Note: Descriptions are shown in the official language in which they were submitted.
BRIEF SUMMARY OF THE INVENTION
... .
This invention relates to processes of ameliorating
cancer diseases in mamma~s such as leukemia. The essential
active ingredient, utilized in the processes în an effective
amount, is a pharmaceutically acceptable salt of an anthraquinone
compound of the formula
O NS-R-N~-~O~
O NH-R-N~-RO~
where R is alkylene having 1-4 carbons, wherein the active
ingredient is present at between about 0.1 and about 400 milli-
grams per milliliter of carrier.
DETAILED DESCRIPTION
.
This invention relates to a pharmaceutical composition
and the use thereof and more particularly to a pharmaceutical
anthraquinone composition and to a process for its administration.
The compound of the above formula wherein R is ethyl has
shown presumptive activity against leukemia in mice used as
standard test animals. Each of the compounds of the above
formula, and their pharmaceutically acceptable salts, would be
expected to show activity against a broad range of cancer
diseases, and especially blood cancer diseases such as leukemia,
in standard test animals and in humans at doses below
substantially toxic levels.
The inventive composition is an anthraquinone composition
of the above formula or pharmaceutically acceptable salts
thereof dispersed in a pharmaceutically acceptable carrier. The
anthraquinone compounds can be prepared according to the methods
disclosed in United States Patent 4,051,155 issued Sept. 27, 1~77.
1~ 3~B~a~
The pharmaceutically acceptable salts
lnclude the acid salts, for example, those of hydrochloric, citric,
succinic, maleic, tartaric, acet~c, and like ac~ds. Of the acid
~alts, the acetate and hydrochloride are preferred. Such salts
are pharmaceutically acceptable in the sense of having no ~ubstan-
t~ally different activity or toxicity compared to the base.
The modes contemplated for carrying out the invention
include pharmaceutical compositions and processes of administra- ¦
tion thereof.
10Solutions of the principal active ingredient as a free
base or salt can be prepared in water or in water suitably mixed
with, for example, surfactants. The preferred compound, where R
is ethyl in the above formula, is slightly soluble in water. It
can, for example, be converted to a partial acetate having a pH in
aqueous solution of about 7.4 which, on analysis, shows about 1-1/2
acetic acid residues/anthraquinone nucleus. A diacetate may also
be produced having a pB in aqueous solution of about 6.2. The
diacetate is soluble in water to the extent of about 400 mg/
milliliter of water. The base or various salts may be made more
soluble by the addition of surfactants such as hydroxypropyl-
cellulose to the composition. Dispersions can also be prepared in
glycerol, liquîd polyethylene glycols, and mi~tures thereof and in
oils. Vnder ordinary conditions of`storage and use, ~hese prepara-
tions ~ontain a preservative to prevent the growth of microoganisms.
The pharmaceutical compositions can be in forms suitable
for injectable use, which forms include sterile aqueous solutions
or dispersions and sterile powders for the extemporaneous prepara
tion of sterile injectable solutions or dispersions In all cases
the form ~ust be sterile and must be fluid to the extent that easy
syrinqabil;ty exists. It must be stable under the oonditions of
manufacture and storage and must be preserved against _he contami-
.
~,' ~''' ~ ' .
~7 ~
nating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for
example, water, ethanol, polyol (for example, glycerol, propylene
glycol, and liquid polyethylene glycol, and the like), suitable
mixtures thereof, and vegetable oils. The proper fluidity can be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersion and by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various anti-
bacterial and antifungal agents~ for example, parabens, chloro-
butanol, benzoalcohol, phenol, sorbic acid, thimerosal, and the
like. In many cases, it will be preferably to include isotonic
agents, for example, sugars or sodium chloride. Prolonged absorp-
tion of the injectable compositions can be brought about by the
use in the compositions of agents delaying absorption, for example,
aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporat-
ing the principal active ingredient or ingredients in the required
amount in the appropriate solvent with various of the other ingre-
dients enumerated above, as required, followed by filtered steri-
lization. Generally, dispersions are prepared by incorporating the
various sterilized active ingredient into a sterile vehicle which
contains the basic dispersion medium and the required other ingre-
dients from those enumerated above.
In the case of sterile powders for the preparation of
sterile injectable solutions, the preferred methods of preparation
are vacuum drying and the freeze-drying technique which yield a
powder of the active ingredient plus any additional desired
ingredient from a previously sterile-filtered solution thereof.
The powders can also be sterilized by use of a gas, for example,
ethylene oxide and subsequently incorporating, with the required
--3--
1~37~ ~ ~
additional ingredients and in the proper particle size, into the
basic powder for later reconstitution with the desired suspending
liquid which, of course, itself must be sterile.
As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings, anti-
bacterial and antifungal agents, isotonic and absorption delaying
agents and the like. The use of such media and agents for pharma-
ceutical ac~ive substances is well known in the art. Except insofar
as any conventional media or agent is incompatable with the active
ingredient, its use in the present compositions is contemplated
within the scope of the invention.
Supplementary active ingredients can also be incorpor-
ated into the inventive compositions.
It is especially advantageous to formulate inventive
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form as used in the specifica-
tion and claims herein refers ~G physically discreet units suited
as unitary dosages for the animal and human subjects to be treated,
each unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect in association
with the required pharmaceutical carrier. The specifications for
the novel dosage unit forms of the invention are dictated by and
directly dependent on (a) the unique characteristics of the active
material and the particular therapeutic effect to be achieved, and
(b) the limitations inherent in the art of compounding such an
active material for the treatment of disease in living subjects
having a diseased condition in which bodily health is impaired as
disclosed in detail in this specification, these being features of
the present invention.
The dosage of the principal active ingredient for the
treatment of the indicated conditions depends upon the age, weight
--4--
and condition of the subject being treated; the particular condi-
tion and its severity; particular form of the active ingredient
and the route of administration. A daily dose of from about 1 to
about 100 mg/kg, given singly or in divided doses of up to 5 times
a day embraces the effective range for the treatment of most con-
ditions for which the compound is effective and substantially
non-toxic. For a 75 kg subject, this translates into between
about 75 and about 7500 mg/day. If the dosage is divided, for
example, into 3 individual dosages, these will range from about 25
to about 2500 mg of the active ingredient. The preferred range is
from about 2 to about 50 mg/kg of body weight/day with about 2 to
about 30 mg/kg/day being more preferred.
The principal active ingredient is compounded for con-
venient and effective administration in effective amounts with
a suitable pharmaceutically-acceptable carrier in dosage unit
form as hereinbefore disclosed. A unit dosage form can, for exam-
ple, contain the principal active ingredient in amounts ranging
from about 0.1 to about 400 mg, with from about 1 to about 30 mg
being preferred. Expressed in proportions, the active ingredient
20 is generally present in from about 0.1 to about 400 mg/ml of carrier.
In the case of compositions containing supplementary
active ingredients, the dosages are determined by reference to the
usual dose and manner of administration of the said ingredients.
Regression and palliation of cancers are attained, for
example, using intraperitoneal administration. A single intra-
venous dosage or repeated daily dosages can be administered~ Daily
dosages up to about 5 or 10 days are often sufficient. It is also
possible to dispense one daily dosage or one dose on alternate or
less frequent days. As can be seen from the dosage regimens, the
amount of principal active ingredient administered is a sufficient
amount to aid regression and palliation of the leukemia or the
--5--
3~l37,~1L
,.
like, in the absence of excessive deleterious side effects of a
cytotoxic nature to the hosts harboring the cancerO In the fol-
lowing data using mice and the base of the above ~ormula where
R is ethylene, it can be seen-that some toxicity exists at about 50
mg/kg and that increasing toxicity occurs from 50 to about 100
m~/kg. Nevertheless, daily dosa~es up to about 100 mg/kg are
within the preferred range/ especially when aclministered on
different regimens and ~or various of the anthraquinone compounds
and salts within the scope of the present inventio~9
10As used herein, cancer is meant blood malignancies such
as leukemia, as well as other solid and non solid malignancies
such as the melancarcinomas, lung carcinomas and mammary tumors.
By regression and pallation is meant arresting or retarding the
growth of the tumor or other manifestation of the disease compared
to the course of the disease in the absence o treatment. In many
oE the gollowing examples, mice are used as standard test animals
to show the efective and toxic levels of the novel compositions.
It is within the scope of the present invention, however, to treat
i higher mammals including humans with the novel composition to aid
in the amelioration and regression of cancer diseases. From the
test data with lower mammals it would be expe-cted that the novel
compositions are so effecti~e below substantially toxic levels~
The following examples set ~orth the manner a~d process
of making and using the inventive compositions. They also include
test data showing the effectiveness of the present compositions in
treating leukemia~like tumors in standard test animals.
Example 1 - Preparation of Base
.
121 grams of para leuco quini~arine, or 2,3-dihydro-1,4-
dihydroxy anthraquinone, were charged with 300 cc of ethyl alcohol
solvent into a 1 liter Elask. The mixture was ayitated to form a
uniform slurry, and to the slurry was charged 124 grams oE N-amino-
--6~
~, .
~13~7l5!~g~
ethylethanolamine. The resulting mixture was agitated at room
temperature for one hour, heated to 75-80C and held at that
temperature for six hours. While the temperature was maintained
at 75-80C, the mixture was aerated until the leuco product was
oxidized as indicated by the product being completely in solution.
The solution was cooled to 10C, filtered, washed with ethyl
alcohol and dried under vacuum. The yield was 138 grams.
Other bases within the scope of this invention can be
made with N-aminoethylethanolamine replaced by N-aminomethylmeth-
anolamine, N-aminopropylpropanolamine or N-aminobutylbutanolamine.
~xample 2 - Preparation of Salts
Any of the bases of Example 1 can be neutralized with
an acid such as acetic or hydrochloric acid to form a salt. An
excess of dilute aqueous acetic acid is added to the dried compound
of Example 1 (derived from N-aminoethylethanolamine) The mixture
is heated to about 50C and held there for about 2 hours. An
excess of chloroform is added and after phase separation, the
organic phase is discarded. The salt is then vacuum dried.
Example 3 - Preparation of Injectable Composition
_
Ten grams of the acetate salt of Example 2 are dissolved
in one liter of saline solution creating a solution with 10 mg/ml
of active ingredient. A five ml dose of this composition thus
provides 50 mg of active ingredient.
Solutions can be prepared of the various bases and salts
of the invention with most standard pharmaceutically-acceptable
solvents. Particularly with the free bases, a surfactant such as
hydroxypropylcellulose improves solubility.
Example 4 - Preparation of Powder Composition
Ten grams of the free base of Example 1, prepared using
N-aminoethylethanolamine is dispersed in l9a grams of glycerine.
A one gram dose of this powder thus provides 50 mg of active in-
gredient.
--7--
1~.3~87~
Powders may be prepared with most standard pharmaceuti-
cally-acceptable dispersion agents. The powder may then be combined
with other agents as desired and encapsulated by conventional
;~techniques.
~; Exampl~ 5
Six male mice of strain CDF~L were injected on day 0
intraperitoneally with 106 cells of L-1210 lymphoid leukemia.
; Beginning on day 1 and daily for a total of 9 days, each mouse was
treated by an intraperitoneal injection of 250 mg/kg of body
10 weight of the compound of Example 1 in a carrier of hydroxypropyl-
¢ ***
cellulose sold as Rluccel. After five days two of the six had
survived. The mean survival time was 6.5 days for the test
animals, 9.9 days for the controls.
Exampsles 6-11
The test of Example S was repeated for groups of six
mice and a group of controls at the doses indicated in Table 1.
The means survival times are indicated in Table 1. The test was
discontinued after 30 days.
Table :L - Lymphoid Leukemia ~L-1210)
Dose mg/kg Survival 'Mean Apparent
20 Example Body Weight at 5 days Survival TimeCures**
250 2/6 6.5
6 125 4/6 6.8
7 62.5 5/6 21~8 2
Control__ o 9.9
8* 95~0 6~6 7.3
9* 62.5 6/6 11.3
10* 42.0 6/6 11.3
11~ 28.0 6/6 18.3 2
Control 0 8.4
*Mouse strain BD~l.
**Mice surviving until end of test.
*** Trade Mark -s
-- 8 --
, ~
1~ ~7~74
It appears from these tests that dosages of 62.5 mg/kg of
body weight and over begin to show some toxicity to mice under this
test regime. Suhstantially improved survival times compared to
the controls ~innoculated only) is found in dosages from about 28
to about 62.5 mg/kg of body weight.
E~ample 12
Six male mice, strain CDFl, were innoculated with P388
lymphocytic leukemia applied intraperitoneally at 106 cells in
ascitic fluid. Beginning the first day after innoculation and
then daily for nine days, the compound of Example 1 was applied
at a close level of 128 mg/kg of body weight in saline solution
with ~Tween-80n. Four of six mice survived after five days and
the median survival time for the six mice was 5.9 days.
Examples 13-29
Example 12 was repeated with groups of six mice at dif-
ferent dosage levels with the results shown in Table 2. This
test was discontinued after 30 days.
Table 2 - Lymphocytic Leukemia (P388~
Dose mg/kg Survival Mean Apparent
20 Example Body Weight at 5 daysSurvival Time Cures
12 128 4/6 5.9
13 64 6/6 6.4
14 32 6/6 8.8
16.0 ~/6 29.7 3
16 800 6/6 29.9
17 4.0 6/6 29.7 3
Control 0 10 8
. . _ ~ ,
* Trade Mark
_9_
1~ 37~7~
Table 2 - Lymphocytic Leukemia (P388) (Continued)
18 128 6/6 6.4
19 64 4/6 6.3
32 6~6 7.8
21 16.0 6/6 10.1
22 8.0 6/6 21.0 %
23 4.0 6/6 2g.7 3
Control 0 11.0
. . _
24 128 2/6 5.0
10 25 64 6/6 6.2
26 32 5/6 8.0
27 16.0 6/6 28.8 2
28 8.0 6/6 23.0
29 4.0 6/6 19.8
Control 0 _ _ 10.8
NOTE: The "%" figure in this and subsequent tables indicates that
the only surviving animals were adjudged upon autopsy to be "no-
takes" for the tumor.
These tests show substantial activity in the 4.0-16.0
mg/kg body weight range. At a dosage of 32.0 mg/kg and especially
64.0 mg/kg, the toxicity of the drug appears to overtake the bene
ficial effects.
Example 30
Ten more male mice, strain BDFl, were innoculated intra-
peritoneally with an unspecified level of the homogenate of tumor
B-16 meloncarcinoma. Beginning the first day after innoculation and
every second day thereafter, the mice were treated with intraperi-
toneal injections of 128 mg/kg of body weight of the compound of
Example 1 in saline solution with "Tween-80". Injections occurred
intraperitoneally on survivors on days 3, 5, 7, 9, 11, 13, 15 and
17. The median survival time was 5.2 days compared to 21.3 days
for the control. Evaluation ended on the 60th day.
--10--
~3r,~ ot~
Examples 31-47
Example 30 was repeated a~ dosage levels shown in Table
3 with the results indicated in Table 3.
Table 3 - Melancarcinoma (B-16)
Dose mg/kg Survival Mean Apparent
ExampleBody Weightat 5 daysSurvival Time Cures
... .. _ _
30128 3/10 5.2
3164.0 8/10 6.1
3232.0 10/10 10.8
33,16.0 10/10 59.8 8
1034 8.0 10/10 59.8 6
354.0 10/10 59O8 6
Control 0 21.3
_
36 128 4/10 5.4
37 64.0 8/10 7.1
38 32.0 10/10 11.1 .
39 16.0 10/10 51.0 tumored survi-
vors only
8.0 10/10 60.0 10
41 4.0 10/10 43.0 %
Control 0 25 2
. . . _ _ . _ _ . . .
20 42 128 10/10 9.3
43 64.0 8/10 16.8
44 32.0 10/10 37.0
45 16.0 10/10 34.0
46 8.010/10 36.0
47 4.010/10 32.0
Control 0 18.8
_ _ _ ... .. _
~ 3~
Table 3 - Melancarcinoma (B-16) (continued)
Dose mg/kg Survival Mean Apparent
_ample Body Weight at 5 days Survival Time Cures
48** 128 7.0
49** 64.0 12.0
50** 32.0 31.0
51** 16.0 31.0
52** 8.0 26.3
53** 4.0 27.0
Control 0 30.3
*The serum of example 30-41 was diluted 10:1 before innoculation
in Examples 42-53. Also the surfactant Tween-80 was omitted.
**In examples 48-53, the injections were on days 1, 3, 5,7, 9, 11,
13, 15 and 17.
Example 54
Six male mice, strain CDFl, were innoculated intraperi-
toneally with 105 cells of L-1210 lymphoid leukemia~ Reginning
on the first day a~ter innoculation and daily for a total of nine
days, the mice were innoculated with intraperitoneal injections of
128 mg/kg of body weight of the compound of Example 1 in saline.
Five of the six mice survived to the fifth day and the median sur-
vival time was 6.1 days. The test was terminated after 30 days.
Examples 55-77
-
Example 54 was repeated at the dosa~e levels indicated
in Table 4. In examples 62-69 the injections were subcutaneous.
In examples 70-77 the compound was given orally.
Table 4 - Lymphoid Leukemia (L-1210)
Dose mg/kg Survival ~ean Apparent
Example Body Weight at 5 days Survival Time Cures
54 _ 128 5/6 6.1
64.0 6/6 7.8
56 32.0 6/6 11.0
57 16.0 6/6 15.3
58 8.0 6/6 16.0
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~3'~7~
Table 4 - Lymphoid Leukemia (L-1210) (Continued)
Dose mg/kg Survival Mean Apparent
Example sody Weight at 5 days Survival Time Cures
59 4.0 6/6 12.8 3
2.0 6/6 12.7
61 1.0 6/6 11.3
62 SC 128 6/6 10.3 3
63 64.0 6/6 11.8
64 32.0 6/6 11.8
16.0 6/6 10.4
66 8.0 6/6 8.4
67 4.0 6/6 8.3 3
68 2.0 6/6 8.4
69 1.0 6/6 8.2
70 Oral 512 6/6 8.1
71 256 6/6 9.0
72 128 6/6 8.8
73 64.0 6/6 8.8
74 32.0 6/6 8.4
16.0 6/6 8.4
76 8.0 6/6 9.2
77 4.0 6/6 9.2
Control 0 8.0
~ . . . _ _ . . _ _ . . .
When given intraperitoneally, the compound showed substantialy
activity at dosages of 16.0 and 8.0 mg/kg of body weight. More
limited activity was seen in this particular test series when the
same or higher dosages were injected subcutaneously or were intro-
duced by oral administration.
Example 78
Ten male mice, strain BDFl, were innoculated with Lewis
lung carcinoma homogenate at unspecified dosage intravenously.
Beginning on the first day after innoculation and for a total of
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~ 3~
nine days, the mice were treated with 32 mg of the compound of
Example 1 per kg of body weight. After five days all 10 mice
survived. The median survi~al time was 8.2 days.
Examples 79-89
Example 78 was repeated at the dosage levels shown in
Table 5. In Examples 84-89, tumor fragments rather than tumor
homogenate were used for innoculation. These tests were discon
tinued after 60 days.
Table 5 - Lewis Lung Carcinoma
.
Dose mg/kgSurvival Mean ~pparent
Example Body Weightat 5 daysSurvival TimeCures
78 32.0 10/10 8.2
79 16.0 10/10 18.0
8.0 10/10 32.0 %
81 4.0 10/10 23.3 %
~2 2.0 10/10 25.0 %
83 1.0 10/10 22.8
Control 0 22.7
84 32.0 10/10 8.4
2085 16.0 10/10 11.0
86 8.0 10/10 28.0
~87 4.0 10/10 27.0
88 2.0 10/10 39.0
~9 1.0 10/10 50.3*
Control 0 24.0
For this tumor, the effect was appreciably over the dosage range
of 2.0-8.0 mg/kg although the results are not as drama~ic as for
other tumors. The high value in Example 89 is somewhat inconsistent
with the toxicity pattern based on body weight change, which peaks
at a dosage of 2.0 mg/kg.
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d ~L
Example _
Six female mice, strain CDFl, were innoculated intraperi-
toneally with 106 cells of P388 lymphocrytic leukemia. On the
the first day after innoculation and on days 5 and 9 for a total of
three days, the mice were treated with 512 mg/kg of body weight of
the compound of Example 1 in saline solution with "Tween-80" surfac-
tant. Tests were discontinued after 30 days. The median survival
time was 2.1 days.
Examples 91-102
Example 90 was repeated at the dosage levels indicated
in Table 6 with the results indicated.
Table 6 - Female Mice
Dose mg/kg Survival Mean Apparent
Example Body Weight at 5 days Survival Time Cures
_
90* 512 0/6 2.1
91* 256 0/6 2.7
92* 128 2/6 5.0
93* 64.0 5/6 7.8
94* 32.0 6/6 29.7
95* 16.0 6/6 26.0
20 Control 0 _ 11.1
96** 64.0 4/6 6.3
97** 32.0 6/6 8.7
98** 16.0 6/6 34.9 4
99** 8.0 6/6 28.0
100** 4.0 6/6 22.3
101** 2.0 6/6 24.0
102** 1.0 5/6 17.9
Control 0 10.5
*Example 90-95 involved injection on days 1, 5 and 9 only.
**Examples 96-102 and their control were continued to the thirty-
fifth day. Injections were daily for nine days.
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7~7~
These tests show substantial activity, particularly at dosages
of about 16.0 mg/kg.
Example 103
Ten male mice, strain BDFl, were innoculated with an
the same unspecified amount of B16 melanocarcinoma tumor homogenate
- as in Examples 30-41, diluted 1:10 as in Examples 42-53, intra-
peritoneally. Beginning on the first day after innoculation, and
every other day thereafter for a total of nine injections, the
mice were injected with ]25 mg/kg of body weight of the compound
of Example 1 in saline solution with hydroxypropylcell~lose, sold
as Kluccel. All ten mice survived after 5 days. The median
survival time was 8.4 days. The test was discontinued after sixty
days.
Example 104-107
Example 103 was repeated at the doses indicated in Table 7.
Table 7
Dose mg/kg Survival Mean Apparent
Example Body Weight at 5 days Survival Time Cures
103 125 10/10 8.4
104 62.5 10/10 16.0 2
105 31.2 10/10 49.0 2
106 16.6 10/10 43.3 2
107 8.3 1~/10 42.8
Control 0 18.7
In these tests, substantial results were shown over the
dosage range of 8.3-31.2 mg/kg. These results further support the
activity against melancarcinoma shown in Examples 30-53.
Example 108
Ten male mice, strain CDFl, were innoculated with a dilute
homogenate of Colon 26 tumor (National Cancer Institute identi~ication
C6). They were then injected with 125 mg/kg of body weight of the
compound of Example 1 in hydroxypropylcellulose solution, sold as
-16-
1~.3~fB~
Kluccel, on days 1, 5 and 9 after innoculation. This evaluationwas continued for 70 days. All ten mice survived the fifth day and
the medium survival time was 27.0 days compared to 26.5 for the
controls.
Examples 109-1_2
Example 108 was repeated at the dosages shown in Table 8.
Table_8 - Tumor C6
Dose mg/kg Survival Median Apparent
Example Body Weight at_5 days Survival Time Cures
108 125 10/10 27.0
109 35.2 10/10 32.0
110 31.2 10/10 29.0
111 16.6 10/10 29.0
112 ~.3 10/10 33.8
Control 0 26.5
These tests show some effectiveness against this partic-
ular tumor. A lesser degree of toxicity was found at the 125
mg/kg level compared to some of the other Examples.
Example 113
Ten male mice, strain CD8Fl, were innoculated with CD8F
mammary tumor homogenate between about 500 and 1000 mg in size,
subcutaneously. On days 1, 8, 15 and 22 after innoculation, the
mice were treated with an injection of 125 mg/kg of body weight
of the compound of Example 1 in hydroxypropylcellulose (Kluccel)
intraperitoneally. Eight of ten mice survived the fifth day.
After 36 days, the mice were killed and the mean tumor weight was
determined to be 630 mg.
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~3~7~
Examples 114-117
Example 113 was repeated at the dosages shown in Table 8.
Table 8 - Mammary Tumor CD8F1 - Tumor Weight
Dose mg/kgSurvival Mean Tumor
Example Body Weightat 5 days Weight (mg~
113 125 8/10 630
114 62.5 9/10 989
115 31.2 10/10 423
116 16.6 10/10 1354
117 8.3 35/35 37
Control 0 1665
These results indicate substantial inhibition of tumor
growth at many levels and apparent decreases in tumor sizes in
some instances.
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