Medical Hypotheses (1992) 39, 22-29
Kaposi's Sarcoma and HIV
E. PAPADOPULOS-ELEOPULOS(1), V. F. TURNER(1), and J. M.
PAPADIMITRIOU(2)
(1) Department of Medical Physics Emergency
Department, Royal Perth Hospital, (2) Department of Pathology University
of Western Australia
Abstract - Recently published informed debate affords strong
indication that in patients with the Acquired Immune Deficiency
Syndrome, HIV cannot, directly or indirectly, be the cause of Kaposi's
sarcoma. This paper provides reasons for disallowing a current
alternative theory that Kaposi's sarcoma is due to an unidentified
sexually transmitted infectious agent and proposes instead that Kaposi's
sarcoma is the result of prolonged and repeated exposure to nitrites
and/or semen. If this alternative hypothesis is strengthened by
confirmation of its predictions then the relationship of HIV to Kaposi's
sarcoma, one of the principal AIDS-associated diseases, becomes somewhat
remote. This may facilitate a shift of emphasis and encourage the
development of alternative therapies.
A theory is a good theory if it satisfies two requirements:It must
accurately describe a large class of observations on the basis of a
model that contains only a few arbitrary elements,and it must make
definite predictions about the results of future observations.
STEPHEN HAWKING
Introduction
In spite of the passage of more than a century since Kaposi's
original description, Kaposi's sarcoma (KS) remains enigmatic with its
precise nature in doubt. Recently even its classification as a malignant
neoplasm has been questioned and John Brooks, a pathologist from the
University of Pennsylvania, has argued that KS is a "benign potentially
reversible hyperplasia that may at times terminate in true malignancy"
(1).
Summary of KS sub-types.
Kaposi's sarcoma is classified on the basis of pathological,clinical
and epidemiological descriptions (2). Epidemiologically Kaposi's sarcoma
occurs as "Sporadic", "Endemic","Iatrogenic" and "Epidemic" disease with
obvious major differences between these sub-groups. The "Sporadic" type
has a predeliction for Italian and Ashkenazy Jewish males over the age
of sixty years (although in a series from the Armed Institute of
Pathology published in 1959 22% of the patients were black (3)). This
sub-type of KS is associated with a near normal life span. However,some
cases exhibit the aggressive form and there are cases occuring in
younger patients under the age of 45 years (4).
The "Endemic" group,which constitutes the highest caseload in the
world,occurs in eastern equatorial Africa. Here KS affects young adults
(25-45 years of age) and children between the ages of two and fifteen.
Any of the clinical patterns may occur in this group and there is an
appreciable incidence of the generalized variety in the young adults and
children,most of whom die within two years of diagnosis (5). Prior to
the AIDS era "Iatrogenic" KS accounted for approximately 15% of all
cases enumerated in Europe and North America (2). These were associated
with immunosuppressive agents administered to organ transplant
recipients or to patients with other diseases. The incidence of post
transplant KS in the United States is 0. 18-0. 3% of all transplant
patients while interestingly the incidence in Saudi Arabia is
considerably higher at 5. 3% (2). Penn,who reported a series of 68 post
organ transplant cases from the USA, considered that 72% were
"benign"(skin and mucosa involved) and 28% malignant(gastrointestinal
and respiratory involvement) (2). The reason why KS and also lymphomas
occur in these patients while there is no increased incidence of the
common epithelial neoplasms is unclear. However,in a comprehensive
review of this subject published in 1982 Kinlen discounted failure of
immune surveillance and argued the case for a specific viral- related
effect in the pathogenesis (6).
In the early 1980's the Centre for Disease Control (CDC) in Atlanta
USA observed a high frequency, 26 cases by July 1981, of KS occurring in
young homosexual men (4). Eight of these patients died within 24 months
of diagnosis. Thus was ushered in "Epidemic" KS,that associated with the
Acquired Immune Deficiency Syndrome (AIDS). In addition to KS many of
these original patients also had opportunistic infections and in four a
diagnosis of Pneumocystis carinii pneumonia (PCP) was made by open lung
biopsy. At this very early stage in the evolution of the
syndrome,AIDS,for all practical purposes,consisted entirely of KS and
PCP. In 1982 Robert Gallo,who had spent many years researching
retroviruses and cancer at the National Cancer Institute, proposed that
the cause of AIDS was a retrovirus (7). In 1983 Luc Montagnier and
fellow researchers at the Pasteur Institute detected a
retrovirus,presently known as Human Immunodeficiency Virus Type I
(HIV-1),in the cultured T cells from a homosexual patient with
lymphadenopathy (8). With few exceptions (9,10), the hypothesis that the
causative agent of AIDS is HIV has been universally accepted. However,as
early as 1984 it became apparent that HIV does not exist in the cells
from the lesions of KS and hence cannot cause KS directly (11). It was
assumed then,that in AIDS patients,HIV indirectly caused KS and
opportunistic infections by its detrimental effects on the immune
system. Alterations in T lymphocyte subsets (T4 and T8 cells) and a
decrease in the T4/T8 ratio were believed to be the hallmark of AIDS and
the immune deficit that defined this condition (7). However, in
heterosexuals, evidence existed that many diverse causes could be
associated with the same (and additional) laboratory abnormalities of
immunodeficiency that were manifest in AIDS patients. These causes
included a number of infections (12),blood transfusion (13),the intake
of many drugs including antibiotics (14) and even solarium exposure
(15). It is noteworthy that in none of these reports was there a single
case of associated KS.
Conversely, some researchers at the time were of the opinion that KS
could result from immunostimulation with angiogenesis-promoting factors
formed as a result of alterations in immunoregulation,a mechanism that
had been earlier suggested in patients receiving immunosuppressive
therapy (16). As recently as 1988 researchers from the Walter Reed Army
Institute of Research,disallowed KS from the definition of AIDS stating
that,"in our system the presence of opportunistic infection is a
criterion for the diagnosis of AIDS,but the presence of Kaposi's sarcoma
is omitted because the cancer is not caused by immune-suppression"(17).
Most recently data has been published confirming the fact that in some
homosexuals KS can occur in the complete absence of both immune
deficiency and HIV (18). Thus neither HIV nor immune deficiency is a
prerequisite for the development of this disease,at least in
homosexuals.
Despite all this uncertainty,acceptance of HIV as the cause of
Kaposi's sarcoma prevailed for over six years until early 1990 (19). In
January of that year Valerie Beral and her colleagues from the CDC
published a paper (20),in which they concluded that "Kaposi's sarcoma in
persons with AIDS may be caused by an as yet unidentified infectious
agent transmitted by sexual contact". This argument was based on the
epidemiological spectrum of KS in different AIDS risk groups and the
fact that in homosexuals KS may appear in the absence of HIV. This
conclusion, to which we cannot accede, is based on the authors'
assumptions that:-
(a) "The agent that causes Kaposi's sarcoma must be the same
irrespective of whether there is any associated HIV infection". Implying
that KS in all individuals, homosexual or heterosexual, African or
European, black or white, is caused by one and the same agent).
(b) The agent is infectious but is not HIV.
Before this theory becomes accepted and as a necessary overture to
our own hypothesis, we will present evidence that:-
(a) There is no need to assume that the same causative agent is
responsible in all cases of KS regardless of age, race or geographic
region.
(b) The assertions upon which Beral and her colleagues base their
infectious theory are themselves only hypotheses which their various
authors acknowledge as being largely unproven and have even suggested
alternative explanations.
(c ) There are plausible explanations for the apparent correlation
between sexual activity and KS in homosexuals other than sexual
transmission of an infectious agent.
Common Aetiology.
It is inconsistent with current knowledge of other neoplasms to
assume that KS is exceptional by having a single cause in all
individuals. At present it is well recognised that many neoplasms have
multiple aetiologies. One may also argue that,since the precise cause of
most if not all neoplasms is unknown,it is impossible to state with any
certainty that a particular type has only one definite aetiology.
Infectious aetiology.
Beral derives support for an infectious origin of KS from the
following data:-
1. The massive increase in KS in AIDS patients-"at least 20,000 times
more common in persons with AIDS than in the general population and 300
times more common than in other immunosuppressed groups".
2. The fact that "few known human carcinogens increase the risk by
more than 100 fold and,in the best documented example, hepatitis-B and
hepatoma,the cause of the cancer is an infection".
3. In immunosuppressed subjects such neoplasms "may have an
infectious cause" (20).
However a high incidence of a relatively rare disease in a confined
population does not necessarily indicate an infectious origin. Malignant
mesotheliomas are exceptionally rare in the general
population,approximately one case per million (21). However,in a study
published in 1988 of a cohort of individuals employed by the Australian
Blue Asbestos Company that operated in Wittenoom in Western
Australia,there were 33 deaths from mesothelioma recorded. Even though
this study grossly underestimates the incidence of mesothelioma,it still
reveals a greater than 5000 fold risk of dying from this disease in
these individuals (22). Asbestos, a non-infectious agent,has been
accepted as the major causal factor in this condition. In another study
of 2271 deaths of insulation workers who came into regular contact with
asbestos the cause of death in 175 was mesothelioma,an incidence of 7706
in 100,000 (8%)(23). The risks quoted in these studies are considerably
higher (50 and 800 times) than that associated with hepatitis-B refered
to by Beral.
The data concerning hepatitis-B virus (HBV) and hepatoma were taken
by Beral et al from a paper by Beasley et al (24). This paper describes
a prospective study of 22,707 male civil servants from Taiwan where it
was found that"the incidence of primary hepatocellular carcinoma (PHC)
among carriers of hepatitis-B surface antigen (HBsAg) was much higher
than among non-carriers (1,158/100,000 vs 5/100,000)". These authors put
forward the hypothesis that hepatitis-B virus has a primary role in the
aetiology of PHC, an hypothesis that so far has not been conclusively
proven. The authors themselves state "alternative explanations of the
very high relative risk among HBsAg carriers are that HBV is a cofactor
with another aetiological agent or is simply a risk factor. Case control
studies have repeatedly shown that PHC does occur in HBsAg negative
subjects. This finding can be taken to mean either that HBV is not
sufficient to cause PHC or that there are several independent causes".
The authors also refer to the geographical correlation between the
amount of aflatoxin in food and the incidence of PHC that occurs in
Africa. They postulate that a similar relationship may exist in Taiwan
but also point out that,due to the eclectic nature of the Chinese
diet,there are insurmountable difficulties in studying this particular
factor. In support of their argument Beral et al also refer to a review
paper published by Kinlen in 1982 (6). This paper is cited as showing
that the increase in KS in immunosuppressed patients is caused by an
infectious agent. However the substance of Kinlen's review is to:
1. Acknowledge the appreciable increased incidence of non-Hodgkins
lymphomas,primary hepatocellular carcinoma,melanoma and KS in
immunosuppressed individuals.
2. To refute the immune surveillance hypothesis of carcinogenesis by
pointing to the fact that these same individuals do not share an
increased incidence in the common epithelial neoplasms.
3. To argue,without any convincing proof,a role for ultraviolet light
in the skin cancers,HBV in hepatocellular carcinoma,Ebstein-Barr virus
(EBV) for lymphoma and cytomegalic inclusion virus (CMV) for Kaposi's
sarcoma.
4. To speculate that antigenic stimulation or even the
immunosuppressive agents themselves may directly cause some of these
neoplasms. Thus Beral and her colleagues base their infectious theory of
KS either on an unproven hypothesis (HBV and hepatoma;lymphomas and EBV)
or on an hypothesis (CMV and KS) which they (and many others) consider
to be incorrect.
Sexual Transmission.
Beral and her co-authors reported several interesting and relevant
findings concerning the incidence of KS in the various AIDS risk groups.
Forty per cent of homosexual and bisexual men in 1985 and approximately
21% in 1988 had KS compared with approximately 1% of haemophiliac AIDS
patients. The next highest incidence,6%,was from patients born in the
Carribean and African countries but living in the USA. There were 73
cases of KS in transfusion recipients. KS was most unusual in patients
less than 15 years old,occuring in 1.6% of all children with AIDS,(13
cases). All but one of these US born children with KS were children of
Haitian women, the other child was born in Central America and raised in
the United States.
These data were interpreted as evidence that:-
(i) KS is "caused by an as yet unidentified sexually transmitted
infection".
(ii) The appearance of the agents in transfused patients older than
15 years "may be by routes other than blood".
(iii) The agent in children younger than 15 may be perinatally
transmitted.
If the above conclusions are correct then because:-
(i) There is no cure for the disease;
(ii) In non AIDS patients the disease is chronic,that is median
survival is 8-13 years;
(iii) Prostitutes have a higher frequency of all the sexually
transmitted diseases especially in Africa where treatment is not readily
available; one would expect a high incidence of KS in families
(mother-child,husband-wife) and prostitutes.
However, in Africa where it was known as far back as 1962 (5) that
"the disease occurs not uncommonly in African children in the first
decade of life and is probably much underdiagnosed", the incidence of KS
in women (mothers) including prostitutes like elsewhere in the world is
low,with a male to female ratio of 17:1. Among the many theories put
forward before the AIDS era regarding aetiology of KS,the two most often
mentioned were infectious and genetic. In order to test these theories
many investigators searched for a familial incidence of KS. A very small
number of cases with a familial distribution of KS were reported before
the AIDS era but in none of these were sexual or mother-child
relationships involved (25). Thus before AIDS there was no evidence to
suggest that:
1. KS, at least in heterosexuals, is sexually transmitted,
2. The cause of KS is an infectious agent.
Even today with the exception of CMV and HIV,which are still
considered by some as major aetiological factors,all the other factors
considered possibly pathogenic are non-infectious (2).
Non-infectious aetiology
We hypothesize that in homosexual AIDS patients KS is caused by
prolonged and repeated exposure to semen,nitrites or both agents
which,under normal circumstances,in non-AIDS patients, are either absent
or largely excluded from contact with endothelial targets in the
vascular or lymphatic system. Both these agents are potent oxidising
agents in biological systems (26,27) and indeed oxidation is essential
for many of their biological properties and effects. For example,sperm
maturation (and thus fertilisation) is a process which requires the
oxidation of sperm nuclear sulphydryl groups to disulphides (28). All
cells exhibit a thiol cycle and this cycle is a principal determinant of
many cellular functions including mitotic rate (26). Thus nitrites and
sperm, like all carcinogens and mitogens,by their oxidative nature may
induce perturbation of the thiol cycle,and this effect may underlie the
ample epidemiological evidence that semen and nitrites are alone the two
factors highly correlated with the appearance of KS in homosexuals
(29,30).
Nitrites.
Nitrites have as a major property a prominent effect on vasculature.
Although the use of nitrites (poppers) is highly correlated with the
appearance of KS in homosexuals, their causative role has been dismissed
because of the belief that it is impossible to disentangle their use
from sexual practices and also because they do not explain "the
occurrence of KS in children and elderly people with parenterally
transmitted HIV and in one tenth of AIDS patients in Africa where
nitrites cannot account for the pattern of occurence of KS" (20). The
only reason for preferring the explanation that an "undefined"
infectious factor relating to sexual behaviour appears to be the cause,
and not the alternative,appears to be a predisposition to favour a
sexually transmitted infection. In fact in homosexuals evidence exists
that the variable most strongly associated with KS is the consumption of
more than four "hits" of nitrites per night of use (30). The fact that
the effects of nitrites and sexual practices are "difficult to
disentangle" does not negate the possibility that nitrites acting alone
or in combination with another highly correlated variable may have a
direct causal role. While it may be true that Africans do not use
nitrites,it is also true that in Africans KS has existed independently
of AIDS, probably for centuries and, although not disproven,an
infectious origin of KS in Africa has been discounted as far back as
1962 (5). The common diagnosis of KS in African patients post 1983 as
AIDS whilst "legal" (19) is a semantic convenience with little, if any,
scientific rationale,especially in relation to a putative common
pathogen.
KS in children
Beral states that,in the thirteen AIDS children with KS,the cases of
KS were "atypical" and admits that "diagnostic biases might exist".
Also,because all children were from Florida where nitrite abuse is most
prevalent and all but one were offspring of women born in Haiti,the
possibility cannot be excluded that:
1. Some of these children may not have developed KS.
2. Children of Haitian women,most of whom are descendents of African
slaves, may, like African children, have an appreciable incidence of KS
that has existed independently for many decades.
The mothers of these children may have used nitrites.
KS in recipients of blood transfusion.
A total of 73 cases of transfusion associated KS have been reported
by the CDC up to March 31st 1989. In these patients not one
of their sexual partners had KS. According to the CDC definition which
"accepts HIV as the cause of AIDS" KS occuring in anyone under the age
of 60 years, even when laboratory evidence regarding HIV infection was
either not obtained or was inconclusive, indicates AIDS. Individuals
with KS who are over the age of sixty and who have a positive antibody
test are also considered AIDS patients. KS which develops in persons who
received high doses or long term systemic corticosteroid or other
immunosuppressive/cytotoxic therapy but which were discontinued three
months before the appearance of the disease also indicates AIDS (19). In
the United States,where approximately 3. 8 million people are transfused
annually,approximately 20% receive blood for treatment of malignant
neoplasia (32).
Although exact data are unavailable it is certain that many of these
patients will have received varying combinations of immunosuppressive
therapy,radiation and chemotherapy,all agents known to be associated
with the appearance of KS (6). It is reasonable to question whether the
occurence of 73 cases of transfusion associated KS over a period of
eight years, an average of 9 cases per year, represents a phenomenon
peculiar either to the specific practice of blood transfusion or to the
AIDS era. In the United States the annual incidence of KS in the general
population pre-AIDS is unknown but is estimated to be 0.2-0.6 cases per
million (4). There are no data available on the incidence of KS in
transfusion recipients pre-AIDS but these persons,50% of whom die within
one year of transfusion, are likely to have a higher incidence than the
general population.
An incidence of nine cases in nearly four million transfused
therefore may not be significantly higher than expected since many of
the post 1981 transfused group would be expected to be under the age of
sixty years (and therefore fulfill the CDC AIDS definition), and/or
suffering from malignancy. There has also been a well documented problem
in establishing a definite diagnosis of KS in AIDS patients, a factor
which relates both to diagnostic bias and histopathological
interpretation (20,32). In the absence of data to prove the contrary the
low incidence of KS documented by Beral et al may simply reflect the
presence,in this population,of other causes of KS which have previously
operated and continue to operate independently of AIDS related factors.
Also in the United States there are 2.5 million exclusively homosexual
males, and perhaps another 2.5 to 7.5 million who may have the
occasional homosexual liaison (33). There are also at least 1.1 million
IV drug users,11% of whom use nitrites. Furthermore there are estimates
that 1% of American students between the ages of 12-17 years of age use
nitrites at least ten times per month (34). The CDC publically accepts
that this is likely to be an underestimate as not every person
questioned would feel comfortable admitting to drug abuse or
homosexuality. We may therefore argue that since KS even post AIDS is so
rarely reported in the non-homosexual non-drug abuser population that
some, if not all, of the blood transfusion-associated KS cases may be
related to one of the above mentioned mechanisms which include
chemotherapeutic agents,radiation,semen and nitrite exposure-that is,to
a cause which is not a sexually transmitted infectious agent. Even if it
is true that not a single African,child or transfusion recipient is
exposed to nitrites there is still no compelling evidence to exclude
nitrites as a cause of KS in homosexuals since there is no proof that KS
in all these groups is caused by the one and the same factor. However in
the case of homosexuals with KS there is also other evidence which
suggests that nitrites may be aetiological agents:
1. One of the only two factors which changed in the lifestyle of
homosexuals in the late 1970's was increasing nitrite abuse (35).
2. In the early 1980's nitrite use became ubiquitous in California
and New York-the two areas where the vast majority of patients with KS
were found (35).
3. The latency period for the appearance of KS in patients treated
with immunosuppressive drugs for organ transplantation is similar to
that between homosexual exposure to nitrite and the appearance of the
disease (36).
4. The decrease in the incidence of KS in homosexual men coincided
with a decrease in nitrite abuse (37).
5. Nitrites and their metabolic products are mitogenic and
carcinogenic (36).
6. Nitrites have major pharmacological effects on blood vessels-the
site of the neoplasm-which is an unusual tissue for neoplastic
transformation (38).
Sexual practices.
A second factor directly relating to the development of KS is sexual
intercourse. While this may suggest that the disease at least in
homosexuals is caused by a sexually transmitted agent there are data
available from numerous large,well designed studies that strongly
support the hypothesis that semen itself has a direct causal role. All
these studies have shown that in homosexuals,the only sexual acts
directly related to both the developement of AIDS and Kaposi's sarcoma
is passive anal intercourse (30,39,40). One can surmise from these data
that if a large group of homosexuals could be studied where any
individual could be guaranteed to practise exclusively passive or active
intercourse and not both,then one would observe that:- (i) KS,like
pregnancy,can only be acquired by the passive partner. (ii) KS,like
pregnancy,cannot be sexually transmitted. As far as the cause is
concerned at least two possibilities can be entertained:-
1. In the passive partner KS could be caused by an infectious agent
found in the ejaculate which is not bidirectionally sexually
transmitted. The active partner would have to acquire the agent by other
means.
In the passive partner KS could be caused by a non-infectious agent
found in semen acting either alone or synergistically with nitrites.
That this is the case is strongly supported by the following data:-
1. Apart from nitrite abuse the second factor which changed in the
lifestyle of homosexuals in the mid 1970's was the high promiscuity rate
(35). There are also many examples from clinical practice of homosexual
men who admit to approximately one thousand partners per year. At 2-3 ml
per ejaculate this provides evidence that deposition of unusually large
amounts of semen into the rectum of an individual can occur,and that as
a consequence,semen may interact with and be absorbed by the intact or
traumatised bowel.
2. Unlike all the other sexually transmitted diseases,where the
possibility of infection is directly related to the number of sexual
partners,in homosexuals the number of sexual partners is only a risk in
relation to the number of episodes of passive anal intercourse (40).
3. Homosexuals have a relatively high incidence of gastrointestinal
cancers other then KS and several researchers have implicated semen in
the developement of these neoplasms (41,42).
4. Reid and Coppelson described the relative high incidence of
cervical cancers in promiscuous Australian women. Amongst other
factors,this was attributed to semen (43).
5. Spermatozoal penetration into the submucosa of the rat uterine
epithelium can induce pre-cancerous changes in the cervix (44).
6. In humans spermatozoa fulfil a well known mitogenic role in
embryogenesis. There is also in vitro evidence that spermatozoa can
penetrate somatic mammalian cells and that sperm DNA is incorporated
into recipient nuclei (45).
Permanent transformation occurs within a few days and this is
associated with abnormalities in morphology and growth of recipient
cells including the appearance of bi- and multi-nucleated cells (45,46).
7. Extracts of pooled human semen are potent promoters of skin tumour
production in the skin of mice previously treated with topical
carcinogen (47).
8. Injection of sperm suspensions directly into the anterior prostate
of experimental rats can produce carcinoma of the prostate with
metastases (48).
9. Intratesticular injection of autologous spermatozoa in the rat can
produce malignant testicular neoplasms (49).
10. Seminal plasma is especially rich in polyamines, a group of
positively charged substances which have a significant role in cellular
proliferation (50,51). Moreover in human semen the polyamine spermine is
present in higher concentrations than in any other tissue or body fluid
and it, like other seminal polyamines, is oxidized by enzymes derived
from seminal vesicle secretion. The presence of polyamines in higher
than normal concentration in malignant tissue has prompted their assay
as a diagnostic aid in cancer patients and serial measurement has been
suggested as a treatment marker during chemotherapy. (Interestingly it
appears that polyamines are essential for optimal growth of most
microorganisms and inhibitors of their biosynthesis have been
successfully employed for the treatment of protozoal diseases including
Pneumocystis carinii pneumonia (52)).
Thus a mitogenic and carcinogenic effect of nitrites and semen (or
their derivatives) may better account for the presently available
epidemiological data on KS in homosexuals than a currently
unspecified,unknown new,sexually transmitted infectious agent.
Conclusions and Predictions
We present evidence that the oxidative effects of semen and/or
nitrites play a pivotal role in the development of KS in homosexual AIDS
patients. If anally deposited semen causes KS, we predict that
case-controlled studies should show that:-
1. In a group of exclusively passive homosexuals who also use
nitrites,cessation of exposure to semen by the use of condoms should
lead to a reduction in the frequency of KS.
2. Women who do not use drugs including nitrites but who practise
anal intercourse should have a higher incidence of KS than those who do
not. If nitrites play an aetiological role in the development of KS then
future observation will show that:-
1. In groups of people who inhale nitrites and who have a high
incidence of KS the frequency should diminish when all other factors are
kept the same but nitrite inhalation is stopped.
2. In case control studies where the test population is identical in
all aspects to the control population apart from inhaling high
concentrations of nitrites,a high frequency of KS should be seen in the
test cases but not in the controls.
If anally deposited semen by itself cannot cause KS,but is an
exacerbating factor when nitrites are used, then case-controlled studies
should show an excess of KS in homosexuals who in addition to inhaling
nitrites, practise exclusive passive anal intercourse.
Most importantly, this theory predicts that reducing agents may
prevent or even ameliorate KS in homosexual AIDS patients. In this
regard, the recent discovery of significant reductions in cellular
reduced glutathione in AIDS patients lends strong support for
contemplating such a therapeutic strategy (53,54,55).
ACKNOWLEDGEMENTS
We wish to thank all our colleagues and especially
Bruce Hedland-Thomas, David Causer, Richard Fox, John Peacock, Rod
Minchin, David Prentice, Ronald Hirsch, Patricia Shalala, Keith Jones,
Alun Dufty, June Rider Jones, Coronary Barrow, Dorothy Davis Julian
Smith and Wallace Turner for their continued support and
assistance.
REFERENCES
1. Brooks JB,Kaposi's Sarcoma:A Reversible Hyperplasia.
Lancet 2:1309,1986.
2. Harawi SJ Kaposi's Sarcoma. p 83 in Pathology and
Pathophysiology of AIDS and HIV-Related Diseases. (SJ Harawi,CJ
O'Hara,eds) Chapman and Hall Medical,London 1989.
3. Cox FH,Helwig AB. Kaposi's Sarcoma. Cancer
12:289,1959.
4. Friedman-Kein AE,Laubenstein L,Marmor M et al.
Kaposi's sarcoma and Pneumocystis carnii pneumonia among homosexual
men-New York and California. Morbidity and Mortality Weekly Report
30:305,1981.
5. Friedman-Kein AE,Saltzman BR. Clinical
manifestations of classical,endemic African,and epidemic AIDS-associated
Kaposi's sarcoma. J Am Acad Dermatol 22:1237,1990.
6. Kinlen LJ. Immunosuppressive Therapy and Cancer.
Cancer Surv 1:565,1982.
7. Gallo RC. The AIDS virus. Scientific American
256:39,1987.
8. Montagnier L,Barre-Sinoussi F,Chermann JC et al.
Isolation of a T-Lymphotrophic Retrovirus from a patient at Risk for
Acquired Immune Deficiency Syndrome (AIDS). Science 220:868,1983.
9. Deusberg PH. Retroviruses as Carcinogens and
Pathogens: Expectations and Reality. Cancer Res 47:1199,1987.
10. Papadopulos-Eleopulos E. Reappraisal of AIDS Is the
oxidation induced by the risk factors the primary cause? Med Hypotheses
25:151,1988.
11.Shaw MS,Hahn BH,Araya JE,Groopman JE,Gallo
RC,Wong-Staal F. Molecular Characterisation of Human T-Cell Leukemia
(Lymphotrophic) Virus Type III in the Acquired Immune Deficiency
Syndrome. Science 226:1165,1984.
12. Williams RC,Koster FT,Kilpatrick KA. Alterations in
Lymphocyte Cell Surface Markers during Various Human Infections. Am J
Med 75:807,1983.
13. Grady RW,Akbar AN,Giardina PJ,Hilgartner MW,de
Sousa M. Disproportionate lymphoid subsets in thalassaemia major:the
relative contributions of transfusions and splenectomy. Br J Haematol
59:713,1985.
14. Finch R. Immunomodulating effects of antimicrobial
agents. J Antimicrob Chemother 6:691,1980.
15. Hersey P,Hasic E,Edwards A,Bradley M,Haran
G,McCarthy WH. Immunological Effects of Solarium Exposure. Lancet 1:
545,1983.
16. Levy JA,Zeigler JL. Acquired Immunodeficiency
Syndrome is an opportunistic infection and Kaposi's sarcoma results from
secondary immune stimulation. Lancet 2:78,1983.
17. Redfield RR,Burke DS. HIV Infection:The clinical
Picture. Scientific American 259:70,1988.
18. Friedman-Kein AE,Saltzman BR,Cao Y,Mirabile M,Li
JJ,Peterman TA. Kaposi's sarcoma in HIV negative homosexual men. Lancet
1:168,1990.
19. Revision of the CDC AIDS Surveillance Case
Definition for the Acquired Immunodeficiency Syndrome. Journal of the
American Medical Association 258:1143,1987.
20. Beral V, Peterman TA, Berkelman RL, Jaffe HW.
Kaposi's sarcoma among persons with AIDS:a sexually transmitted
infection? Lancet 335;123,1990.
21. Peto J. Fibre carcinogenesis and environmental
hazards. In Non-occupational exposure to mineral fibres. IARC Scientific
Publications,Lyon 1989.
22. Armstrong BK, deClerk NH, Musk AW, Hobbs MST.
Mortality in miners and millers of crocidolite in Western Australia Br J
Ind Med 45:5,1988.
23. Craighead JE, Abraham JL, Churg A, Francis HY et
al. The Pathology of Asbestosis-Associated Diseases of the Lungs and
Pleural Cavities:Diagnostic Criteria and Proposed Grading Schema. Arch
Pathol Lab Med 106:544,1982.
24. Beasley RP, Hwang HY, Lin CC, Chien CS.
Hepatocellular carcinoma and Hepatitis-B Virus. Lancet
2:1129,1981.
25. Oettle AG. Geographical and Racial Differences in
the frequency of Kaposi's sarcoma as evidence of environmental or
genetic causes. Unio Internarionalis Contra Cancrum 18:330,1962.
26. Papadopulos-Eleopulos E. A Mitotic Theory. J theor
Biol 96:741,1982.
27. Singlemann E, Wetzel E, Adler G, Steffen C.
Erythrocyte Membrane Alterations as the Basis of Chlorate Toxicity.
Toxicology 30:135,1984.
28. Pellicciari C, Hosokawa Y, Fukada M, Manfredi
Romanini MG. Cytofluormetric study of nuclear sulphydryl and disulphide
groups during sperm maturation in the mouse. J Reprod Fertil
68:371,1983.
29. Haverkos HW. Factors associated with the
Pathogenesis of AIDS. J Infect Dis 156:251,1987.
30. Marmor M. Epidemic Kaposi's Sarcoma and Sexual
Practices Among Male Homosexuals. p 291 in AIDS:The Epidemic of Kaposi's
Sarcoma and Opportunistic Infections. (AE Freidman-Kein,LJ
Laubenstein,eds) Masson Publishing USA Inc,Chicago 1984.
31. Haverkos HW. Epidemiology of AIDS in Haemophiliacs
and Blood Transfusion Recipients. Antibiot Chemother 38:59,1987.
32. Giard C, Johnson WC, Graham JH. Cutaneous
angiosarcoma. Cancer 26:868,1970.
33. Anonymous. CDC Paints a Picture of HIV Infection in
U.S.[Editorial]. Science 239:253,1988.
34. Haverkos HW, Dougherty J. Health Hazards of Nitrite
Inhalants. Am J Med 84:479,1988.
35. Levine AS. The Epidemic of Acquired Immune
Dysfunction in Homosexual Men and Its Sequelae-Opportunistic Infections,
Kaposi's Sarcoma, and Other Malignancies:An Update and Interpretation.
Cancer Treatment Reports 66:1391,1982.
36. Newell GR, Mansell PW, Spitz MR, Reuben JM, Hersh
EM. Volatile Nitrites Use and Adverse Effects Related to the Current
Epidemic of the Acquired Immune Deficiency Syndrome. Am J Med
78:811,1985.
37. Haverkos HW, Friedman-Kien AE, Drotman P, Morgan
Meade W.The changing incidence of Kaposi's sarcoma among patients with
AIDS. J Am Acad Dermatol 22:1250,1990.
38. Nickerson M. Vasodilator Drugs. p 745 in The
Pharmacological Basis of Therapeutics. 5th ed. (LS Goodman,A
Gilman,eds) The Macmillan Company,London 1970.
39. Kingsley LA, Detels R, Kaslow R et al. Risk Factors
for seroconversion to human immunodeficiency virus among male
homosexuals. Lancet 1:345,1987.
40. Godfried JP, van Griensven G, Tielman R et al. Risk
factors and prevalence of HIV antibodies in homosexual men in the
Netherlands. Am J Epidemiol 125:1048,1987.
41. Daling JR, Weiss NS, Hislop TG et al. Sexual
practices, sexually transmitted diseases,and the incidence of anal
cancer. NEJM 317:973,1987.
42. Kondlapoodi P. Anorectal Cancer and Homosexuality.
Journal of the American Medical Association 248:2114,1982.
43. Reid BL, French PW, Singer A, Hagan BE, Coppleson
M. Sperm Basic Proteins in Cervical Carcinogenesis:Correlation with
Socioeconomic Class. Lancet July 8th:60,1978.
44. Stein-Werblowsky R. The induction of precancerous
changes in at the uterine epithelium of the rat:the role of spermatozoa.
Gynecol Oncol 5:251,1977.
45. Bendich A, Borenfreund E, Sternberg SS. Penetration
of Somatic Mammalian Cells by Sperm. Science 183:857,1974.
46. Bendich A, Borenfreund E, Beju D. Alteration of
Mammalian Somatic Cells Following Uptake of Spermatozoa. Acta Cytol
18:544,1974.
47. Tokuda H, Ito Y, Kanaoka T, Yoshida O. Tumour
promoting activity of extracts of human semen in Sencar mice. Int J
Cancer 40:554,1987.
48. Stein-Werblowsky R. On the aetiology of cancer of
the prostate. Eur Urol 4:370,1978.
49. Stein-Werblowsky R. On the aetiology of testicular
tumours. An experimental study. Eur Urol 4:57,1978.
50. McCann PP, Pegg AE, Sjoerdsma A, eds. Inhibition of
Polyamine Metabolism Biological Significances and Basis for New
Therapies. Academic Press Inc. ,Orlando,1987.
51. Bachrach U, Heimer YM, eds. The Physiology of
Polyamines Volume I. CRC Press Inc., Florida,1989.
52. Sjoerdsma A, Golden JA, Schechter PJ, Barlow JR,
Santi DV. Successful Treatment of Lethal Protozoal Infections with the
Ornithine Decarboxylase Inhibitor,alpha Difluoromethylornithine. Trans
Assoc Am Phys 97:70,1984.
53. Buhl R, Jaffe JA, Holroyd KJ et al. Systemic
glutathione deficiency in symptom-free HIV seropositive individuals.
Lancet 2:1294,1989.
54. Turner VF. Reducing Agents and AIDS-Why are we
waiting? Medical Journal of Australia 153:502,1990.
55. Papadopulos-Eleopulos E, Hedland-Thomas B, Causer
DA, Dufty AP. An alternative explanation for the radiosensitization of
AIDS patients. Int J Radiat Oncol Biol Phys 17:695,1989.