm.nih.gov/pubmed?term=%22Plass%20C%22%5BAuthor%5D>

C, Marcucci

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Marcucci%20G%22%5BAuthor%5D> G,

Chan <http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chan%20KK%22%5BAuthor%5D>

KK, Grever

<http://www.ncbi.nlm.nih.gov/pubmed?term=%22Grever%20MR%22%5BAuthor%5D> MR,

Byrd <http://www.ncbi.nlm.nih.gov/pubmed?term=%22Byrd%20JC%22%5BAuthor%5D>

JC.

Division of Hematology-Oncology, Department of Internal Medicine, The Arthur

G. Comprehensive Cancer Center, Columbus OH, USA.

==

In this case there was toxicity and no epigenetic activity at the lower

dose.

All the best,

~ Karl

Patients Against Lymphoma

Patients Helping Patients

Non-profit | Independent | Evidence-based

www.lymphomation.org | Current News: http://bit.ly/f2A0T

How to Help: www.lymphomation.org/how-to-help.htm