Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Treatment of HPV infections and Cancer
The present invention relates to prevention and treatment of human papilloma
virus infections and also to the prevention and treatment of cancer.
Many different forms of cancer exist, and it is believed that there are many
different causes of the disease. The incidence of cancer varies, but it
represents the
second highest cause of mortality, after heart disease, in most developed
countries.
Current estimates suggest that one in three Americans alive at present will
suffer from
some form of cancer. Methods of treatment for cancer exist, although there is
a well
recognised need to develop new and improved techniques. Furthermore, there is
also a
requirement to develop chemopreventative agents that could be used to inhibit
the
development of cancer in the general population, susceptible high-risk
individuals or
as an agent to prevent re-occurrence of disease in individuals already
affected.
Human tumour viruses are emerging as a major cause of human cancer and
there is now a great deal of evidence which supports the contention that these
viruses
cause cancer by inducing geiletic instability in infected cells. For example,
the E6
protein from high risk forms of the human papilloma virus such as type 16
(HPV16)
is known to induce genetic instability producing abnormal numbers of
centrosomes,
multinucleation and nuclear atypia although the mechanisms underlying this
process
are poorly understood.
According to a first aspect of the invention there is provided the use of an
agent that inhibits the chymotryptic activity of the 26s unit of the
proteosome in the
manufacture of a topical medicament to prevent infection,, or to effect,
eliznination, of
human papilloma virus (HPV) from tissues of subjects infected with, or
susceptible to,
such viruses.
According to a second aspect of the preserit invention there is provided a
method for the prevention of infection, or to effect elimination, of human
papilloma
virus (HPV) from tissues of subjects infected with, or susceptible to, such
viruses
comprising topically administering to a patient in need of such treatment an
effective
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amount of an agent that inhibits the chymotryptic activity of the 26s unit of
the proteosome.
The inventors have found to their surprise that agents which inhibit the
chymotryptic activity of the 26s unit of the proteosome (some of which have
been
proposed for use as orally ingested medicaments for the systemic clinical
management of retroviral infections such as HIV) are also clinically useful
for topical
administration to tissues to prevent or treat malignancies caused by human
papilloma
virus.
The invention has been based on the inventors findings relating to the effects
of agents according to the first aspect of the invention, such as indinavir,
on HPV
infections and particularly cancers associated with such infections. It has
been
recognised that high-risk human papilloma virus type 16 (HPV 16) or human
papilloma virus type 18 (HPV18) are particularly associated with the aetiology
of
cervical carcinoma whereas low-risk viruses such as HPV6/11 are associated
with
genital warts. Low and high risk HPVs produce different forms of the viral E6
oncoprotein with HPV 16 E6 or HPV 18 E6 producing effects, which are thought
to
more readily promote malignant conversion than, for example, HPV6 E6. Clearly
there is a great deal of interest in the cellular targets of such viral
oncoproteins since it
is realised that these may be proteins with a pivotal role in the
transformation process.
HPV 16 E6 is known to associate with a cellular protein E6 accessory protein
(E6AP)
that is an E3 ubiqitin ligase. This interaction causes a gain of function
activation of
the E3 ligase which inappropriately labels (ubiquitinylates) several important
cellular
proteins for degradation by the 26S proteasome eg p53. Since p53 is the most
widely
studied of all tumour suppressor proteins, this interaction is believed to be
important
in the development of HPV related malignant disease.
The inventors conducted experiments that demonstrated that both HPV16 and
6 E6 proteins interacted very strongly with the tissue, serine protease
inhibitor alpha-
1-antichymotrypsin (AACT). This interaction is likely to inhibit the activity
of AACT
thereby implying that activation of chymotryptic activity may: be a
consequence of
HPV infection. Furthermore, since this interaction was observed with both low
and
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high risk HPV E6 proteins this implies that it is necessary for HPV related
disease per se.
However the proteasome is very complex and the inventors are the first to
realise that the chymotryptic activity of the proteasome may be the preferred
target for
treatment of HPV infections. It is known that Indinavir and related inhibitors
can
suppress the chymotryptic activity of the 26S proteasome but have little
effect on the
petidyl-glutamyl-peptide hydrolysing activity of this complex or the three
peptidase
activities of the 20S proteasome. Thus the inventors are the first to propose
that the
anti-chymotryptic activity of indinavir and related compounds may be useful
for the
treatment of HPV infections
Since the E6 protein from low risk virus also interact with AACT the
inventors results indicate that agents according to the invention are also
useful for the
treatment of low risk HPV infections (e.g. genital warts caused by HPV6/11) as
well
as high risk H.PV infections (HPV 16, HPV 18 etc) that can lead to the
development
of cancer (eg. in the cervix).
Furthermore they have realised that these effects make indinavir, and related
compounds, particularly useful for topical application to a site of infection
(or site of
potential infection) and thereby act as a treatment or prophylactic against
HPV
infection and the development of HPV related cancers.
It is preferred that the agents according to the first aspect of the invention
are
used to prevent the development of cancer or treat cancers. The inventors have
found
that the agents are particularly useful for preventing the development of
cancers
caused by HPV. Accordingly asymptomatic HPV infected individuals (i.e. those
with
a viral infection but no evidence of malignant disease) or HPV infected
individuals
with pre malignant cells may be treated according to the invention by topical
administration of the agents with a view to treating the viral infection and
thereby
preventing the development of cancer.
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The invention, to the extent that it is applicable to the prevention and
treatment of cancer, may be applied to range of cancers, in which HPV is
implicated,
such as cervical, vulval, anal and oral carcinomas The invention is applicable
particularly, but by no means exclusively, to pre-cancerous conditions and
cancers
caused by oncogenic viruses, e.g. transforming human papilloma viruses (HPVs).
The inventors have further established that agents as defined herein are
useful
for eliminating HPV from tissues and thereby reverse the predisposition state
of
"HPV positivity". It will be appreciated that the elimination of this virus
will reduce
the risk of malignancies associated with infection as well as being useful for
reducing/preventing other conditions/diseases associated with this virus.
According to a preferred embodiment of the invention the agents may be
topically applied to the vulva, anus or penis to treat, or prevent, genital
warts (e.g.
caused by the abovementioned low risk HPV6/11)
According to another preferred embodiment of the invention the agents may
be topically applied to the larynx or oral cavity to treat, or prevent, HPV
related oral
conditions such as recurrent respiratory papillomatosis.
According to another preferred embodiment of the invention the agents may
be topically applied to skin to treat, or prevent cutaneous HPV related warts
caused by
HPV type 2 and others.
According to a further preferred embodiment of the invention the inhibitors
may be topically applied to the vulva, anus, cervix or penis to treat, and
particularly
prevent, the development of cancer caused by high risk HPVs (e.g. HPV 16 or
HPV
18).
Examples of agents that may be used according to the invention include
amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir,
tipranavir, saquinavir, ABT-378, AG 1776, and BMS-232,632. Other agents
inhibitors which may be used according to the present invention are disclosed
in EP 0
541 168.
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The inventors have found that certain HIV protease inhibitors (e.g.
ritonavir) do not have the same activity as agents according to the first
aspect of the
invention. Accordingly ritonavir and related compounds do not fall with the
scope of
the present invention.
A list of preferred agents (and their sources) that may be used according to
the
inventions is given in Table 1.
Table 1:
Brand name INN Lab code no. Company/Source
Lexiva fosamprenavir GSK/Vertex
Agenerase amprenavir GSK
Reyataz atazanavir BMS
Crixivan Indinavir Merck
Viracept Nelfinavir Agouron
Invirase/Fortovase saquinavir Roche
tipranavir PNU-140690 Beohringer Ingelheim
GW-433908 GSK
GW-640385 GSK
RO-033-4649 Roche
TMC-114 Tibotec Virco
L-756,423 Merck
mozenavir DMP-450 Triangle
velcade PS-341 Millenium
A most preferred agent is indinavir and salts thereof. Functional derivatives
of
indinavir are also preferred inhibitors for use according to the invention.
Examples of
such derivatives are known to the art. For instance US 5,413, 999 discloses a
number
of molecules related to indinvar that may be usefully employed according to
the
present invention. By way of example only, the molecules defined by Claim 1 of
US
5,413, 999 may be used according to the first or second aspects of the present
invention.
A preferred salt of indinavir is indinavir sulphate (see the formula 1).
Indinavir sulphate is a white to off-white, hygroscopic, crystalline powder
with a
molecular formula of C36H47N504.H2SO4 and a molecular weight of 711.88.
Indinavir
sulphate is soluble in both water, preferably at acidic pHs, and methanol.
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N OH HO = H2SO4
H
N N,
N
~ 0
O'" NHC(CH3)3
Formula I
Indinavir sulphate is marketed by Merck & Co. as CRIXNAN .
CRIXNAN comprises indinavir sulphate, anhydrous lactose and magnesium
stearate within a capsule (consisting of gelatin, dyes, titanium dioxide,
silicon dioxide
and sodium lauryl sulphate. Such capsules may be used according to the
invention.
However CRIXIVAN is formulated for oral ingestion and it is preferred that
indinavir sulphate is formulated such that it is better suited for topical
application to
the target tissue as discussed in more detail below.
The inventors have found that the agents according to the first aspect of the
invention are not only useful for treating HPV related cancer but are also
surprisingly
useful for preventing the development of HPV related cancer. Accordingly
compounds such as indinavir have a most preferred use as a prophylactic.
The agents may be given to subjects with a genetic disposition to developing
cancer (most particularly cervical carcinoma) or even those facing
environmental risk
(e.g. people exposed to carcinogens). In a preferred embodiment the inhibitors
may
be given to women who are at risk of developing cancer. Such women can include
those who have been diagnosed as having a high risk HPV infection (e.g.. HPV16
or
HPV18) of the urino-genital tract (and particularly the cervix). There may not
be any
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symptomatic evidence that such women have a HPV infection, cervical carcinoma
or even precancerous cells of the cervix. However women with such infections
are
believed by the inventors to be at risk of developing cervical cancer.
Therefore,
according to a preferred embodiment of the invention, the agents may be
topically
applied to the cervix, vulva or anus of women with a viral infection at these
sites with
a view to preventing the development of cancer at a future date.
The agents may be used to prevent or treat cancer as a monotherapy (i.e. use
of the inhibitor alone) or in combination witli other compounds or treatments
used in
cancer therapy (e.g. chemotherapeutic agents, radiotherapy).
It is most preferred that the agents are used to treat liumans (e.g. women at
risk
of developing cervical, vulval or anal cancer or at risk of HPV infection).
However it
will be appreciated that the agents may also have some veterinary use.
The medicaments used according to the invention may take a number of
different forms depending, in particular on the manner in which the medicament
is to
be applied topically. Thus, for example, the medicament may be in the form of
a
powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol,
spray, micelle,
liposome or any other suitable form that may be administered to a person or
animal. It
will be appreciated that the vehicle of the medicament of the invention should
be one
which is well tolerated by the subject to whom it is given and enables
delivery of the
inhibitors to the effected or target site.
It is most preferred that the agents are formulated for topical use (e.g as
creams or ointments). For instance, when used to treat (or prevent the
development
of) cervical cancer, it is preferred that they are formulated as creams or
ointments that
may be applied directly to the vulva, penis or cervix by techniques known to
the art.
Alternatively the agents may be formulated in a pessary according to
techniques
known to the art.
Examples of preferred formulations for use according to the invention are gels
or hydro-gels containing the active agent and which are specifically
formulated for
application to the target tissue (e.g. the cervix). A more preferred hydro-gel
may be
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composed of: polyoxyethylene or polyoxypropylene block copolymers.
Alternatively it may comprisetive ethylene oxide, styrene oxide di-block
copolymers
or poly(ethylene oxide)-block-poly(DL-lactide) copolymers.
Most preferred hydro-gels for use for vaginal delivery according to the
invention may comprise monoolein (e.g. the Myverol 18-99)/water lyotrophic
liquid
crystalline gels. These gels show good bioadhesive characteristics and will
bind to the
cervix when delivered into the vagina and thereby represent a good means of
delivering the active agent to a target tissue. Furthennore such gels are able
to absorb
water when delivered to the vagina until they reach an equilibrium water
content of
approximately 40% in the vagina but still maintain there physical integrity.
Such gels
can delivery (to the cervix) the active agent over a time period of
approximately 18
hours and will follow square route of time kinetics (i.e. the rate of release
of the agent
is diffusion controlled).
Alternatively the hydrogel may comprise a triblock copolymer of pol(epsilon-
caprolactone) and poly (oxyethylene). Such gels also exhibit good release
properties
of agents according to the first aspect of the invention within the vagina
(e.g. for use
in the prevention of cervical cancer).
It will be appreciated that the amount of the agent required is determined by
biological activity and bioavailability which in turn depends on the mode of
administration, the physicochemical properties of the compound employed and
whether the compound is being used as a monotherapy or in a combined therapy.
The
frequency of administration will also be influenced by the abovementioned
factors
and particularly the half-life of the coinpound within the subject being
treated.
Optimal dosages to be administered may be determined by those skilled in the
art, and will vary with the particular compound in use, the strength of the
preparation,
the mode of administration, and the advancement of the disease condition.
Additional
factors depending on the particular subject being treated will result in a
need to adjust
dosages, including subject age, weight, gender, diet, and time of
administration.
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Known procedures, such as those conventionally employed by the
pharmaceutical industry (e.g. in vivo experimentation, clinical trials, etc.),
may be
used to establish specific formulations of compositions and precise
therapeutic
regimes (such as daily doses of the compounds and the frequency of
administration).
Generally, a daily dose of between 0.01 g/kg of body weight and 1.0 g/kg of
body weight of an agent (e.g. indinavir) may be used for the prevention or
treatment
of cancer - depending upon which specific compound is used. More preferably,
the
daily dose is between 0.01 mg/kg of body weight and 100 mg/kg of body weight.
When given topically, it is preferred that a hulnan adult is given a
sufficient
amount of inhibitor to ensure that a dose of between about 0.1 M and 10mM
reaches
the target cells. Accordingly an ointment or cream should comprise at least
between
about 0.1 M and 10mM of an inhibitor according to the invention and
preferably a
greater concentration that will be effective for delivering an effective
concentration of
inhibitor to the tissue being treated by the ointment or cream. However, it
will be
appreciated that the required dose may be varied since it is known that agents
according to the first aspect of the invention (such as indinavir) can be
substrates for
multi-drug resistance gene product p-glycoprotein. The agent may therefore be
co-
administered with a p-glycoprotein inhibitor such as verapamil, tariquidar
XR9576,
zosuquidar LY335979, laniquidar R101933 and OBT-093.
Daily doses may be given as a single administration (e.g. as a pessary).
Alternatively, the agent used may require administration twice or more times
during a
day. As an example, indinavir for preventing the development of cervical
cancer may
be administered as a hydrogel or cream, once, twice, three or more times a day
in an
amount sufficient to ensure between about 0.1 M and 10mM of the inhibitor
reaches
the target cells.
This invention further provides a pharmaceutical composition comprising a
therapeutically effective amount of an agent according to the first aspect of
the
invention and a pharmaceutically acceptable vehicle. In one embodiment, the
amount
of the agent is an amount from about 0.01 mg/ml to about 100 mg/ml. In another
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embodiment, the amount is from about 0.1 mg/ml to about 100 mg/ml. When
the agent is indinavir sulphate, the amount of indinavir sulphate may be an
amount
from about 0.01 mg/ml to about 20 mg/ml; and more preferably about 1 mg/ml to
about 10 mg/ml.
In one embodiment, the vehicle is a liquid and the composition is a solution.
In
another embodiment, the vehicle is a gel and the composition is a suppository
or
pessary. In a further embodiment the vehicle is an emulsion (or other
pharmaceutically acceptable base) and the composition is a cream.
This invention provides a process for making a pharmaceutical composition
comprising combining a therapeutically effective amount of an agent according
to the
first aspect of the invention and a pharmaceutically acceptable vehicle.
By "therapeutically effective amount" we mean any amount of an agent or
composition which, when administered to a subject suffering from a disease
against
which the agent is effective, causes reduction, remission, or regression of
the
malignant disease or HPV infection or prevents the development of malignant
disease
or HPV infection.
A "subject" is a vertebrate, mammal, domestic animal or preferably a human
being.
The "pharmaceutically acceptable vehicle" may be any physiological vehicle
known to those of ordinary skill in the art useful in formulating
pharmaceutical
compositions.
Liquid vehicles are used in preparing solutions, suspensions, emulsions,
syrups, elixirs and pressurized compositions. The active ingredient can be
dissolved
or suspended in a pharmaceutically acceptable liquid vehicle such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable oils or
fats. The
liquid vehicle can contain other suitable pharmaceutical additives such as
solubilizers,
emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending
agents,
thickening agents, colors, viscosity regulators, stabilizers or osmo-
regulators.
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Suitable examples of liquid vehicles for oral and parenteral administration
include
water (partially containing additives as above, e.g. cellulose derivatives,
preferably
sodium carboxymethyl cellulose solution), alcohols (including monohydric
alcohols
and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g.
fractionated
coconut oil and arachis oil). For parenteral administration, the vehicle can
also be an
oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid
vehicles are
useful in sterile liquid form compositions for parenteral administration. The
liquid
vehicle for pressurized compositions can be halogenated hydrocarbon or other
pharmaceutically acceptable propellent.
The invention will be further described, by way of Example and with
reference to the following figures:-
Figure 1(A) illustrates a Western Blot, referred to in Example 1, of proteins
isolated from indinavir treated vector control transfected C33A-V and HPV16 E6
transfected C33A-E6 Cells which were immuniprobed with anti-p53 antibody and
for
which the lane order was as follows:
1- 5= C33AE6 plus 1mM, 0.5mM, 0.1mM, 0.05mM and 0 Indinavir
6 - 9= Wild type C33A plus 0.05mM, 0.1mM, 0.5mM and 1mM Indinavir;
Figure 1(B) and (C) illustrate the effects of different concentrations of
Indinavir, as used in Fig 1(A), on the growth of C33A-E6 and C33A-V cells;
Figure 2 illustrate the effects of different concentrations of the HIV
protease
inhibitor ritonaviron the growth of C33A parental, C33A-E6 and C33A-V cells;
and
Figure 3 illustrates a Western Blot, referred to in Example 2, of proteins
isolated from C33A-E6 Cells treated with (A) increasing amounts of ritonavir
and (B)
30 M ritonavir wherein both blots were immunoprobed with an anti p53 antibody.
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EXAMPLE 1
Experiments were conducted to demonstrate that Indinavir, an inhibitor
according to the invention, was useful for preventing or treating malignant
conditions
caused by HPV infections.
C33A-E6 (wildtype C33A cells transfected with E6) and C33A-V (wildtype
C33A cells transfected with vehicle for E6 only) cervical carcinoma cells were
inoculated at a density of 4.0 x 105 cells per well into six well multiwell
dishes,
cultured in 5% CO2 at 37 C and incubated with various concentrations of
Indinavir for
48 hours (0 - 1mM). Cells were counted and lysed in 2x Laemli buffer and the
equivalent of 106 cells per track applied to 12 % PAGE followed by
electroblotting
onto Hybond C Extra. The blot was blocked with skimmed milk and immunoprobed
with an anti p53 antibody followed by a horse radish peroxidase conjugated
secondary. The signals were visualised by the use of an ECL detection system
and
exposure to Hyperfilm for various time intervals up to a maximum of 3 minutes
(see
Figure 1A). Cell counts obtained were plotted and are shown in Figures 1B and
1C.
The data illustrated in Figure 1 show that the expression of the HPV 16 E6
protein in C33A cervical carcinoma cells activates the 26S proteasome to
induce the
degradation of the tumour suppressor p53 protein. Lanes 6-9 are loaded with
proteins
from C33A-V control cells and have a much stronger signal than lanes 1-5.
However,
treatment of E6 expressing cells with increasing amounts of Indinavir inhibits
the E6
mediated proteasomal degradation of p53 and at 1mM the p53 protein is seen to
accumulate in the E6 expressing C33A cells. C33A parent cells were not
originally
dependent on continued expression of E6 although the inventors observed
selective
toxicity with indinavir against E6 expressing cells when compare to C33A-V
control
cells (see Figures 1B and 1C). These data indicate that expression of HPV16 E6
in
C33A cells produced the well known effect of oncogene addiction. Thus the
ability of
indinavir to block the function of E6 in these cells inhibits both cell growth
and the
chymotryptic activity of the 26S proteasome, which produces an increase in the
levels
of the p53 protein.
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These results indicate that Indinavir and Indinavir like compounds will be
useful as a topically applied treatment for genital and non-genital HPV
infections. It
is particularly important to note that indinavir is protective for non-
transformed cells,
This surprisingly indicates that agents according to the invention are useful
as a
prophylactic and can prevent HPV infection. It will be appreciated that the
prevention
of such infections will be protective against the development of cancers.
Taking all these observations together with our observation on E6 interaction
with AACT, this implies that Indinavir may be useful for the treatment of HPV
related disease. Indeed there is evidence to suggest that high risk HPVs
remain
associated with and contribute to the growth of HPV related tumours such as
cervical
carcinomas. Therefore Indinavir and related compounds are useful for the
treatment of
non-malignant HPV infection and HPV related malignancies.
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EXAMPLE 2
Experiments were conducted to compare the activity of an inhibitor according
to the invention (i.e indinavir) with the activity of an HIV protease
inhibitor
(ritonavir) which falls outside the present invention.
Growth curves were conducted on parental HPV -ve cervical C33A cells,
HPV16 E6 expressing C33A-E6 cells and C33A-V cells (see previous Example 1) in
the presence of increasing concentrations of ritonavir. Cells were seeded into
a 96
well plate at a density of 2.0 x 103 cells per well and left to attach
overnight in 5% CO2
at 37 C prior to adding ritonavir. Viable cell numbers were determined at each
time
point by addition of Cell AQ 96 reagent (Promega), incubated for 4 hours in 5%
CO2
at 37 C, after which the optical density was measured at 490nm wavelength.
Figure 2 shows that ritonavir is highly toxic to all the cell types tested
with
minimal selectivity for the presence or absence of the HPV16 E6 protein. Total
cell
protein was harvested from C33A-E6 cells treated with increasing amounts of
ritonavir upto 15 M, western blotted as described previously (Example 1) and
the
results shown in Figure 3A. Despite the toxicity observed at 15 M and higher
concentrations, unlike indinavir treated C33A-E6 cells, immunoprobing this
blot
showed no increase in levels of the p53 indicating that the toxicity observed
with
ritonavir was non-specific and not related to blocking the function of the E6
protein.
C33A E6 cells were also treated with 30 gM of ritonavir for a time course of
0-8 hours, protein harvested and western blotted with exposure times of
greater than
30 minutes. Again in contrast to the results obtained with indinavir (Example
1) the
p53 signal did not show any increase in activity (Figure 3B) indicating that
ritonavir
exhibits non-specific toxicity and is less likely to be useful as a specific
antiviral agent
for the topical treatment of HPV infections. Accordingly it is preferred that
ritonavir
is not included as an inhibitor for use according to the present invention.
Indeed
ritonavir treatment actually reduces the levels of p53 found in C33A-E6 cells.
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These data clearly show that not all HIV protease inhibitors are effective for
the treatment, or prevention of HPV infections and cancer. This illustrates
the
selective, and surprising, anti HPV activity of indinavir and other agents
that inhibit
the chymotryptic activity of the 26s unit of the proteosome compared to more
general
HIV protease inhibitors.
