ddodell@stjhmc.fidonet.org (David Dodell) (03/04/91)
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among the common side effects. The two most important findings
so far, according to Dr. Fischl, are: 1) as with alpha
interferon, piritrexim appears to be most useful in early KS,
where tumor regressions have been seen, and 2) there is both
test-tube and human evidence to suggest that piritrexim may also
be useful in preventing pneumocystis pneumonia. Dr. Fischl
explained that daily dosing with a low dose seems to be superior
to the cyclic schedule used in the first study.
Dr. Fischl plans to present the data from these two studies
to the ACTG for consideration of future studies. She told us that
the main question that needs to be considered in deciding where
to go next with this drug is whether or not piritrexim will have
any significant advantage over alpha interferon. She pointed out
that interferon does show activity against HIV in addition to
early KS, whereas piritrexim does not have any anti-HIV activity.
* A number of small studies have also been conducted with
the chemotherapy drugs doxorubicin (adriamycin), epirubicin,
idarubicin, and mitoxantrone. In general, results have been
inconsistent or not dramatic. Test-tube studies have suggested
that mitoxantrone should be pursued, whereas previous clinical
studies have been disappointing. Dr. Chew told us that data
which is awaiting publication suggests that idarubicin, recently
approved for acute leukemia, acts more quickly than daunorubicin
in leukemia and thus might be more effective in KS. We will
continue to follow developments in new chemotherapy drugs for KS.
Anti-Angiogenesis Compounds
With the exception of a single trial (of pentosan, described
below), the U. S. government-sponsored clinical trials in KS have
focused on the use of chemotherapy and interferon by themselves
and in combination with anti- retrovirals and the white blood
cell growth factors (GM- CSF and G-CSF) discussed earlier in this
article. However, a growing number of scientists working in the
areas of cancer and basic research are focusing their attention
on an entirely different class of compounds, those which
interfere with angiogenesis (the growth of new or abnormal blood
vessels).
Most solid tumors rely on an abundant blood supply, provided
by an extensive network of blood vessels, for their growth.
Anti-angiogenesis research has generated an intense level of
scientific interest because of the theoretical possibility of
being able to "starve" solid tumors by preventing further blood
vessel development. These compounds may be useful in KS because
KS appears to be a proliferation of abnormal blood vessels. It
is believed that many of the growth factors involved in the
development of blood vessels in solid tumors are the same as
those involved in the development of KS lesions.
Over the past several months we have published reports on
the much-publicized Japanese compound first brought to public
attention by Robert Gallo, M. D., of the U. S. National Cancer
Institute (see AIDS TREATMENT NEWS issues #99 and #100) and
fumagillin analogues (see AIDS TREATMENT NEWS issue #117). These
are both believed to interfere in angiogenesis. None of the
compounds we have reported on in these articles are currently
available by prescription or for purchase from other sources;
they are still in the very early stages of development by
pharmaceutical companies and/or university laboratories. However,
they have immediate importance for research, and potential long-
range importance for treatment.
These compounds and/or others in the same class may prove
to be more specific and thus less toxic than the cancer
chemotherapy drugs which are currently in widespread use for KS.
Although many of the most promising compounds are still in very
early preclinical development, some drugs in this class are
currently being used for other conditions. This means that they
are available for scientists to study both in laboratory
experiments and in clinical trials with humans now. Some
physicians and researchers in the AIDS community, including
Joseph Sonnabend, M. D., from New York, have been discussing,
writing about, and urging further research in this area for
several years.
Hundreds of compounds are being studied in laboratories
around the world for their anti-angiogenic properties. A
computer search revealed over 1,000 articles in the scientific
literature in this area. The retinoids mentioned earlier in this
article are believed to have anti-angiogenic properties. We will
describe briefly only a few additional compounds, including
pentosan, PF4 (platelet factor 4), fumagillin analogues, vitamin
D3 analogues, and a synthetic heparin/steroid combination. These
are not necessarily the most promising compounds, nor the most
available; they are simply the ones which have received the most
attention so far in the AIDS research, treatment, and activist
communities.
It is our strong belief that the experts in the field of
angiogenesis and cell differentiation, whether or not they are
involved in HIV, should be actively recruited by the government-
sponsored research agencies to share their knowledge, theories,
data and expertise in the effort to find safe and effective
treatments for KS.
* Pentosan is a sulfated polysaccharide being studied for
safety and dosage at the National Cancer Institute (NCI).
Pentosan is an anti-coagulant which is believed to have both
anti-HIV and anti-KS properties. We spoke with James Pluda, M.
D., who is directing this study. So far, three doses have been
studied in groups of three to six patients. Patients in the
lowest dose group have been receiving the drug for several
months. Some patients using the second dose showed some anti-
coagulant effects; therefore, it was decided to test an
intermediate dose rather than trying to increase the dose any
further. Other side effects seen so far have included reversible
liver function test abnormalities, and thrombocytopenia
(decreased platelet count).
Dr. Pluda explained that this drug does not kill the KS
cells; it just stops their growth, so it takes some time to see
an effect. He emphasized that he does not know how to use this
drug safely yet, and that people who have obtained it should only
use it with the careful monitoring of a physician experienced
with the drug. All slots for the NCI study have been filled.
* rPF4 is a recombinant (genetically engineered) version of
a protein which is found in platelets, a type of blood cell. It
has been found by researchers at Repligen Corporation to inhibit
angiogenesis in test tube studies and in animals with of a
variety of different tumors. It does not cure the tumors, but
prevents further growth.
According to Theodore Maione, Ph.D., principle investigator
of the animal studies, the activity of the compound has been
specifically targeted to the cell type found in blood vessels
(endothelial cells). KS lesions include a large number of fast
growing endothelial cells. Therefore, it is hoped that PF4 will
specifically target the cells which comprise the KS lesions.
While no formal toxicity tests have been conducted yet, no
toxicities have been observed in animals.
rPF4 is not yet ready to enter human trials. After animal
testing is completed, Dr. Maione told us that Repligen will file
an application with the FDA to do testing in people with KS. The
initial studies will use intralesional injections to determine if
there is a local tumor response. The FDA application will not be
filed until the end of 1991. In the meantime, Repligen is
scaling up production of the compound.
* Fumagillin analogues are synthetic variations of a
naturally occurring antibiotic. We asked Donald Ingber, M. D.,
Ph.D., the author of a recent article in Nature, about these
compounds. He told us that fumagillin itself is too toxic to be
used in humans but that the synthetic analogues have shown tumor
response in every solid tumor tested in animals to far. As with
PF4, the tumors generally do not regress, but their growth stops.
Dr. Ingber described these compounds as very specific to growing
tumors and non-toxic. He anticipates that therapy with this type
of compound would be life-long, as with diabetes.
No tests have yet been conducted in humans. The drug
company, Takeda Chemical Industries, Ltd., is attempting to
increase production of the compounds in order to begin clinical
trials, hopefully, within the next two years. These trials may
not, however, be in people with KS. The company is also involved
in an active search for other anti-angiogenesis compounds.
* "Gallo's Japanese KS Drug." For background on the
scientific and political issues involved in this area, refer to
Project Inform's PI Perspectives, issue number 9, October, 1990
(National 800/822-7422; California 800/334-7422) and AIDS
TREATMENT NEWS issue #99, March 16, 1990.
* Vitamin D3 analogues also appear to have anti-
angiogenesis properties in test-tube studies. Vitamin D3 itself
was not found to be effective in these studies. The authors
suggest that these vitamin D3 analogues may work by a similar
mechanism as the retinoids discussed earlier in this article.
* Synthetic heparin substitutes in combination with specific
steroids have been found to inhibit angiogenesis in two
experimental models. Heparin is a potent anti- coagulant;
however, fragments of the compound which have lost their anti-
coagulant properties retain anti- angiogenic activity when
combined with certain steroids. The most potent heparin
substitute reported on in this paper was beta-cyclodextrin
tetradecasulfate. This compound actually stimulated angiogenesis
when used alone, but was inhibitory in combination with a
steroid.
The heparin substitutes were combined with the steroid
hydrocortisone or with a hydrocortisone derivative which has lost
most of its steroid properties. We have spoken with many
physicians and researchers about this particular combination.
Without exception, two concerns were raised. The first was the
need to use heparin substitutes rather than heparin in order to
avoid the anti-coagulant effects. The second was that steroids
have been shown to stimulate the growth of KS when they have been
given to patients for other purposes. Therefore, while heparin
substitutes and steroid derivatives which lack the usual steroid
properties appear to be a potentially useful anti-angiogenic
combination, a standard heparin/steroid combination could be more
harmful than helpful.
Biological Response Modifiers in KS
Another area of intense scientific interest is in the use of
immune modulators, or biological response modifiers, in the
treatment of a wide variety of illnesses, including cancer and
HIV infection. Many of the biological response modifiers being
studied now are compounds which the body's cells produce
naturally as a part of the immune response or in normal blood
cell production (IL-2, the interferons, G-CSF, GM-CSF). Some
others are drugs which have been used for completely different
indications, but are suspected to have biological response
modifier properties as well (cimetidine, levamisole), and some
technologies have been developed specifically for this purpose
(Prosorba column).
Many people believe that one of the keys to managing HIV
infection will be combining one or more biological response
modifier(s) with various antivirals and prophylactic agents. It
is hoped that the biological response modifiers will, in a sense,
give the immune system a "boost" in fighting the various
infections, cancers, and KS associated with HIV infection.
* Interleukin-2 (IL-2) is a naturally occurring compound
which is being studied in people with KS at the U. S. National
Institutes of Health. A small study of IL-2 and AZT has recently
completed enrollment. A second study is using IL-2 plus alpha
interferon in people with HIV infection, including people with
KS. We were unable to reach anyone at the NIH or at Cetus
Corporation about these studies, and thus we are not sure of the
safety or efficacy of IL-2 in people with KS.
A study published in 1989 showed exacerbation of KS in three
of four patients using a combination of IL-2 and beta interferon.
It was suggested by the authors of that study that investigators
who use IL-2 should avoid intermediate to high dose bolus
(injection over a very short period of time) therapy. In
addition, it was suggested that levels of an undesirable type of
interferon, gamma-interferon, be monitored in these patients and
that therapy be adjusted if these levels increase significantly.
It will be important to know whether these changes were made
in the NIH studies and, if so, how such changes have affected the
outcome of people with KS who are using IL-2.
* Cimetidine (Tagamet) is an ulcer medication which has been
found to have both anti-angiogenic and immunomodulatory effects.
We first reported on the use of cimetidine in patients with KS in
1989 (see AIDS TREATMENT NEWS #80). Interest in studying this
drug for use in HIV and cancer has been nearly nonexistent since
that time. We have heard speculation that there might be little
interest in further studies because the patent is running out in
the next year, significantly decreasing the drug's profitability.
A small study performed by Thomas Smith, M. D., from the
Massey Cancer Center in Richmond, Virginia, was recently
published as a letter in the Journal of the National Cancer
Institute. Of the eight patients treated for skin, oral, and/or
gastrointestinal KS lesions, one experienced a complete response,
one a partial response, and one a mixed response. There were no
subjective or objective toxicities reported.
We spoke with Dr. Smith who told us that his impression is
that cimetidine is most effective in people with relatively high
T-helper cell counts. He explained that it seems to be useful in
skin and oral lesions, not just in gastrointestinal lesions.
Cimetidine appears to enable Natural Killer (NK) cells, the
immune system's main defense against cancer, to fight the KS.
Dr. Smith believes that cimetidine will ultimately be most
useful in combination with cancer chemotherapy and/or other
biological response modifiers. He also told us that patients who
cannot tolerate low doses of alpha interferon, his first choice
treatment in combination with AZT, may benefit from cimetidine.
Dr. Smith did not know of anyone else studying cimetidine.
Because of the small patient population where he practices, he is
not planning future studies of this drug in people with KS. If
he gets funding, he will be studying the drug in patients with
cancer.
* Levamisole is also a prescription drug which may have some
immunomodulatory function. Originally approved for the treatment
of worms, its approval was recently expanded to include the
treatment of advanced colon cancer (stage C) when it is used in
combination with fluorouricil, a cancer chemotherapy agent.
Although it is ineffective alone in colon cancer, it appears to
enhance the effect of the chemotherapy in this particular case.
This is another drug about which we have spoken to many
researchers and clinicians. Although none of them seemed greatly
enthusiastic about it, we believe that a small pilot study should
be conducted to determine if levamisole might have any efficacy
in KS, given its limited toxicity, immunostimulatory properties,
and utility in enhancing chemotherapy in colon cancer.
* We first discussed the Prosorba (tm*) Column (Protein A)
in 1989 (see AIDS TREATMENT NEWS issue #75) when we described the
four year experience of Dobri Kiprov, M. D., at Children's
Hospital in San Francisco. Dr. Kiprov and others conducted a
Phase I study of the Prosorba column in people with KS and
reported a response rate of 42%. Because of the relative safety
and efficacy demonstrated in this early clinical trial, Dr.
Kiprov told us that he feels that further studies should be
pursued rapidly. (*Prosorba is a registered trademark of IMRE
Corporation.)
The Prosorba column is used to remove circulating immune
complexes from the blood. These complexes, comprised of
antibodies and antigen, are believed to play a role in
suppressing the immune system. Therefore, it is believed that
the Prosorba column may be effective against both KS and HIV.
Frank Jones, Ph.D., CEO of IMRE Corporation, the
manufacturer of the Prosorba column, told us that financial
difficulties have delayed additional studies in people with KS.
However, a Phase II protocol is written, and Dr. Jones hopes to
implement it at up to five institutions some time this year.
This clinical trial will involve about 100 patients and run for
one and a half to two years.
Dr. Kiprov suggested that the Prosorba column should be
tested in combination with other biological response modifiers,
such as interferon. According to Dr. Kiprov, these combinations
are being used to treat people with breast cancer in Europe. He
also believes that such combinations may be effective in treating
the primary HIV infection.
The Prosorba column is currently approved for use in
idiopathic thrombocytopenia purpura (platelet count below
100,000/mm3). Dr. Jones told us that some U. S. physicians are
currently using it in KS even though it is not yet approved for
that indication.
A Note on Hyperthermia
Whole body hyperthermia made dramatic press headlines and
was quickly dismissed as an HIV "cure" by most researchers,
clinicians, and activists last year. However, the local or
regional use of heat to enhance chemotherapy treatment or
radiation has been and continues to be evaluated in a wide number
of cancers by researchers throughout the world. Hyperthermia may
well prove to be a useful adjunctive therapy in the treatment of
cancer and KS.
Conclusion and Comment
There are two general approaches to take in dealing with KS.
The first is to take the existing therapies available today,
combine them or refine them, and try to make them as effective as
possible, with the minimum amount of toxicity. This is being
done by the ACTG, the US government-sponsored group which has the
biggest responsibility for testing AIDS-related drugs. The
latest plans for ACTG trials include combining chemotherapy drugs
with the newer anti-retrovirals ddC and ddI, in the hopes that
these combinations will be less toxic than AZT with chemotherapy.
The importance of the use of GM-CSF and, by assumption, G-CSF in
KS has also been demonstrated by ACTG studies; as these drugs
become available, they will probably have a small but significant
impact on the lives of people with KS.
The second approach which must be taken is to recruit the
basic research experts to work on understanding the mechanisms
involved in KS and to develop novel approaches to dealing with
this condition. When advances in understanding are made, as they
are being made in the area of angiogenesis, these advances need
to be applied to people as quickly as is safely possible.
Preclinical screening tests need to be conducted to compare a
large number of compounds to find the most effective and safest.
Then some agency needs to be ready to go with human trials. We
believe instituting this approach should be a very high priority
among those who set research policy in KS.
References
1. Fischl, MA, Krown, SE, Lane, HC, and others. Alpha
interferon: the questions and answers. PAACNOTES. May/June,
1990; volume 2, number 3, pages 115-121.
2. Krown, SE. The role of interferon in the therapy of epidemic
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number 2, supplement 3, pages 27-33.
3. Northfelt, DW. Clinical presentation and treatment of AIDS-
related Kaposi's sarcoma. AIDS Medical Report. September 1990;
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