A method of treatment of breast cancer in susceptible animals whose
ovarian hormonal secretions are blocked by surgical or chemical
means, e.g., by use of an LH-RH agonist, e.g., [D-Trp.sup.6, des-Gly-NH.sub.2.sup.10
]LH-RH ethylamide with a therapy comprising administering an antiandrogen,
e.g., flutamide and an optionally, an inhibitor of adrenal sex steroid
biosynthesis e.g., aminoglutethimide, pharmaceutical compositions
useful for such treatment and two, four and five component pharmaceutical
kits containing such compositions are disclosed.
What is claimed:
1. A kit comprising in separate containers pharmaceutical compositions
for combined use in treating breast cancer in a warm-blooded female
animal which comprises (1) a pharmaceutical composition comprising
an antiandrogen and (2) a pharmaceutical composition comprising
a LH-RH agonist or antagonist.
2. The kit of claim 1 wherein the pharmaceutical compositions are
3. The kit of claim 1 wherein the LH-RH agonist pharmaceutical
composition comprises the LH-RH agonist in one container and a solvent
for parenteral administration in another container.
4. A kit comprising in separate containers pharmaceutical compositions
for combined use in treating breast cancer in a warm-blooded female
animal which comprises (1) a pharmaceutical composition comprising
an LH-RH agonist or an LH-RH antagonist (2) a pharmaceutical composition
comprising an antiandrogen (3) a pharmaceutical composition comprising
an inhibitor of sex steriod biosynthesis (4) a pharmaceutical composition
comprising hydrocortisone and (5) a pharmaceutical composition comprising
5. The kit of claim 4 wherein the pharmaceutical compositions are
6. The kit of claim 4 wherein the LH-RH agonist or antagonist pharmaceutical
composition comprises the LH-RH agonist or antagonist in one container
and a solvent for parenteral administration in another container.
7. The kit of claim 4 wherein the pharmaceutical compositions of
the antiandrogen and of the antiestrogen and the inhibitor of sex
steroid bioxynthesis are each oral compositions.
BACKGROUND OF THE INVENTION
This invention relates to a method of treatment of breast cancer
in susceptible warm-blooded female animals including humans using
a therapy comprising administering an antiandrogen to such animals
after the hormone output of their ovaries has been blocked by surgical
or chemical means. The invention also includes pharmaceutical compositions
useful for such treatment and pharmaceutical kits containing such
compositions. In its most preferred aspect, this invention relates
to treatment of breast cancer in warm-blooded animals by parenterally
administering an LH-RH agonist or LH-RH antagonist, in association
with orally administering an antiandrogen and orally administering
an antiestrogen and orally administering an inhibitor of sex steroid
While various investigators have been studying hormone-dependent
breast and prostate cancer, none have proposed the combination therapy
of this invention.
A. V. Schally et al., Cancer Treatment Reports, 68, (No. 1) 281-289
(1984), summarize the results of animal and clinical studies on
growth inhibition of hormone-dependent mammary and prostate tumors
by use of analogues of luteinizing hormone-releasing hormones, the
so-called LH-RH agonists and suggest that LH-RH analogs and/or antagonists
may have potential for treating breast cancer.
T. W. Redding and A. V. Schally, Pro. Natl. Acad. Sci. USA, 80,
1459-1462 (1983), disclose reduction of estrogen-dependent mammary
tumors in rats and mice by use of an LH-RH agonist, [D-Trp.sup.6
]LH-RH or of two specific antagonists.
In U.S. Pat. No. 4,071,622, it is disclosed that use of certain
LH-RH agonists causes regression of DMBA-induced mammary carcinoma
In U.S. Pat. No. 4,472,382, it is disclosed that certain LH-RH
agonists alone may be useful in the treatment of prostate adenocarcinoma
and hormone-dependent mammary tumors. While the use of certain LH-RH
agonists and an antiandrogen are disclosed for treatment of prostate
adenocarcinoma and benign prostate hypertrophia, there is no disclosure
or suggestion of the present invention.
Some clinical improvement in premenopausal women with breast cancer
by use of the two LH-RH agonists, Buserelin and Leuprolide, is also
reported by H. A. Harvey et al. "LH-RH analogs in the treatment
of human breast cancer", LH-RH and Its Analogs--A New Class
of Contraceptive and Therapeutic Agents (B. H. Vickery and J. J.
Nestor, Jr., and E. S. E. Hafez, eds) Lancester, MTP Press, (1984)
and by J. G. M. Klijn et al. "Treatment with luteinizing hormone
releasing hormone analogue (Buserelin) in premenopausal patients
with metastatic breast cancer", Lancet, 1, 1213-1216 (1982).
Treatment of advanced breast cancer with aminoglutethimide after
therapy with the antiestrogen, Tamoxifen is disclosed by A. V. Buzdar
et al., Cancer, 50, 708-1712 (1982).
H. Flax et al., Lancet, 1204-1207, (1973), suggest some women's
breast cancers are androgen-dependent.
F. Labrie et al., The Prostate, 4, 579-594 (1983), disclose that
use of a combination therapy of an LH-RH agonist (Buserelin) and
an antiandrogen (Anandron) to treat advanced prostate cancer in
previously untreated patients effects simultaneous elimination of
androgens of both testicular and adrenal origin.
F. Labrie et al., J. Steroid Biochem., 19, 99-1007 (1983), disclose
the treatment of prostate cancer by the combined administration
of an LH-RH agonist and an antiandrogen. Labrie et al. disclose
animal and clinical data in support of the proposition that the
combined LH-RH/antiandrogen treatment neutralizes the stimulatory
influence of all androgens on the development and growth of androgen-dependent
In U.S. Pat. No. 4,094,994, it is disclosed that the use of antiestrogens
such as meso-3,4-bis(3'-hydroxyphenyl)hexane inhibits MCF7 human
breast tumor cells. In fact, the inhibitory activity of the antiestrogen
was antagonized by estradiol. cells. In fact, the inhibitory activity
of the antiestrogen was antagonized by estradiol.
H. Mouridsen et al,. Cancer Treatment Review 5, 131-141, (1978),
disclose that Tamoxifen, an antiestrogen is effective in remission
of advanced breast cancer in about 30% of the patients treated.
J. G. M. Klijn et al., (J. Steroid Biochem, Vol. 20 (No. 6B), 1381
(1984), disclose the combined use of the antiestrogen, Tamoxifen,
and the LH-RH agonist, Buserelin, for treatment of breast cancer
is known, but objective remission of such cancers remains low (35%).
BRIEF DESCRIPTION OF THE INVENTION
In its broadest aspect, the invention provides a method of treating
breast cancer in a warm-blooded female animal in need of such treatment
which comprises blocking the ovarian hormonal secretions of said
animal by surgical or chemical means and in association therewith,
administering to said animal a therapeutically effective amount
of an antiandrogen or a pharmaceutical composition thereof. In one
aspect, the invention provides a method of treating breast cancer
in a castrated warm-blooded female animal, i.e., such a female animal
whose ovaries were previously blocked by surgical or chemical means
from secreting estrogen, which comprises administering to such a
female in need of such treatment an antiandrogen in association
with at least one inhibitor of sex steroid biosynthesis and, optionally,
an antiestrogen, or pharmaceutical compositions thereof, in amounts
sufficient to treat breast cancer. By completely blocking sex steroids
(androgens and estrogens) production and/or action, the present
invention provides a method of inhibiting the growth of hormone-sensitive
breast tumors in warm-blooded animals having such tumors.
In female mammals, the ovaries may be surgically removed (oophorectomy)
but preferably the secretion of estrogens from the ovaries is blocked
by chemical castration by administering an effective amount of an
LH-RH agonist or antagonist. Thus, in a preferred aspect, the present
invention provides a method of treating breast cancer in a warm-blooded
female animal, which comprising administering to such a female in
need of such treatment an LH-RH agonist or antagonist, in association
with an antiandrogen and at least one inhibitor of sex steroid biosynthesis,
or pharmaceutical compositions thereof, in amounts sufficient to
treat breast cancer.
In its preferred aspect, the LH-RH agonist is administered parenterally
(subcutaneously or intramuscularly) and, in association therewith,
the antiandrogen and the inhibitor of sex steroid biosynthesis are
each administered orally. The invention also provides kits or single
packages combining the two, four and five separate preferred pharmaceutical
compositions; the two component kit provides the antiandrogen oral
pharmaceutical composition and the LH-RH agonist or LH-RH antogonist
parenteral composition; the four component kit provides the LH-RH
agonist or LH-RH antagonist parenteral pharmaceutical composition,
the antiandrogen oral pharmaceutical composition and, the sex steroid
biosynthesis inhibitor oral pharmaceutical composition and the hydrocortisone
oral pharmaceutical composition and the five component kit provides
the LH-RH agonist or LH-RH antagonist parenteral pharmaceutical
composition, the antiandrogen oral pharmaceutical composition, the
antiestrogen oral pharmaceutical composition, the sex steroid biosynthesis
inhibitor oral composition and the hydrocortisone oral pharmaceutical
Thus, this invention provides a novel method for effective treatment
of breast cancer, in the absence of an antiestrogen. In addition,
the amounts of antiestrogen required when administered in association
with this combined therapy are lower than normally used in prior
art methods, e.g., J. G. M. Klijn et al., J. Steroid Biochem. 20
(No. 6B) 1381 (1984), to treat breast cancer, and thus, the harmful
effects of relatively large doses of antiestrogen are minimized.
DETAILED DESCRIPTION OF THE INVENTION
In one preferred aspect, the present invention provides an effective
method of treating breast cancer in warm-blooded female animals
in need of such treatment by administering an LH-RH agonist or antagonist,
in association with an antiandrogen and an inhibitor of sex steroid
biosynthesis or pharmaceutical compositions thereof in amounts sufficient
to inhibit breast tumor growth. These active compounds can be administered
together or in any order as discussed hereinafter. To assist in
determining the effect of the treatment, blood plasma concentrations
of the sex steroids of adrenal origin, i.e., adrenal androgens and
estrogens, and tumor size are measured. Lowered concentrations of
sex steroids and reduction in tumor size are indicative of successful
treatment, e.g. inhibition of tumor growth using active compounds
described herein in accordance with the present invention. The concentrations
of adrenal androgens and estrogens such as dehydroepiandrosterone
(DHEA), DHEA-sulfate (DHEAS), androst-5-ene-3.beta.,17.beta.-diol
(.DELTA..sup.5 -diol) and, the ovarian estrogen, 17.beta.-estradiol
(E.sub.2) are measured by standard methods well known to those skilled
in the art, see for example F. Labrie et al., The Prostate, 4, 579-594
The change in tumor size is measured by standard physical methods
well known to those skilled in the art, e.g., bone scan, chest X-ray,
skeletal survey, ultrasonography of the liver and liver scan (if
needed), CAT-scan and physical examination.
While a LH-RH agonist or a LH-RH antagonist may be used in one
preferred aspect of the present invention, the use of a LH-RH agonist
is more preferred.
By the term "LH-RH agonist" is meant synthetic analogues
of the natural luteinizing hormone-releasing hormone (LH-RH), a
decapeptide of the structure:
Typical suitable LH-RH agonists include nonapeptides and decapeptides
represented by the formula:
wherein X is D-tryptophyl, D-leucyl, D-alanyl, iminobenzyl-D-histidyl,
3-(2-naphthyl)-D-alanyl, O-tertbutyl-D-seryl, D-tyrosyl, D-lysyl,
D-phenylalanyl or N-methyl-D-alanyl and Y is L-leucyl, D-leucyl,
N.sup..alpha. -methyl-D-leucyl or N.sup.60 -methyl-L-leucyl or D-alanyl
and wherein Z is glycyl-NHR.sub.1 or NHR.sub.1 wherein R.sub.1 is
H, lower alkyl or haloloweralkyl. Lower alkyl includes straight
or branched chain alkyls having 1 to 6 carbon atoms, e.g., methyl,
ethyl, propyl, pentyl or hexyls, iso-butyl, neopentyl and the like.
Haloloweralkyl includes straight and branched chain alkyls of 1
to 6 carbon atoms having a halogen substituent, e.g., --CF.sub.3,
--CH.sub.2 CF.sub.3, --CF.sub.2 CH.sub.3. Halogen means F, Cl, Br,
with F being preferred.
Preferred nonapeptides wherein Y is L-leucyl and X is an optically
active D-form of selected amino acids and Z is NHC.sub.2 H.sub.5
are [D-Trp.sup.6, des-gly-NH.sub.2.sup.10 ]-LH-RH ethylamide (X=D-Trp.sup.6);
[D-Ser-(t-BuO).sup.6, des-gly-NH.sub.2.sup.10 ]-LH-RH ethylamide
[X=D-Ser(t-BuO.sup.6)]; [D-Leu.sup.6, des-gly-NH.sub.2.sup.10 ]-LH-RH
ethylamide (X=D-Leu.sup.6); [D-His(Bzl).sup.6, des-gly-NH.sub.2.sup.10
]-LH-RH ethylamide (X=iminobenzyl-D-His.sup.6) and [D-Ala.sup.6,
des-gly-NH.sub.2.sup.10 ]-LH-RH ethlamide (X=D-Ala.sup.6).
Preferred decapeptides include [D-Trp.sup.6 ]-LH-RH wherein X=D-Trp,
Y=L-leucyl, Z=glycyl-NH.sub.2, [D-Phe.sup.6 ]-LH-RH wherein X=D-phenylalanyl,
Y=L-leucyl and Z=glycyl-HN.sup.2) or [D-Nal(2).sup.6 ]-LH-RH which
is [(3-(2-naphthyl-D-Ala.sup.6 ]-LH-RH wherein X=3-(2-naphthyl)-D-alanyl,
Y=L-leucyl and Z=glycyl-NH.sub.2.
Other LH-RH agonists useful within the scope of this invention
are the .alpha.-aza analogues of the natural LH-RH, especially,
[D-Phe.sup.6, Azgly.sup.10 ]-LH-RH, [D-Tyr(Me).sup.6, Azgly.sup.10
]-LH-RH, and [D-Ser-(t-BuO).sup.6, Azgly.sup.10 ]-LH-RH disclosed
by A. S. Dutta et al. in J. Med. Chem., 21, 1018 (1978) and U.S.
Pat. No. 4,100,274 as well as those disclosed in U.S. Pat. Nos.
4,024,248 and 4,118,483.
Typical suitable LH-RH antagonists include [N-Ac-D-p-Cl-Phe.sup.1,2,
D-Phe.sup.3, D-Arg.sup.6,D-Ala.sup.10 ]-LH-RH disclosed by J. Ercheggi
et al., Biochem. Biophys. Res. Commun. 100, 915-920, (1981); [N-Ac-D-p-Cl-Phe1,2,
D-Trp.sup.3, D-Arg.sup.6, D-Ala.sup.10 ] LH-RH disclosed by D. H.
Coy et al., Endocrinology, 110: 1445-1447, (1982); [N-Ac-D-(3-(2-naphthyl)-Ala).sup.1,
D-p-Cl-Phe.sup.2, D-Trp.sup.3, D-hArg(Et.sub.2).sup.6, D-Ala.sup.10
]-LH-RH and [N-Ac-Pro.sup.1, D-p-F-Phe.sup.2, D-(3-(2naphthyl)Ala.sup.3,6
]-LH-RH disclosed by J. J. Nestor et al. J. Steroid Biochem., 20
(No. 6B), 1366 (1984); the nona- and decapeptide LH-RH analogs useful
as LH-RH antagonists disclosed in U.S. Pat. Nos. 4,481,190 (J. J.
Nestor et al.); analogs of the highly constrained cyclic antagonist,
cycle [.DELTA..sup.3 Pro.sup.l, D-p-Cl-Phe.sup.2, D-Trp.sup.3,6,
N-Me-Leu.sup.7, .beta.-Ala.sup.10 ]-LH-RH disclosed by J. Rivier,
J. Steroid Biochem., 20, (No. 6B), 1365 (1984), and [N-Ac-D-(3-(2-naphthyl)Ala.sup.1,
D-p-F-Phe.sup.2, D-Trp.sup.3, D-Arg.sup.6 ]-LH-RH disclosed by A.
Corbin et al., J. Steroid Biochem. 20 (No. 6B) 1369 (1984).
Other LH-RH agonist and antagonist analogs are disclosed in LH-RH
and Its Analogs (B. H. Vickery et al.) at pages 3-10 (J. J. Nestor)
and pages 11-22 (J. Rivier et al.) and pages 23-33 (J. J. Nestor
The LH-RH agonists and antagonists useful in this invention may
conveniently be prepared by the method described by Stewart et al.
in "Solid Phase Peptide Synthesis" (published in 1969
by Freeman & Co., San Francisco, page 1) but solution phase
synthesis may also be used.
The nona- and decapeptides used in this invention are conveniently
assembled on a solid resin support, such as 1% cross-linked Pro-Merrifield
resin by use of an automatic peptide synthesizer. Typically, side-chain
protecting groups, well known to those in the peptide arts, are
used during the dicyclohexylcarbodiimide-catalyzed coupling of a
tert-butyloxcarbonylamino acid catalyzed coupling of a tert-butyloxycarbonylamino
acid to the growing peptide attached to a benzhydrylamine resin.
The tert-butyloxycarbonyl protecting groups are removed at each
stage with trifluoroacetic acid. The nona- or decapeptide is cleaved
from the resin and deprotected by use of HF. The crude peptide is
purified by the usual techniques, e.g., gel filtration and partition
chromatography and optionally lyophilization. See also D. H. Coy
et al., J. Med. Chem. 19, pages 423-452, (1976).
Typical suitable antiandrogens include nonsteroidal antiandrogens
such as the imidazolidines, especially 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione
(alson called Anandron) described in U.S. Pat. No. 4,097,578, or
4'-nitro-3'-trifluoromethylisobutyranilide (also called flutamide)
described in U.S. Pat. No. 4,329,364 as well as the N-(phenylalkanoyl)aniline
derivatives disclosed in U.S. Pat. No. 4,386,080 and the 3,4- disubstituted-branached-chain
acylanilides disclosed in U.S. Pat. No. 4,239,776 (A. T. Glen et
al.). Flutamide is the preferred antiandrogen.
Typical suitable steroidal antiandrogens include 6-chloro-1,2-dihydro-17-(acetyloxy)-3'H-cyclopropa[1,2]pregna-1,4,6-triene
-3,20-dione, available under the tradename of Androcur from Schering
A.G., W. Berlin, 17-(acetyloxy)-6-methyl-pregna-4,6-diene-3,20-diene,
also called megestrol acetate and available from Mead Johnson &
Co., Evansville, Ind. under the tradename of Megace.
Typical suitable antiestrogens include those steroidal and non-steroidal
antiestrogens such as (1RS,2RS)-4,4'-diacetoxy-5,5'-difluoro-(1-ethyl-2-methylene)di-m-phenylene
diacetate, which is available from Biorex under the tradename of
which is available from Eli Lilly & Co., Indianapolis, Ind.
under the tradename of Clometherone, 6-chloro-17-hydroxypregna-1,4,6-triene-3,20-dione
which is available as the acetate salt from Syntex Labs, Palo Alto,
Calif. as Delmadione Acetate, 17-hydroxy-6-methyl-19-norpregna-4,6-diene-3,20-dione
which is available from Theramex under the name of Lutenyl, 1-[2-[4-[1-(4-methoxyphenyl)-2-nitro-2-phenylethenyl]phenoxy]ethyl]-pyrrol
idine which is available as the citrate salt from Parke-Davis Div.
of Warner-Lambert Co., Morris Plains, N.J. under the name of Nitromifene
Citrate, substituted aminoalkoxyphenylalkenes such as (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
which is available as the citrate salt from Stuart Pharmaceuticals,
Wilmington, Del. as Tamoxifen Citrate (see also Belgian Patent 637,389,
March 1964), 3,4-dihydro-2-(p-methoxyphenyl)-1 -naphthyl p-[2-(1-pyrrolidinyl)ethoxy]phenyl
ketone which is available as the methane sulfonate salt from Eli
Lilly & Co. under the tradename of Trioxifene Mesylate, 1-[4'-(2-dimethylaminoethoxy)-phenyl)-1-(3'-hydroxyphenyl)-2-phenyl-but-1-
ene, which is available from Klinge Pharma, 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl[2-(1-pyrrolidinyl)-ethoxy
phenyl]ketone which is available from Eli Lilly & Co. (LY-117018),
y]phenyl)methanone, which is available form Eli Lilly & Co.
as the hydrogen chloride salt (LY-156758) and meso-3,4-bis(3'-hydroxyphenyl)hexane
as well as the dimethyl, dipropyl and 3'-acetoxyphenyl analogues
which are described in U.S. Pat. No.4,094,994 and a series of 1-phenyl-alkane
and -alkenes, e.g. (E)-3-cyclopentyl-1-(4-hydroxyphenyl)-1-phenyl-1-butene
and 2-cyclopentyl-1-[4-hydroxy-or methoxyphenyl]-3-phenyl-2-propen-1-ol
and FC-1157 which is available as the citrate salt from Farmos Group,
Ltd., Turku, Finland (see also Eur. Pat. Appln. EP 78,158). FC-1157,
LY-117018, LY-156578 and Tamoxifen are the preferred antiestrogens.
A pure antiestrogen is more preferred.
The inhibitors of sex steroid biosynthesis found useful in the
present invention include those compounds which inhibit biosynthesis
of sex steroids and precursor sex steroids of adrenal origin, preferably
of ovarian and adrenal origin.
Thus, in another preferred aspect of the present invention, an
inhibitor of sex steroid biosynthesis such as 3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione
which is commonly called aminoglutethimide, which is an inhibitor
of sex steroid biosynthesis of adrenal but also ovarian origin and
which is available from Ciba Pharmaceutical Co., Summit, N.J. under
tradename Cytadren, or ketoconazole which is available from Janssen
Pharmaceutica, Piscataway, N.J. under the tradename Nizoral is administered
in combination with the LH-RH agonist or antagonist, the antiandrogen
and optionally the antiestrogen for treatment of breast cancer.
When an inhibitor of adrenal sex steroid biosynthesis, e.g., aminoglutethimide
is administered, cortisol biosynthesis is blocked. Accordingly,
hydrocortisone is administered in physiological amounts sufficient
to maintain normal glucocorticoid levels.
In this invention, the association of the LH-RH agonist or antagonist,
antiandrogen and the inhibitor of steroid biosynthesis and hydrocortisone
and optionally antiestrogen are administered as pharmaceutical compositions
via topical, parenteral or oral means. The LH-RH agonist or antagonist
is administered parenterally, i.e., intramuscularly, subcutaneously
or intravenously by injection or infusion by nasal drops or intra-vaginally
by suppository. The LH-RH agonist or antagonist also may be microencapsulated
in or attached to a biocompatable, biodegradable polymer, e.g.,
poly(d,l-lactide-coglycolide) and subcutaneously or intramuscularly
injected by a technique called subcutaneous or intramuscular depot
to provide continuous, slow release of the LH-RH agonist or antagonist
over a period of 30 days or longer. The most preferred route of
administration of the LH-RH agonist or antagonist is subcutaneous
depot injection. Preferably the antiandrogen and antiestrogen (when
used) will each be administered orally. Preferably the inhibitor
of sex steroid biosynthesis, e.g. aminoglutethimide and/or ketoconazole
are administered orally.
The amount of each component administered is determined by the
attending clinicians taking into consideration the etiology and
severity of the disease, the patient's condition and age, the potency
of each component and other factors.
The LH-RH agonist or antagonist is generally administered at from
about 10 to 5000 .mu.g per day, with contemplated dosage ranges
of about 10 to 1500 .mu.g per day and about 200 to 500 per day for
the LH-RH agonist, and about 50-5000 .mu.g per day for the LH-RH
antagonist being preferred.
In the most preferred embodiment of this invention, the LH-RH agonist
or antagonist is administered subcutaneously in a daily dose of
about 500 .mu.g for the first 30 days and thereafter subcutaneously
in a daily dose of about 250 .mu.g regardless of the patients body
weight. When the LH-RH agonist or antagonist is administered, once
every 30-day period or even longer, by intramuscular or subcutaneous
depot injection, a dose from about 300 to 150000 .mu.g per 30-day
period is used, with a dose of about 750 to 15000 .mu.g per 30-day
period being preferred.
The antiandrogen compositions are generally administered in a dosage
range of about 0.20 to 40 mg/kg (body weight) per day with 750 mg
per day in three equally divided doses being preferred.
The antiestrogen compositions (when used) are administered in a
dosage range of about 0.1 to 10 mg/kg body weight per day, with
10 mg in two equally divided doses being preferred.
The aminoglutethimide compositions when used are administered initially
in a dosage of about 250 mg given at 8-hour intervals and the dosage
may be increased in increments of about 250 mg daily up to a total
daily dose of about 2 grams.
The hydrocortisone compositions are administered orally in a dosage
range of about 0.1 to 20 mg/kg body weight per day. Preferably,
the hydrocortisone is administered orally at the dose of about 10
mg in the morning and about 5 mg doses in the afternoon and in the
The ketoconazole compositions when used are administered orally
in a dose of about 250 mg given at 8-hour intervals and may be increased
to about 2 grams per day.
The LH-RH agonist or antagonist and antiandrogen and and inhibitor
of sex steroid bisoynthesis and antiestrogen (when used) each may
be administered separately or when the modes of administration are
the same, all or two of them may be administered in the same composition,
but in any case the preferred ratio of LH-RH agonist to antiandrogen
to antiestrogen to inhibitor of sex steroid biosynthesis administered
daily will be about 250 .mu.g of LH-RH agonist to about 750 mg of
antiandrogen to about 15 mg of antiestrogen to about 750 mg of sex
steroid biosynthesis inhibitor.
In the most preferred aspect of this invention, the LH-RH agonist
is [D-Trp.sup.6,des-Gly NH.sub.2.sup.10 ]LH-RH ethylamide which
is administered subcutaneously in single daily dose of about 500
.mu.g for the first thirty (30) days about 250 .mu.g ; the antiandrogen
is 4'-nitro-3'-trifluoromethyl-isobutyranilide, i.e., flutamide,
which is administered orally in three equally divided daily doses
of about 250 mg; the inhibitor of sex steroid biosynthesis is ketoconazole
or aminoglutethimide which is administered orally in three equally
divided daily doses of about 250 mg; the hydrocortisone is administered
orally at a dose of about 10 mg in the morning and two equally divided
doses of about 5 mg, 8 and 16 hours thereafter. The antiestrogen,
when used, is (Z)-2-[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl
ethylamine (Tamoxifen) which is administered orally in three equally
divided doses of about 10 mg every 12 hours.
The inhibitor of steroid biosynthesis and antiandrogen are preferably
administered to a female in need of the breast cancer treatment
of this invention one or two days before the LH-RH agonist or antagonist
is administered, but the attending clinician may elect to start
administration of the LH-RH agonist or antagonist, the antiandrogen
and the inhibitor of sex steroid biosynthesis on the first day of
When patients whose ovaries have already been removed are treated
according to this invention, the antiandrogen and the inhibitor(s)
of steriod biosynthesis such as aminoglutethimide and or ketoconazole
administration and dosage are the same as indicated when the antiandrogen
or the association of the antiandrogen and inhibitor(s) of sex steroid
biosynthesis are used in combination with the LH-RH agonist or antagonist
as well as the optional ingredient, the antiestrogen.
The LH-RH agonists or antagonists useful in the present invention
are typically amorphous solids which are freely soluble in water
or dilute acids, e.g., HCl, H.sub.2 SO.sub.4, citric, acetic, mandelic
or fumaric. The LH-RH agonist or antagonist for subcutaneous injection
is supplied in vials containing 6 mL of sterile solution with the
LH-RH agonist or antagonist at a concentration of about 1.0 mg/mL.
A typical pharmaceutical composition of the LH-RH agonist or antagonist
include the LH-RH agonist or antagonist or a pharmaceutically acceptable
acid salt thereof, benzyl alcohol, a phosphate buffer (pH=6.9-7.2)
and sterile water.
The LH-RH agonist or antagonist for intramuscular or subcutaneous
depot injection may be microencapsulated in a biocompatible, biodegradable
polymer, e.g., poly (d,1-lactide-co-glycolide) by a phase separation
process or formed into a pellet. The microspheres may then be suspended
in a carrier to provide an injectable preparation or the depot may
be injected in the form of a pellet. See also European Patent Application
EPA No. 58,481 published Aug. 25, 1982 for solid compositions for
subdermal injection or implantation or liquid formulations for intramuscular
or subcutaneous injections; containing biocompatible, biodegradeable
polymers such as lactide-glycolide copolymer and an LH-RH agonist,
e.g., D-Ser-t-BuO.sup.6, Azgly.sup.10 -LH-RH.
The aminoglutethimide and ketoconazole and hydrocortisone are typically
compounded in customary ways for oral administration, e.g., in tablets,
capsules and the like.
The antiandrogens useful in the present invention are typically
formulated with conventional pharmaceutical excipients, e.g., spray
dried lactose and magnesium stearate into tablets or capsules for
oral administration. The antiestrogens, when used with the invention,
are typically compounded in customary ways for oral administration,
e.g., in capsules, tablets, as dragees or even in liquid form, e.g.,
suspensions or syrups. One or more of the active substances, with
or without additional types of active agents, can be worked into
tablets or dragee cores by being mixed with solid, pulverulent carrier
substances, such as sodium citrate, calcium carbonate or dicalcium
phosphate, and binders such as polyvinyl pyrrolidone, gelatin or
cellulose derivatives, possibly by adding also lubricants such as
magnesium stearate, sodium lauryl sulfate, "Carbowax"
or polyethylene glycols. Of course, taste-improving substances can
be added in the case of oral-administration forms.
The therapeutically active antiestrogen compound should be present
in a concentration of about 0.5-90% by weight of the total mixture,
i.e., in amounts that are sufficient for maintaining the above-mentioned
As further forms of administration, one can use plug capsules,
e.g., of hard gelatin, as well as closed soft-gelatin capsules comprising
a softener or plasticizer, e.g., glycerine. The plug capsules contain
the active substance preferably in the form of a granulate, e.g.,
in mixture with fillers, such as lactose, saccharose, mannitol,
starches, such as potato starch or amylopectin, cellulose derivatives
or highly-dispersed silicic acids. In soft-gelatin capsules, the
active substance is preferably dissolved or suspended in liquids,
such as vegetable oils or liquid polyethylene glycols.
In place of oral administration, all the active compounds may be
administered parenterally. In such case, one can use a solution
of the active substance, e.g., in sesame oil or olive oil.
Following the above treatment using the described regime, breast
tumor growth is inhibited and in some instances complete remission