Re: Re: re: In response to Nicholas Bennett 27 August 2004
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Jean UMBER,
Agrégé de chimie
France

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Re: Re: Re: re: In response to Nicholas Bennett

Nicholas Bennett wrote :

" The lack of triphosphorylation reference is from the Perth Group, and I'm inclined to reject that out of hand for the following simple reason: if you put AZT into a virus culture it prevents replication unless resistance mutations exist in the virus. Clearly it MUST be active... "

The Perth Group are not alone to say that AZT cannot work in cells. Here is what a french team from CEA have found :

http://www-dsv.cea.fr/content/cea_eng/avan/annee_2003/actu03_azt.htm

"This high-performance analysis method recently resulted in an unexpected discovery concerning the intracellular metabolism of AZT. On the basis of in vitro experiments it had been thought that AZT was metabolised at the intracellular level ultimately to produce AZT triphosphate. However, intracellular assays carried out in patients being treated with AZT revealed the presence of the triphosphorylated metabolite of d4T, another retroviral agent of the same family used, like AZT, in multitherapy. The concentrations of d4T-triphosphate found in patients treated with AZT are compatible with an antiviral activity."

But how can D4T been synthetized ?

In the pubmed abstracts from the same experiment

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pub med&dopt=Abstract&list_uids=12598776

the french team writes :

"It has been previously shown that zidovudine (ZDV) and its phosphorylated metabolites can be chemically reduced into the corresponding stavudine (d4T) forms in solution"

I insist upon the words "chemically reduced".

Thus it has been demonstrate that AZT is a oxidizing agent. When ? In 1988 by Handlon & Oppenheimer and in 1994 by Reardon & al.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pub med&dopt=Abstract&list_uids=8206896

"The product mixture from reduction of AZT 5'-monophosphate at pH 7.1 and 25 degrees C was composed of 2,3'-anhydro-beta-D-threo-thymidine 5'- monophosphate (6.4%), 3'-amino-3'-deoxythymidine 5'-monophosphate (19.6%), beta-D-threo-thymidine 5'-monophosphate (6.8%), thymine and 3-amino-2,3- dideoxyribal 5-monophosphate (8.9%), beta-D-threo-thymidine 3',5'-cyclic monophosphate (9.1%), 3'-deoxy-2',3'-didehydrothymidine 5'-monophosphate (31.5%), and 3',5'-anhydro-beta-D-threo-thymidine (17.8%). Thymine and 3',5'-anhydro-beta-D-threo-thymidine were also products of reduction of AZT and AZTTP"

3'-deoxy-2',3'-didehydrothymidine 5'-monophosphate is stavudine monophosphate. It is very resonable to assume that thiols (cysteine) have reduced AZT in the cells (french experiment). If 37% of AZT is reduced in d4T by thiols in this experiment, one must assume that the other products (AMT and the oxetane product particularly) are synthetized. Therefore the whole AZT has been reduced and cannot work int the way of an ARV. All the reflexions about resistance against AZT are groundless.

Competing interests: None declared