(ATN) New Study: Tat and NF-kB Inhibitors Work MUCH Better Together

(ATN) New Study: Tat and NF-kB Inhibitors Work MUCH Better Together

AIDS TREATMENT NEWS #188, December 3, 1993
John S. James

In a potentially important laboratory study published December 1, a research team at Dana-Farber Cancer Institute and Harvard Medical School found that two different drugs (the Tat inhibitor recently abandoned by Hoffmann-La Roche [Ro 24-7429], and pentoxifylline, a prescription drug) worked much better together in a laboratory test than would have been expected from how well they worked separately -- so much better that the concentration of both drugs could be reduced almost ten times to still produce the same effect as the larger concentration of each substance alone.

The mechanism of action of both of these drugs involves a part of the HIV virus known as the LTR (long terminal repeat). When the LTR is activated, it causes the virus to reproduce. But there are at least two different, independent pathways to activate the LTR. One is stimulated by the Tat protein, which is produced in HIV-infected cells but never in normal cells. Another is stimulated by NF-kB (NF-kappa B), a substance which is normal and necessary in the body. When both stimuli are present, they can cause a "superactivation" of HIV -- as much as 60 times the effect of each one alone. [The laboratory test reported did not test the drugs on live HIV, but instead used a genetically engineered cell developed to easily screen for substances which inhibit the LTR.]

The new study suggests that the combination of both drugs might be an effective treatment, even if each one alone is not sufficient.

Ro 24-7429 was abandoned after a report at the International Conference on AIDS (June 1993, in Berlin) that it did not show an antiviral effect in patients -- even though blood levels should have been enough to produce that effect. But there have been a number of questions about whether it was abandoned too early. There are rumors which we plan to investigate further -- one, for example, that some people in the trial never took the drug, but gave it to friends who were more seriously ill but who could not get into the trial themselves.

If you have any information about human use of Ro 24-7429 -- especially anyone taking it either with pentoxifylline, or with antioxidants such as NAC or vitamin E -- please contact AIDS TREATMENT NEWS, 415/255-0588.

References

Biswas DK, Ahlers CM, Dezube BJ, and Pardee AB. Cooperative inhibition of NF-kB and Tat-induced superactivation of human immunodeficiency virus type 1 long terminal repeat. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA. December 1, 1993; volume 90, pages 11044-11048.

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