The Story

How in the world is a molecule like AZT brought into being? How does it cure people? How does it rock the stock market? Why does it bring protestors onto the street? How do scientists, the state, business, cancer, chemical warfare, DNA, RNA, AIDS and patients relate to this molecule? Or this molecule relate to them?

Where does the history of AZT start? I guess it has to be when it was synthised back in 1964 by Jerome Horwitz at Wayne State University School of Medicine, funded by the US National Institute of Health. But, like all of us, its birth was conceived. For AZT the impulse to cure cancer and the impulse to kill with chemical agents in warfare intertwined and AZT was one of the results.

No scientific story is complete without serendipity or an accident so lets start there. In 1913 The English chemist Hans Thacher Clarke was working with the renknowned Emil Fischer in Berlin. He broke a flask and spent two months in hospital with burns caused by the contents. Fischer’s report on this accident to the German Chemical Society sent the German Empire on the road to chemical weapons.

When 2000 mustard gas bombs landed on United States forces in the port of Bari in Italy in 1943 a doctor from New Jersey, Lieutenant Colonel Stewart Alexander was sent to investigate. He saw that the mustard gas was stopping the victim’s cells from dividing in their bone marrow and immune system. He speculated that such an agent might aid in the treatment of some cancers. Very soon mustard gas chemicals were being actively investigated for their therapeutic role in cancer. In the 1950s drugs based on mustard gas were developed which are still used today in chemotherapy.

It was appreciated that killing dividing cells would always be toxic as cell division is required in healthy people as well as in cancers. Investigations showed that changing the precise chemical structure of these mustard gas derivates and testing their efficacy and toxity could deliver better therapeutic agents. One of the successes, still used today, was Mercaptopurine, approved for clinical use in the US in 1953.

Mercaptopurine was synthesized by Gertrude Elion and George Hitchings at Burroughs Wellcome Pharmaceutical Company in New York state. They went on to investigate its therapeutic application in collaboration with what is now the Memorial Sloan Kettering Cancer Center in New York where Cornelius Rhoads was the director. He had run chemical weapons programs for the US army and been involved in the discovery that nitrogen mustards could be used as cancer drugs. Experiments into the mechanism of action of mercaptopurine showed it was blocking the synthesis of DNA.

Jerome Horwitz was looking for a cure for cancer when he synthesized AZT in 1964. He was making compounds that resembled the building blocks of DNA in the hope that they, like mercaptopurine, would interfere with the synthesis of DNA and thereby block cell division. Blocking cell division despite the side effects was and even now is a prime candidate for anti cancer therapy. The work ended, or so it seemed then, in disappointment as none of the moleucles he synthesized did work as anti cancer drugs. He put them on the shelf and moved on to other work. AZT is one of very few clincal drugs which was designed to do what it does. It was designed to inhibit DNA synthesis. It failed to inhibit the normal DNA synthesis which was known about then. We now know it does inhibit the very unusual, and unknown at that time, DNA synthesis which uses RNA as a template for the DNA to be synthesized. This is the unique thing that retroviruses do as part of their life cycle.

Even today drug design strategies rarely bare fruit. Extraordinary advances in visualizing enzyme mediated chemical reactions have been made. Normal DNA synthesis and the more recently discovered retroviral form of DNA synthesis from an RNA template mediated by the enzyme reverse transcriptase have been compared in great detail. However, this has not led to compounds which are better at discriminating between these two types of DNA synthesis than AZT. Yes, AZT was designed but it was not designed to make this discrimination and yet it is this ability to discriminate between the two types of DNA synthesis which makes it so valuable as a therapeutic agent. But we are jumping ahead.

While all this effort in chemical weapons and anti cancer drugs was going on there was parallel and intertwined work on infectious diseases. Like cancer cells, infectious organisms need to divide to cause disease and to divide they need to replicate their DNA. In short they need to synthesize DNA. Cancer cells are derived from our own normal cells and consequently offer few targets for therapies which don’t also exist in our normal cells and make them vulnerable to the therapy. Viruses are so paired down that they present very few targets. Also the viruses are likely to be derived if not from us as individuals then from other members of our species or not so distant species, for example other mammals. Protozoan and to an even greater extent bacterial infectious organisms are very different to us belonging to different kingdoms of the tree of life. As such there are a large number of chemicals, many referred to as antibiotics, which are selectively toxic to to these organisms and non-toxic to us. So, the hunt for antiviral agents was more akin to the hunt for cancer therapies than antibacterial or anti protozoan infections.

In 1974, Wolfram Ostertag of the Max Plank Institute in Germany got AZT back off the shelf and found it specifically targeted Friend virus, a retrovirus. At the time no human disease was known to be caused by a retrovirus so there was little medical potential for this discovery then. However, just under 10 years later, in 1983 researchers in the US and France discovered Human Immunodeficiency Virus, identified it as a retrovirus and as the cause of Aquired Immunodeficiency Syndrome. The National Cancer Institute in the US devloped a culture of human immunity cells called T cells that could be grown in the laboratory and infected with HIV. They started testing chemicals for their ability to prevent the cells from becoming infected with HIV while at the same time monitoring the T cells for toxic affects of the chemicals. AZT, having been shown to be active against the Friend retrovirus, was an obvious candidate for these tests. It passed the test.

In 1985 the National Cancer Center moved their trial of AZT into humans. These Phase 1 trials showed that AZT could be safely used in AIDS patients and that it increased their immune cell counts, T cell immunity and improved symtoms of AIDS.

At this point in the story most of the action and most of the expenditure on AZT has been in state institutions although the earlier work which resulted in the cancer drug mercaptopurine was done by the Nobel prize winning team at Burroughs Wellcome. When it comes to large Phase 2 clinical trials pharmaceutical companies tend to be given the job and and so this became the responsibility of Burroughs-Wellcome. Having done these and confirmed the results of the Phase 1 trials, Burroughs-Wellcome were awarded the patent for AZT in 1985. The FDA approved the drug in 1987. The award of the AZT patent to Burroughs-Wellcome provoked a furious reaction and litigation but the patent remained in force.

Most drugs, including mercaptopurine, are not designed. They are found to be active and hence useful, AZT is one of the few drugs we have which was designed