A CRITICAL ANALYSIS OF THE PHARMACOLOGY OF AZT AND ITS USE IN AIDS

By Eleni Papadopulos et al.

The genetic information of our own cells as well as that of many viruses is encoded by the linear sequence of the constituent building blocks of DNA. The building blocks are known chemically as nucleotides and there are four such nucleotides one of which is thymidine Every set of three nucleotides in DNA signifies an instruction to insert a particular amino acid building block into a growing protein chain. To produce the protein chain the DNA is not used directly but is copied (transcribed) into an RNA chain which in turn codes for the proteins (translation). Some viruses contain only DNA and this DNA is used to produce the viral proteins via RNA. Other viruses including retroviruses contain only RNA and in some of these the RNA directly codes for the synthesis of viral proteins. According to retrovirologists, retroviruses are an exception in that their RNA is first copied "backwards" into DNA whereupon this stretch of DNA is inserted into the cellular DNA where it is carried as a DNA "provirus". There it lays dormant until the cell is activated following which the proviral DNA is transcribed into RNA and thence the RNA instructions are used to construct proteins in the usual manner. To facilitate the copying of their RNA into the DNA provirus, retroviruses contain an enzyme (catalyst) called reverse transpcriptase.

The chemistry of producing DNA chains has two essential requirements:

1. The synthesis requires energy. This energy is carried in three phosphate groups attached to the 5’-OH group of each nucleotide. Thus every nucleotide next to be incorporated at the growing end of the DNA chain must be triphosphorylated
2. The last nucleotide in the growing chain must have a free 3’ hydroxyl (3’-OH) group in order to attach the next nucleotide in the chain.

AZT is an analogue of the nucleotide thymidine, that is, AZT is similar overall in structure to thymidine differing only in a small manner. The difference is that the 3’ hydroxyl group of thymidine is replaced by an azido (nitrogen atom) group in AZT. Because of the similarity of AZT to thymidine, AZT can "trick" a growing DNA chain into taking it up in place of thymidine. However, since AZT lacks the 3’hydroxy group, once AZT is attached to the end of the DNA chain, no further DNA synthesis can take place.

In 1985 and 1986 researchers from the US National Cancer Institute (including Dr. Robert Gallo), Duke University, and the Wellcome Research Laboratories claimed to have shown that in cell cultures:

1. The cells are able to convert "inactive" AZT lacking the three phosphate groups into the "active" triphosphorylated form.
2. The triphosphorylated form of AZT inhibits the synthesis of HIV DNA. This means that no new cells can be infected with HIV and since cells already infected have a limited lifespan (days), any person taking AZT should rapidly become virus free and cured of infection.

Although the claims of these groups have been disproved by many other researchers [1-5], in 1986 AZT was introduced into clinical practice and still remains the most frequently used drug against HIV infection. However, since:

1. To act as an antiretroviral agent AZT must be triphosphorylated.
2. The AZT administered to patients is not triphosphorylated.
3. The cells of "HIV infected" individuals are not capable of triphosphorylating AZT

AZT cannot be an anti-HIV drug, either when used alone or in combination with other drugs.

As early as 1988 the HIV/AIDS experts including the researchers from the US National Cancer Institute, Duke University, and the Wellcome Research Laboratories expressed the view that due to its high toxicity AZT was of limited value in the treatment of patients who already had advanced disease, that is, AIDS [6]. At present, evidence exists showing that AZT causes "a significant increased risk of death among the patients treated early", that is, in patients who commence treatment when asymptomatic [7]. In other words, instead of curing patients or prolonging life AZT shortens it. Furthermore, since some of the clinical and laboratory manifestations of AZT toxicity mimic AIDS, it is impossible to differentiate between AZT toxicity and AIDS. *

References:

1. Antimicrobial Agents and Chemotherapy. 1986. 30: 933-937.

2. Journal of Virology. 1987. 61:3769-3773.

3. AIDS Research and Human Retroviruses. 1991. 7:751.

4. Antimicrobial Agents and Chemotherapy. 1994. 36:115-121.

5. AIDS. 1994. 18:F1-F5.

6. Annals of Internal Medicine. 1988. 108:534-540.

7. New England Journal of Medicine. 1997. 336:958-959.