U.S. patent application number 11/370363 was filed with the patent office on 2006-10-05 for therapeutic agent for soft tissue sarcoma.
This patent application is currently assigned to Fujisawa Pharmaceutical Co. Ltd.. Invention is credited to Tatsuo Ito, Mamoru Ouchida, Toshifumi Ozaki.
Application Number | 20060223747 11/370363 |
Document ID | / |
Family ID | 33549590 |
Filed Date | 2006-10-05 |
United States Patent
Application |
20060223747 |
Kind Code |
A1 |
Ito; Tatsuo ; et
al. |
October 5, 2006 |
Therapeutic agent for soft tissue sarcoma
Abstract
A therapeutic agent for soft tissue sarcoma (particularly
synovial sarcoma) contains a histone deacetylase inhibitor
(particularly compound of formula I) as an active ingredient
##STR1##
Inventors: |
Ito; Tatsuo; (Okayama-shi,
JP) ; Ozaki; Toshifumi; (Okayama-shi, JP) ;
Ouchida; Mamoru; (Okayama-shi, JP) |
Correspondence
Address: |
ELMORE PATENT LAW GROUP, PC
209 MAIN STREET
N. CHELMSFORD
MA
01863
US
|
Assignee: |
Fujisawa Pharmaceutical Co.
Ltd.
Osaka-shi
JP
|
Family ID: |
33549590 |
Appl. No.: |
11/370363 |
Filed: |
March 8, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10875382 |
Jun 25, 2004 |
7056883 |
|
|
11370363 |
Mar 8, 2006 |
|
|
|
Current U.S.
Class: |
514/19.3 ;
514/21.1; 530/317 |
Current CPC
Class: |
A61K 31/19 20130101;
A61K 31/4406 20130101; A61K 38/005 20130101; A61P 35/00 20180101;
A61P 43/00 20180101; A61K 38/12 20130101 |
Class at
Publication: |
514/010 ;
530/317 |
International
Class: |
A61K 38/12 20060101
A61K038/12; C07K 7/64 20060101 C07K007/64 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 27, 2003 |
JP |
2003-183643 |
Claims
1-8. (canceled)
9. A method for treating soft tissue sarcoma, which comprises
administering an effective amount of a histone deacetylase
inhibitor.
10. The method of claim 9, wherein the soft tissue sarcoma is
synovial sarcoma.
11. The method of claim 10, wherein the synovial sarcoma is SYT-SSX
protein expressing sarcoma.
12. The method of claim 9, wherein the soft tissue sarcoma is
selected from the group consisting of malignant fibrous
histocytoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma,
synovial sarcoma, fibrosarcoma, malignant schwannoma, angiosarcoma,
and clear cell sarcoma.
13-16. (canceled)
17. The method of claim 9, wherein the histone deacetylase
inhibitor is SAHA or trichostatin A.
18. The method of claim 17, wherein the soft tissue sarcoma is
synovial sarcoma.
19. The method of claim 18, wherein the synovial sarcoma is SYT-SSX
protein expressing sarcoma.
20. The method of claim 17, wherein the soft tissue sarcoma is
selected from the group consisting of malignant fibrous
histocytoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma,
synovial sarcoma, fibrosarcoma, malignant schwannoma, angiosarcoma,
and clear cell sarcoma.
21-23. (canceled)
Description
RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 10/875,382, filed Jun. 25, 2004, now pending. The entire
teachings of the above application are incorporated herein by
reference.
TECHNICAL FIELD
[0002] The present invention relates to a therapeutic agent for
soft tissue sarcoma, which contains a histone deacetylase inhibitor
as an active ingredient.
BACKGROUND ART
[0003] In general, when there is a report on a substance or a
compound having an antitumor activity and the report is based
solely on in vitro results, it has been pointed out that such
reported results do not directly suggest in vivo results. In other
words, a substance showing an antitumor activity in vitro does not
necessarily show an antitumor activity in vivo, and application of
a substance showing an antitumor activity in vitro directly as an
antitumor agent is difficult.
[0004] For example, it has been reported that a compound
represented by the formula (I) ##STR2## (hereinafter to be also
referred to as compound A; SEQ ID NO: 1), particularly a
stereoisomer of the formula (II) ##STR3## (hereinafter to be also
referred to as compound B or FK228), selectively inhibits histone
deacetylase to derive a potent antitumor activity, and that this
substance causes high acetylation of histone in the treated cells,
thereby inducing transcription-regulatory activity of various
genes, cell cycle inhibitory activity and apoptosis (e.g.,
JP-B-7-64872 (corresponding to U.S. Pat. No. 4,977,138),
"Experimental Cell Research", US (1998), vol. 241, pp. 126-133). As
the situation now stands, however, there are many problems yet to
be solved, such as whether or not in vitro results are directly
applicable in vivo, whether or not a useful in vivo effect can be
afforded in any tumor, and the like. No report has ever verified in
vitro and in vivo antitumor activities against soft tissue sarcoma
(particularly synovial sarcoma) of the present invention.
[0005] Histone deacetylase is a metallo-deacetylating enzyme
coordinating Zn at an active center (M. S. Finnin et al., Nature,
401, 188-193 (1999)). This enzyme is considered to change affinity
of various acetylated histones for DNA. The direct biological
phenomenon brought thereby is a change in the chromatin structure.
The minimum unit of the chromatin structure is a nucleosome wherein
146 bp DNA is wound 1.8 times anticlockwjse around a histone
octamer (H2A, H2B, H3 and H4, each 2 molecules, core histone). The
core histone stabilizes the nucleosome structure by interaction of
the positive charge of the N-terminus of each histone protein with
DNA. Acetylation of histone is controlled by the equilibrium
between an acetylation reaction involving histone acetyltransferase
and a deacetylation reaction involving histone deacetylase. It is
considered that the histone acetylation occurs at a lysin residue
where the histone protein N-terminus is evolutionally preserved
well, due to which a core histone protein loses charges at the
N-terminus, interaction with DNA is attenuated, and the structure
of nucleosome becomes unstable. Accordingly, the histone
deacetylation is considered to be the reverse thereof, namely, a
shift toward stabilization of the nucleosome structure. However, to
what degree the acetylation changes the chromatin structure and how
it relates to the transcriptional regulation etc. secondarily
induced thereby are unclear in many aspects.
[0006] As genetic characteristics of synovial sarcoma, it has been
reported that, in about 97% of the entire synovial sarcomas, SYT
gene present in the 18th chromosome and SSX gene present on the X
chromosome are fused due to chromosomal translocation t (18,X) to
express a chimera protein called SYT-SSX, and SYT protein
constituting the N-terminal region of this protein is bound with a
chromatin remodeling-associated protein such as p300 and BRM to
form a complex (Josiane E. Eid et al., Cell, 102, 839-848 (2000)).
Synovial sarcoma is one kind of soft tissue sarcoma developed in
the four limbs and trunk of the body of males and females, and its
primary therapy includes removal of tumor by operation and
chemotherapy before and after the operation. However, chemotherapy
is associated with poor prognosis and a five-year survival rate is
about 60-70%. Thus, an effective cure has not been established as
yet.
DISCLOSURE OF THE INVENTION
[0007] An object of the present invention is to provide a
therapeutic agent for soft tissue sarcoma (particularly synovial
sarcoma), which contains a histone deacetylase inhibitor,
particularly compound A, compound B, its reduction products,
metabolites, derivatives, prodrugs, and other analogs known to have
a strong histone deacetylase inhibitory activity, or a
pharmaceutically acceptable salt thereof, as an active
ingredient.
[0008] In an attempt to solve the above-mentioned problems, the
present inventors have considered that, in synovial sarcoma,
formation of the aforementioned complex of SYT-SSX protein, a
chromatin remodeling-associated protein and histone deacetylase
(HDAC)-associated protein enhances histone deacetylase activity,
which in turn has an effect on the canceration, development and/or
proliferation, of synovial sarcoma, and have conducted intensive
studies of the effect of histone deacetylase inhibition on various
synovial sarcoma cell strains (HS-SY-2, YaFuSS, SYO-1) that express
SYT-SSX protein. As a result, they have found that compound B and
tricostatin A, which are histone deacetylase inhibitors, exhibit a
potent antiturnor activity in vitro and in vivo against SYT-SSX
protein expressing cells. Furthermore, they have found that they
also exhibit a potent antitumor activity against a synovial sarcoma
cell strain (HTB93; which is the ATCC identification number of cell
line SW982) not expressing SYT-SSX protein. Accordingly, the
present invention provides the following. [0009] (1) A therapeutic
agent for soft tissue sarcoma, which comprises a histone
deacetylase inhibitor as an active ingredient. [0010] (2) The
therapeutic agent of the above-mentioned (1), wherein the soft
tissue sarcoma is synovial sarcoma. [0011] (3) The therapeutic
agent of the above-mentioned (1) or (2), wherein the soft tissue
sarcoma or synovial sarcoma is an SYT-SSX protein expressing
sarcoma. [0012] (4) The therapeutic agent of the above-mentioned
(1), wherein the histone deacetylase inhibitor is compound A or
compound B, or a reduced form thereof, an analog thereof, a prodrug
thereof or a pharmaceutically acceptable salt thereof. [0013] (5)
The therapeutic agent of the above-mentioned (4), wherein the soft
tissue sarcoma is synovial sarcoma. [0014] (6) The therapeutic
agent of the above-mentioned (5), wherein the synovial sarcoma is
SYT-SSX protein expressing sarcoma. [0015] (7) A pharmaceutical
composition for the treatment of soft tissue sarcoma, which
comprises a histone deacetylase inhibitor and a pharmaceutically
acceptable carrier. [0016] (8) The pharmaceutical composition of
the above-mentioned (7), wherein the histone deacetylase inhibitor
is compound A or compound B, or a reduced form thereof, an analog
thereof, a prodrug thereof or a pharmaceutically acceptable salt
thereof. [0017] (9) A method for treating soft tissue sarcoma,
synovial sarcoma, or an SYT-SSX protein expressing sarcoma, which
comprises administering an effective amount of a histone
deacetylase inhibitor. [0018] (10) The method of the
above-mentioned (9), wherein the histone deacetylase inhibitor is
compound A or compound B, or a reduced form thereof, an analog
thereof, a prodrug thereof or a pharmaceutically acceptable salt
thereof. [0019] (11) Use of a histone deacetylase inhibitor for the
production of a therapeutic agent for soft tissue sarcoma. [0020]
(12) The use of the above-mentioned (11), wherein the histone
deacetylase inhibitor is compound A or compound B, or a reduced
form thereof, an analog thereof, a prodrug thereof or a
pharmaceutically acceptable salt thereof. [0021] (13) A commercial
package comprising the pharmaceutical composition of the
above-mentioned (7) and a written matter associated therewith the
written matter stating that said pharmaceutical composition can or
should be used for the treatment of soft tissue sarcoma.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The foregoing and other objects, features and advantages of
the invention will be apparent from the following more particular
description of preferred embodiments of the invention, as
illustrated in the accompanying drawings in which like reference
characters refer to the same parts throughout the different views.
The drawings are not necessarily to scale, emphasis instead being
placed upon illustrating the principles of the invention.
[0023] FIG. 1 is a graph showing an in vitro antitumor action of
FK228 against HS-SY-2 synovial sarcoma cell strain, which is one of
the SYT-SSX protein expressing synovial sarcoma cell strains.
[0024] FIG. 2 is a graph showing an in vitro antitumor action of
FK228 against YaFuSS synovial sarcoma cell strain, which is one of
the SYT-SSX protein expressing synovial sarcoma cell strains.
[0025] FIG. 3 is a graph showing an in vitro antitumor action of
FK228 against SYO-1 synovial sarcoma cell strain, which is one of
the SYT-SSX protein expressing synovial sarcoma cell strains.
[0026] FIG. 4 is a graph showing an in vivo antitumor action of
FK228 against SYO-1 synovial sarcoma cell strain, which is one of
the SYT-SSX protein expressing synovial sarcoma cell strains.
[0027] FIG. 5 is a graph showing an in vitro antitumor effect of
FK228 on HTB93 synovial sarcoma cell strain, which is one of the
synovial sarcoma cell strains that do not express SYT-SSX
protein.
DETAILED DESCRIPTION OF THE INVENTION
[0028] A description of preferred embodiments of the invention
follows.
[0029] The "histone deacetylase inhibitor", also referred to as
"HDAC inhibitor" or "HDACi", in the present invention is a compound
that binds to an active site of histone deacetylase competitively
with substrates, and/or a compound that reduces or inhibits the
enzyme activity of histone deacetylase, and includes any compound
(whether synthetic or natural) reported or will be reported in the
future to have a histone deacetylase inhibitory activity. To be
specific, the aforementioned compound A, a salt thereof and a
derivative thereof (e.g., acetylated compound A, thiol form
(reduced form) with reduced S-S bond as described in WO02/06307,
analogs thereof (e.g., compounds described in U.S. Pat. No.
6,403,555 etc.), prodrugs thereof, etc.) can be mentioned. In
addition, Trichostatin A, sodium butyrate, suberoylanilide
hydroxamic acid (SAHA), MS-275, cyclic hydroxainic-acid-containing
peptide, Apicidin, Trapoxin and the like are the compounds reported
to have a histone deacetylase inhibitory activity.
[0030] While compound A (and other HDACi's) may have a stereoisomer
(e.g., compound B) based on an asymmetric carbon atom or a double
bond, such as an optically active form, a geometric isomer and the
like, all these isomers and mixtures thereof are also encompassed
in the scope of the histone deacetylase inhibitor to be used in the
present invention.
[0031] In the present specification, unless particularly specified,
a simple reference to compound A means a group of compounds
regardless of stereoisomerism, which include a compound B
represented by the formula (II).
[0032] Moreover, solvate compounds (e.g., inclusion compounds
(e.g., hydrate etc.)), anhydrous forms, other crystal polymorphs
and pharmaceutically acceptable salts thereof of HDACi's, such as
compound A, compound B and salts thereof, are also encompassed in
the scope of the present invention.
[0033] The compound A or a salt thereof are known and available
substances. For example, compound B, which is one of the
stereoisomers of compound A, can be obtained by culturing a strain
belonging to the genus Chromobacterium, which is capable of
producing compound B, under aerobic conditions, and harvesting the
substance from its culture broth. As the strain belonging to the
genus Chromobacterium, which is capable of producing compound B,
for example, Chromobacterium violaceum WB968 (FERM BP-1968) can be
mentioned. More specifically, compound B can be obtained from a
compound B producing strain as described in JP-B-7-64872
(corresponding to U.S. Pat. No. 4,977,138). The compound B is
preferably harvested from a strain belonging to the genus
Chromobacterium, which is capable of producing compound B, because
it can be obtained more easily. Synthetic or semi-synthetic
compound B is also advantageous in that further purification step
is not necessary or the number of steps can be reduced. Similarly,
compounds A other than compound B can be also obtained by
semi-synthesis or total synthesis by conventionally known methods.
To be more specific, it can be produced according to the method
reported by Khan W. Li, et al. (J. Am. Chem. Soc., Vol. 118,
7237-7238 (1996)).
[0034] A pharmaceutically acceptable salt of HDACi's, such as the
salt of compound A or compound B, includes salts with a base or an
acid addition salt such as salts with inorganic base (e.g., alkali
metal salts such as sodium salt, potassium salt etc., alkaline
earth metal salts such as calcium salt, magnesium salt etc.,
ammonium salt), salts with an organic base (e.g., organic amine
salts such as triethylamine salt, diisopropylethylamine salt,
pyridine salt, picoline salt, ethanolamine salt, triethanolamine
salt, dicyclohexylaxnine salt, N,N'-dibenzylethylenediamine salt
etc.), inorganic acid addition salts (e.g., hydrochloride,
hydrobromide, sulfate, phosphate etc.), organic carboxylic acid or
sulfonic acid addition salts (e.g., formate, acetate,
trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate,
benzenesulfonate, toluenesulfonate etc.), salts with a basic or
acidic amino acid (e.g., arginine, aspartic acid, glutamic acid
etc.) and the like.
[0035] In the present invention, in vivo and in vitro mean as they
are generally used in this field. Namely, "in vivo " means a state
where functions and reactions of the target living organism can be
expressed in living organisms, and in vitro" means that such
functions and reactions can be expressed in vitro (tissue culture
system, cell culture system, cell-free system etc.).
[0036] Soft tissue sarcomas include malignant fibrous histocytoma,
liposarcoma, rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma,
fibrosarcoma, malignant schwannoma, angiosarcoma, clear cell
sarcoma and the like.
[0037] In addition, gene diagnosis of SYT-SSX protein expressing
synovial sarcoma enables selection of patients before treatment,
for whom the histone deacetylase inhibitor of the present invention
proves effective.
[0038] The therapeutic agent for soft tissue sarcoma of the present
invention can be used in the form of a pharmaceutical preparation
such as a solid, semisolid or liquid preparation (tablet, pellet,
troche, capsule, suppository, cream, ointment, aerosol, powder,
liquid, emulsion, suspension, syrup, injection etc.) containing a
histone deacetylase inhibitor as an active ingredient, which is
suitable for transrectal, intranasal, pulmonary, vaginal, external
(topical), oral or parenteral (including subcutaneous,
implantation, intravenous and intramuscular) administration.
[0039] The therapeutic agent for soft tissue sarcoma of the present
invention can be also produced by conventional methods using
various organic or inorganic carriers conventionally used for
forming pharmaceutical preparations, such as excipients (e.g.,
sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose,
talc, calcium phosphate, calcium carbonate etc.), condensation
agents (e.g., cellulose, methyl cellulose, hydroxypropyl cellulose,
polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol,
sucrose, starch etc.), disintegrants (e.g., starch, carboxymethyl
cellulose, carboxymethyl cellulose calcium, hydroxypropyl starch,
sodium starch glycolate, sodium hydrogen carbonate, calcium
phosphate, calcium citrate etc.), lubricants (e.g., magnesium
stearate, aerosil, talc, sodium lauryl sulfate etc.), corrigents
(e.g., citric acid, menthol, glycine, orange powder etc.),
preservatives (e.g., sodium benzoate, sodium hydrogen sulfite,
methylparaben, propylparaben etc.), stabilizers (citric acid,
sodium citrate, acetic acid etc.), suspensions (e.g., methyl
cellulose, polyvinyl pyrrolidone, aluminum stearate etc.),
dispersants (e.g., hydroxypropylmethyl cellulose etc.), diluents
(e.g., water etc.), wax base materials (e.g., cacao butter,
polyethylene glycol, white petrolatum etc.) and the like.
[0040] While the administration method of the therapeutic agent for
soft tissue sarcoma of the present invention is not particularly
limited, intravenous, intramuscular or oral administration is
preferable. In addition, while a therapeutically effective amount
of HDACi's, such as, compound A or compound B or a pharmaceutically
acceptable salt thereof, when it is used for a human as an active
ingredient varies depending on the age and condition of individual
patient to be treated, and the kind of soft tissue sarcoma, in the
case of an intravenous administration, the daily dose of compound A
and compound B is generally 0.1-100 mg, preferably 1-50 mg, more
preferably 5-30 mg, in the amount of compound A, per 1 m.sup.2 of
human body surface area, which is given for the treatment of
sarcoma by continuous infusion.
[0041] Furthermore, the HDAC1's in the present invention can be
administered alone or in combination with an additional anti-tumor
treatment, such as surgery, radiation therapy and/or chemotherapy.
Examples of chemotherapeutic agents include DNA cross-linkers,
alkylating antitumor agents, antimetabolite antitumors, and
taxanes. Preferred chemotherapeutic agents include cipslatin,
5-fluorouracil, paclitaxel(taxol), docetaxel, and the like.
EXAMPLES
[0042] The present invention is specifically explained in detail in
the following by referring to Examples, which are not to be
construed as limitative.
Example 1
[0043] An SYT-SSX protein expressing synovial sarcoma cell line
HS-SY-2 (established and kindly provided by Dr. Hiroshi Sonobe,
Department of Pathology, National Fukuyama Hospital), YaFuSS
(established and kindly provided by Dr. Junya Toguchida, Department
of Tissue Regeneration, Institute for Frontier Medical Sciences,
Kyoto University) and SYO-1 (established and kindly provided by Dr.
Akira Kawai, Department of Orthopedics, Faculty of Medicine,
Okayama University (now Department of Orthopedics, National Cancer
Center)) were cultured in DMEM (Dulbecco's modified Eagle's medium)
containing 10% (v/v) fetal bovine serum (FBS), 100 U/ml penicillin
and 100 .mu.g/ml streptomycin at 37.degree. C. under 5% CO.sub.2
environment. These cells were plated and cultured for 24 hr,
detached with 0.25% (w/v) trypsin and recovered. For cell growth
ability, an MTT analysis kit (Colorimetric (MTT) assay for cell
survival and proliferation kit of CHEMICON International, Inc.) was
used. Each cell strain was plated in a 96 well microtiter plate at
10.sup.3 cell/well, and after culture for 24 hr, exposed to a 0.1%
(v/v) dilute ethanol solution of FK228 at a concentration
distribution of 0.1 nM, 0.2 nM, 1 nM, 50 nM and 100 nM, and 0.1%
(v/v) ethanol (Et-OH 0.1% in FIG. 1) as a control. After exposure
for 24 hr, 48 hr and 96 hr, each culture was passed through a 570
nM filter and the absorbance was measured. All were performed with
n=4.
[0044] The results are shown in FIG. 1, FIG. 2 and FIG. 3. FK228
showed an in vitro antitumor effect on SYT-SSX protein expressing
synovial sarcoma, a soft tissue sarcoma.
Example 2
[0045] Inbred male (BALB/C/nu/nu) nude mice were supplied by
Charles River Japan, Inc. The animals were all fed and handled
according to the Animal Test Guideline, Animal Resources Division,
Advanced Science Research Center, Okayama University. FK228 was
administered after 10 days from subcutaneous implantation of
10.sup.5 cells each of the SYO-1 cell strain. The tumor volume was
assumed by measuring two diameters perpendicular to each other
using calipers and from the following formula (tumor volume=1/6.pi.
[(d1.times.d2).sup.3/2] (wherein d1 and d2 are two perpendicular
diameters)). The dose was evaluated by intravenously administering
a dilute FK228 solution (50 .mu.l, 10% HCO60 which is
polyoxyethylene (60) hydrogenated castor oil, diluted with
physiological saline) at 0 mg/kg, 1.6 mg/kg or 3.2 mg/kg to 20
animals, and as a control, a 3.2 mg/kg dilute FK228 solution was
intravenously injected to 7 animals free of tumor implantation. The
administration was performed 3 times every 4 days, the tumor volume
was also measured every 4 days, as well as after completion of the
administration.
[0046] The results are shown in FIG. 4, wherein the measurement
days are shown in terms of the number of days after the
subcutaneous implantation. FK228 showed an in vivo antitumor effect
on SYT-SSX protein expressing synovial sarcoma, a soft tissue
sarcoma.
Example 3
[0047] An SYT-SSX protein non-expressing synovial sarcoma cell line
HTB93 (purchased from ATCC: American Type Culture Collection) was
cultured in DMEM (Dulbecco's modified Eagle's medium) containing
10% (v/v) fetal bovine serum (FBS), 100 U/ml penicillin and 100
.mu.g/ml streptomycin at 37.degree. C. under 5% CO.sub.2
environment. These cells were plated and cultured for 24 hr,
detached with 0.25% (w/v) trypsin and recovered. For cell growth
ability, an MTT analysis kit (Colorimetric MTT) assay for cell
survival and proliferation kit of CHEMICON International, Inc.) was
used. Each cell strain was plated in a 96 well microtiter plate at
2.times.10.sup.3 cell/well, and after culture for 24 hr, exposed to
a 0.1% (v/v) dilute ethanol solution of FK228 at a concentration
distribution of 0.001 nM, 0.01 nM, 0.1 nM, 0.5 nM, 1 nM, 5 nM, 10
nM, 50 nM and 100 nM, 0.1% (v/v) ethanol as a control and the
medium alone as a blank. After exposure for 24 hr, 48 hr, 72 hr and
96 hr, each culture was passed through a 570 nM filter and the
absorbance was measured. All were performed with n=4.
[0048] For the results, average values of the FK228 addition
sample, control and blank were taken, and using numerical values
obtained by subtracting a blank value from the value of the FK228
addition sample or control, a percentage corresponding to the ratio
of the numerical value of the FK228 addition sample relative to
that of the control was taken as survival rate (%). The results are
shown in FIG. 5. FK228 showed an in vitro antitumor effect also on
SYT-SSX protein non-expressing synovial sarcoma, which is one kind
of soft tissue sarcoma.
[0049] Sequence Listing Free Text [0050] SEQ ID NO: 1: Xaa is an
amino acid represented by the formula
NH.sub.2C(CHCH.sub.3)COOH.
[0051] In the formula COOHCH.sub.2CH(CHCHC.sub.2H.sub.4SH)OH, the
carboxylic group is bonded with the amino group of the first amino
acid Val, the hydroxyl group is bonded with the carboxylic group of
the fourth amino acid Val, and the SH group is bonded with the SH
group of the second amino acid Cys via a disulfide bond.
INDUSTRIAL APPLICABILITY
[0052] The therapeutic agent for soft tissue sarcoma of the present
invention, which contains a histone deacetylase inhibitor
(particularly FK228) as an active ingredient, has a superior
antitumor action not only in vitro but also in vivo. Accordingly,
it can be clinically used, particularly preferably for the
treatment of soft tissue sarcoma.
[0053] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims. All
patents and patent publication and other publications identified or
referenced herein are incorporated by reference in their
entirety.
[0054] This application is based on and claims the benefit of
patent application No. 183643/2003 filed in Japan, the contents of
which are hereby incorporated by reference.
Sequence CWU 1
1
1 1 4 PRT Artificial Sequence Synthetic Peptide 1 Val Cys Xaa Val
1
* * * * *