Berlin Treatment Leads

The following are two of a number of treatment leads
presented at the IX International Conference on AIDS, held in
Berlin on June 6-11, 1993.

** Topotecan

Topotecan is a chemical now being tested in patients by
SmithKline Beecham as a potential cancer treatment. Its
possible use against AIDS was first proposed by researchers
at Harvard Medical School, in a paper published in the March,
1993, Proceedings of the National Academy of Sciences, USA.
This paper reported laboratory studies showing that topotecan
inhibits HIV in chronically as well as acutely infected cells
(which AZT, ddI, etc. do not do), and that it is effective at
a concentration 200 times lower than that which has been
tolerated by cancer patients -- suggesting that as an AIDS
treatment the drug may have a large therapeutic range
(between effective and toxic doses).

The anti-HIV activity of topotecan was found by a screening
test which looked for inhibitors of the "long terminal
repeat" (LTR) of HIV, which is important in activation of the
virus. The same test also found that curcumin, the ingredient
which gives curry its yellow color, has the same kind of
anti-HIV activity (see AIDS TREATMENT NEWS #176, June 4,
1993, for background on curcumin, which also is effective
against HIV in chronically as well as acutely infected
cells). The laboratory tests found that topotecan is more
powerful than curcumin as an inhibitor of HIV. But topotecan
also has a disadvantage in that so far it is only available
in an intravenous form (although an oral form may be
developed). And there is no way to obtain topotecan at this
time, whereas curcumin is readily available. This is why
there has been more public interest in curcumin than in
topotecan.

The Berlin talk, by Boston AIDS researcher Clyde Crumpacker,
M.D., who is one of the authors of the PNAS report, gave
additional details that were not in the paper. In laboratory
studies with cells acutely infected by HIV, topotecan worked
about as well as AZT, and better than ddI. But it also worked
well in chronically infected cells, where very little effect
was found with AZT, and none with ddI. And topotecan was also
effective against an HIV isolate highly resistant to AZT
(with three different mutations for AZT resistance), giving
50 percent inhibition at about 0.08 micromolar concentration.

The research team is now trying to develop topotecan-
resistant virus, in order to learn more about the mechanism
of action of topotecan, which is largely unknown. But so far
they have not identified any significant resistance.

The Berlin talk, on June 8, was to a large and attentive
audience. Since then there has been considerable professional
interest in getting topotecan tested as an HIV treatment (it
has not yet been tested in people with HIV). We will follow
this effort as it develops.

[Incidentally, during the question period Dr. Crumpacker was
asked if he and his colleagues would continue looking at
curcumin. He answered that, "Curcumin is not as active as
topotecan on a microgram per microgram basis, but it is found
as a normal food product, and many parts of the world consume
this. We are pursuing curcumin, but how it would be developed
in a clinical trial is unclear yet." The problem, apparently,
is the old one of natural treatments not being tested because
they are low cost and no company has a monopoly on them.]

** Hydroxyurea

Hydroxyurea is a readily available drug that has been in use
for three decades in treating certain kinds of leukemia and
other cancers; it may also be promising for treatment of
sickle cell disease. The exact mechanism of action has been
unknown. It has been known that hydroxyurea immediately
inhibits DNA synthesis without inhibiting the synthesis of
RNA or protein, but until recently it was not known how it
did this.

On June 8, Robert Gallo, M.D., presented laboratory work, by
researchers at the U.S. National Cancer Institute and
elsewhere, which seems to explain the mechanism of action of
this drug.(1) This new work, not presented before, also
suggests that hydroxyurea might be useful as a new kind of
anti-HIV agent.

Dr. Gallo suggested the approach of targeting not the virus,
but the cell -- "cell gene products which the virus needs and
the cell could afford to lose a little bit of without undue
toxicity." Viruses must live in cells, and they need many
cellular chemicals to complete their life cycle; HIV may need
more than most viruses. The advantage of targeting the cell,
Dr. Gallo explained, is (1) that it opens a whole new avenue
for treatment development, and (2) cells mutate far less
rapidly than HIV does, so resistance to these drugs is
unlikely to develop.

In 1986, Gallo, Zagury, and others showed that while HIV
could enter the resting T-helper cell, it could not complete
its life cycle unless the cell was activated.(2) Others
showed that in resting T-cells, little HIV DNA was created,
and almost all of that was incomplete. At the International
Conference on AIDS in Florence two years ago, Gallo suggested
that this might be because of inadequate supply of the four
building blocks of DNA. These are found at low levels in
resting T-cells, but at much higher levels in activated T-
cells, because those cells need to make DNA since they are
about to reproduce. The great majority of T-cells are
resting.

Due to work at the NCI and elsewhere, it has been learned
that hydroxyurea inhibits an enzyme which is necessary for
one step in the process of preparing the building blocks of
DNA. Apparently it does this by quenching a free radical
which that enzyme produces. In the laboratory, activated
cells were converted to resting status, blocking the
synthesis of HIV DNA.

But a negative result came from a laboratory study, reported
at the 1992 International Conference on AIDS, which suggested
that hydroxyurea would not be useful as a treatment.(3) In
this study, "The concentrations used [to inhibit HIV in the
laboratory] make it an impractical drug for anything other
than ex vivo studies." If this is correct, attempts to use
the drug for HIV would give only its side effects but no
benefit. All the information available should be reviewed by
qualified professionals who can evaluate the contradictory
reports. But clearly there is enough need for new treatments
today that an otherwise-promising lead should not be
dismissed because of one negative report, without further
investigation.

How does this translate into a practical treatment
possibility? Hydroxyurea is a drug that must be used with
care, because it can cause bone-marrow suppression. The
Physician's Desk Reference advises that blood tests for
hemoglobin, total leukocyte counts, and platelet counts,
should be performed at least weekly while the drug is used.
But hydroxyurea is commonly used with chemotherapy and/or
radiation, so it can be tolerated with these treatments,
which also can cause bone-marrow suppression. The risk for
persons with HIV -- especially if they are using other drugs
which can suppress bone marrow, such as AZT -- is unknown.

It is also possible that lower doses than used for leukemia
might be enough for HIV treatment. Probably the first HIV
trials will start with low doses and very careful monitoring
of blood tests for side effects, and use a test for viral
activity (such as the ICD p24 antigen test, for those who are
positive on this test) as an indicator to show which dose is
effective. (Even this indicator might be slow to respond,
however, since the drug may only shut off viral reproduction,
not other activity of the virus which already exists. Perhaps
some other test would be more appropriate.)

AIDS TREATMENT NEWS would be interested in hearing from
anyone who has information about possible AIDS-related uses
of hydroxyurea.

References

1. Gallo RC. Perspectives for the future control of HIV.
International Conference on AIDS, Berlin, June 6P11, 1993
[talk OP-01-1]. (Note: there is no information about
hydroxyurea in the published abstract. An audiotape, tape
#27, is available from Intrec, in Utrecht, The Netherlands,
fax number 31-30-340334.)

2. Zagury D, Bernard J, Leonard R. and others. Long-term
cultures of HTLV-III--infected T cells: a model of
cytopathology of T-cell depletion in AIDS. SCIENCE. February
21, 1986; volume 231, number 4740, pages 850-850.

3. Meyerhans A, Vartanian JP, Hultgren C, Eriksson S, and
Wain-Hobson S. The intracellular nucleotide pool affects HIV
replication. International Conference on AIDS, Amsterdam,
July 19-24, 1993 [abstract #PoA 2118].

4. Kiernan R, Doherty RR, and McPhee D. Production of HIV-1
protein but not infectious virus in G1 arrested MT-2 cells.
International Conference on AIDS, Florence, June 16-21, 1992
[abstract #M.A.1053].

5. Getman DP, DeCrescenzo GA, Heintz RM, and others.
Discovery of a novel class of potent HIV-1 protease
inhibitors containing the (r)-(hydroxyethyl)urea isostere. J.
MED.CHEM. January 22, 1993, volume 36, number 2, pages 288-
291.