EVALUATION
OF CHEMOTHERAPEUTIC
AGENTS
IN MAMMARY
CARCINOMA
INDUCED BY3-METHYLCHOLANTHRENE
IN WISTARRATB@
A. P .
(Fels
Research
Institute
, M . Gruenstein
, Temple
Uhiversity
, and M . B . Shimkin
School
of Medicine
, Philadelphia
, Pennsylvania)
SUMMARY
Forty-five
nonhormonal
agents
were tested
for antitumor
activity
against mammary carcinoma
induced
by gastric
Instillations
of 3-methyicholanthrene
(NSC-219 70) in female Wistar rats . Animals
given the potential
antitumor
agent (T) were compared
to untreated
(C) or ovarlectomized
(0) controls,
by determining T/C and T/O values for inhibition of tumor volume and of development
of additional
tumors.
Judged by both criteria , the agents produced the following
responses
: At Day 14 , discounting
groups of
rats with excessive
mortality
due to the drug , 1 7 of 43 compounds
were active compared with untreated
controls
(T/C of 0 . 5 or less) . Two of these compounds
were also active compared with ovariectomized
controls
. At Day 42 , five of 41 agents
were active
compared
with untreated
controls : NSC-l 026 (l
aminocyclopentanecarboxylic
acid)
, NSC-3425
(6-azauracil)
, NSC-9698
(mannitol
(5-fluorouracil)
, and NSC-235l9
(5-cliazouracil)
. None were more effective
NSC- 1026 and 9698 produced
inhibition
approximately
equal to that produced
, NSC-l9893
than ovariectomy
by ovariectomy.
, and only
INTRODUCTION
This report summarizes
the results
of testing
45 agents , which have been used in experimental
or
clinical
cancer therapy , against
breast tumors induced in female Wistar rats by gastric instillations
of
3—methylcholanthrene
(NSC-2l970;
MCA) . The data from this investigation
will be used for comparing
the ability of this screening
system to predict clinically
effective
compounds
with that of transplant
tumor
systems In mice.
Previous experience
(3 ,4) has shown that most MCA-induced
breast tumors in female Wistar rats
are adenocarcinomas
. The tumors are partially
hormone dependent
and have a low rate of spontaneous
regression
. Under standard
conditions
their induction
and growth are reproducible
. If the animals are
kept until the tumors are large , metastases
to the lung and lymph nodes are occasionally
observed.
MATERIALSAND METHODS
@______
Female Wistar rats were penbred from an animal colony maintained
in the Fels Research Institute
for 20 years without the introduction
of outside
stock.
After being weaned,
the rats were housed mdi
vidually
in metal cages with wire mesh bottoms . Rockland
complete rat diet and water were provided
weighed
catheter
Gastric
instillations
of the carcinogen
were begun when the animals were 5-6 weeks of age and
60-80 gm . A solution
of 5 mg of MCA in 0 . 5 ml of olive oil was administered
by a soft rubber
daily except Sunday for 9 weeks , a total of 240- 270 mg.
Palpable
breast tumors began to appear 8 weeks after the start of MCA administration.
Tumors
developed in about 85%of the animals within a year.
er, the animals used in our investigation
were
those in which tumors developed
within 10 weeks after the completion
of the MCA course.
Thus about
65% of the original
population
was usable
for screening.
animal
The experimental
rats were weighed weekly and palpated
twice a week for breast tumors . Each
was assigned
randomly to a group when at least 1 tumor had grown to an estimated
diameter
of
at least 6 mm. Each experimental series consisted of 1 untreated control group with a minimum of 6 rats
1 Supported
Cancer
by
contract
Institute
SA-43-ph-4344
, National
Institutes
from
the
of Health
Cancer
, Public
1
Chemotherapy
Health
National
Service
Center,
National
Service.
This
One
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
2
Cancer Research
Vol. 26, February 1966, Part 2
and 8-1 5 treated groups of 6 rats each . In 2 groups of 6 rats each , the ovaries were removed surgically
and the animals were used for comparing the effects of chemotherapeutic
agents with the effects of ovari
ectomy.
National
The agents (Table 1) were supplied
Cancer Institute.
by the Cancer
Chemotherapy
National
Service
Center
(CCNSC),
The dose ranges
were selected
from information
in the literature
(1 , 2 , 6) and by a preliminary
toxicity determination
in normal male rats . The solution of the drug was freshly prepared
and 0 . 01 ml/gm
body weight of the solution was injected
intraperitoneally
into each rat . Five injections
were given by 1
of 2 treatment
schedules : 1 injection
daily or 1 every other day.
After the start of treatment , rats were weighed and the tumor diameters
were measured
3 times a
week for 42 days . The volume of each tumor was calculated
from the diameters
by the formula 4/3 11?.
On Day 42 all survivors
were killed and their tumors were excised
and weighed.
The appearance
and
growth of additional
tumors were observed , providing another criterion
for the determination
of therapeutic
effect.
Past experience with untreated rats has been that additional
tumors , involving
one or more breasts,
developed
during the 42-day observation
period in about 65% of the rats that had initial tumors.
RESULTS
Table 2 gIves the gross toxic effects (lethality and body weight loss) of the 45 compounds . Despite
the preliminary toxicity determinations
, 3 or more of 6 rats died by Day 14 with 2 compounds
and by Day 42
with 4 compounds
. Data on these compounds
are given but were not used in the subsequent
analyses.
Thus at Day 14 data on 43 compounds were analyzed; the 2 agents deleted were NSC-30 69 (chloramphenicol)
and NSC-22185
[methylglyoxal
bis (guanylhydrazone)
] . At Day 42 data on 41 compounds
were analyzed;
the 2 additional
drugs deleted were NSC-750 (Myleran) and NSC-30909
(2 , 5-bis[( nitratomercuri)
methyl]p-dioxane).
The toxicity
appeared
to be about the same for both treatment
schedules
though comparable
data
are available
on only 3 compounds
(NSC-762 , 19893, and 26271) . Additional
studies on the effects of
altering the dose schedule
are obviously
desirable
for compounds
that appear to have antitumor
activity.
Table 2 shows the average body weight on the 1st day of treatment
and 10 days thereafter,
since
treatment
that did not kill in 42 days caused
the greatest
weight change by Day 10 . With 16 of the 45
compounds
no loss or a slight gain in weight was observed
at Day 10 . With 1 1 compounds
the animals
lost up to 5% of body weight;
with 10 , from 5 to 9%; and with 7 , from 10 to 22%. NSC-lOlO7
(Nitromin)
caused
the most severe body weight loss . However practically
all the weight was regained
by Day 42
with
nonlethal
doses
of all
compounds.
Table 3 summarizes
data on the growth of tumors and appearance
of additional
tumors in 3 groups
of untreated
controls
and in 2 groups of ovariectomized
controls . These data were used in the analysis
of the effects
of therapy.
Histologic
examination
of about 40 tumors from these groups confirmed the
diagnosis
of adenocarcinoma
of the breast in each instance.
Note
that
1 qf 2 1 tumors
that was grossly
complete
average of 1 . 22 additional
and only 3 addItional
ones
initially
observed
in 18 untreated
rats
underwent
spontaneous
regression
at Day 42 . However 22 additional
tumors appeared
in the other animals , an
tumors per rat.
In the ovariectomized
rats , 6 of the initial tumors regressed
appeared;
at Day 42 , four of 12 rats were free of gross tumors.
Table 4 presents
data on the treated groups of rats . The calculated
the mean number of additional
tumors at Days 1 4 and 42 are given for each
total tumor volume per rat and
compound and dose.
Table 5 compares the results in the treated groups (T) with those In the untreated
controls
(C) and
in the ovariectomized
controls
(0) . The values of T/C and T/O were calculated
for total tumor volume
per rat and for mean number of additional tumors at Days 14 and 42. A value of 0.5 or less was considered
positive
(÷). T/C and T/O were not calculated
for groups of animals with less than 4 of 6 survivors.
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
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sse.tho.zd UT ST Au@@n@ioum@u@ bup@aoqs S1@OTUXe43
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tp.ivdsd2! J1d@UV3
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
DAVIS
et al.
Cancer
Chetrwtherapy
Screening
Data
5
REFERENCES
1.
GoldEn , A. ; Venditti , J. M . ; Kline , I. ; and Mantel , N .
cinoma CA-755 in Mice.
Cancer Res . (Suppl.) , 2l(No.
2.
Griswold , D . P . ; Laster, W. R. , Jr. ; Snow , M . Y. ; Schabel , F . M . , Jr . ; and Skipper , H . E . Experi
mental Evaluation
of Potential
Anticancer
Agents . XII.
@.ianUtat1ve Drug Response
of the SA18O,
CA755 , and Leukemia L1210 Systems to a “Standard List― of “Active“
and “Inactive―Agents . Cancer
Res. (Suppl.),@(No.
Evaluation
of Chemical
Agents
10 , part 2):617-9 1 , 1961.
Against
Car
4, part 2):271—5l9,1963.
3.
Shay , H . ; Gruenstein
, M . ; and Kessler,
Some Considerations
of Methylcholanthrene
.@2:503—l3, 1961.
4.
Shay , H . ; ruei,
carbamoylhydrazine
(Id-
W . B . Experimental
Dosage and Hormonal
Mammary
Treatment
M . ; and Shimkin , M . B . Inhibition
of Mammary
33 , 828) . Cancer Res . , @j:9@
8—
1 00 1 , 1964.
Adenocarcinoma
of Rats:
. J . Nat . Cancer Inst.,
Cancer
in Rats by a Dithio
5.
. Effect of Casein , Lactalbum.tn , and Ovalbum.tn on 3-Methylcholanthrene-Induced
Carcinoma in Rats.
J. Nat. Cancer Inst.,
:243-53,
1964.
6.
Skipper,
Systems.
H. E.; and Schmidt, L. H. A Manual on Quantitative
Cancer chemotherapy
Rep., 17:1-178,
1962.
Drug Evaluation
In Experimental
Mammary
Tumor
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
Cancer Research
6
Vol. 26, February 1966, Part 2
TABLE 1
List of Agents Tested
(vehicle
ENTRY
No.NSC
and source
codes
explained
at the end of the table)
FORMULAVEHICLESOURCE
No.NAMEMOLECULAR
O2C4H5
B
20
Glutamic acid , N-[p- [[(2 , 4-diamino
6-pteridlnyl)methyl]methylamino
]benzoyl ]-; methotrexate
N8O5C20H22
D
229A
743
Purin,
2 , 6-diamino-
N6C5H6 .H2O
C
37
68373
747
Acam,
N-methyl
NOC3H7
B
49
68374
749
z,-Triazolo[4
5-amino-;
,5-d]pyrimidin-7-ol,
8-azaguanine
N60C4 H4
C
50
68375
750
Methanesulfonic
05S2C5H14
C
37
68370
629
Butane , 1 , 2 : 3 , 4 -diepoxy-;
epoxide
68371
740
68372
@
butad.iene
, hydrate
S tetramethylene
ester; Myleran
68376
751
Butyric acid , DL-2-amino-4-(ethyl
thio)-;
DL-ethionlne
NO2 SC6 H13
C
63
68377
753
Purine
N4C6H4
E
317P
68378
754
2-Thiophenealanine;
thienylalanine
NO2SC7H9
E
318P
68379
755
N4SC@H4 .H2O
E
37
68380
756
N5O2C4H3
E
50
68381
762
A
4
NO2C6 H11
E
17A
N5C5H5
C
62A
B
20
@-2-
urin'-th.t,
hydrate;
purine,
hydrate
6-mercapto
u-TrIazolo[4
,5-d]pyrimidine-5
diol; 8-azaxanth.tne
am,
17-
2 , 2 ‘-dichloro
I
hydrochloride;
NC12C5H11
.HC1
nitrogen
mustard
68382
1026
Cyclopentanecarboxylic
68383
1393
Lqyr,
4-amino-;
pyrimidine
acid , 1-amino
4-d]pyrimid.tne,
4-aminojyrazolo@3
,4-d]-
68384
1578
3-Pyridinesulfonic
68385
2066
Theophylline;
urin,
di,
1 , 3-dimethyl
L@J,3ff)-
N402C7H6
C
66B
68386
2083
Salicylic
salicylic
p-amino
NO3C7 H7
C
74A
acid,
acid, 4-amino-;
acid
sodium
salt
NO3SC5H5.Na
salt
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
DAVIS et al.
Cancer
Chemotherapy
Screening
Data
7
TABLE 1
(Continued)
ENTRY
No.NSC
No.NAMEMOLECULAR
68387
2107
Hydantoin,l-[(5-nitrofurfurylideneamino) ]-; .Furadantin
N4O5C8H6
E
97
68388
3051
Formamide, N-methyl-
NOC2H5
A
20
68389
3061
Pyrimidine, 2,4—diamino—5-(p—
chlorophenyl)6-ethyl-;
Daraprim
N4C1C12H13
C
37P
68390
3069
Acetamide,
2,2—dlch1oro—N-[@—
hydroxy-cr-(hydroxymethyl)
p-nitrophenethyl]-;
chloramphenicol
N2O5C12C11H12
C
27P
68391
3073
Folic acid; glutamic
acid, N-[p[[(2-amino-4-hydroxy-6pteridinyl)methyl
Jamino ]-
N706C19H19
D
229A
N6C1C11H14.HC1
B
130
FORMULAVEHICLESOURCE
benzoyl ]-
68392
3080
s-Triazine, 4,6-d.tamino-1-(m-chlorophenyl)-1 ,2-dihydro-2 ,,
hydrochloride
68393
3088
Butyric acid, 4—[p—[bis(2-chloro—
ethyl)aminoJphenyl]-;
chlorambucil
N02C12C14H19
C
37P
68394
3425
aa—Triazine—3,5(2ff,4H)-d.tone;
6-azauracil
N302C3H3
C
201
68395
4911
9H-Purine—6—thiol, 9—@—D—ribo—
furanosyl-;
6-mercaptopurine
ribonucleoside
N404SC10H12
E
20
68396
6396
Phosphine
thioTEPA
N3PSC6H12
A
1
68397
9698
d—Mannitol, 1,6—bis[(2—chloroethyl)—
am,
xy,
dihydrochloride;
mannitol mustard
N2O4C12C10H22
. 2 HC1
A
401
68398
9706
e—Triazine, 2,4,6—tris(1—
aziridinyl)-;
TEM
N6C9H12
A
229A
68399
101 07
B
273
B
36
sulfide,
am,
S
tris(1-aziridinyl)-;
2 , 2 ‘—dichloro—N—
xi,
21
.HC1
hydrochloride;
Nitromin
68400
14210
DL—Atanlne,
3—(p—[bis(2-chloroethyl)—
N2O2C12C13H18
amino]phenyl) - , hydrochloride;
.HC1
sarcolysin
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
8
Cancer
Research
Vol.
26, February
1966,
Part
TABLE 1
(Continued)
@
@
MOLECULAR
ENTRY
J
No .1
No .
[NSC
68401
14574
68402
17663
68403
18016
NAME
J
Th.toxanthen-9-one,1-[[2-(diethylammin,
hydrochloride;
Miracil D
AlrLt,
N, N.-hlroe,
hydrochloride;
alanine
FORMULAVEHICLESOURCE
N2OSC20H24.HC1
F
1
A
218
O3SC1C3H7
C
213A
N2O2FC4H3
A
217P
N5
.H2S04
. 1 1/2 H20
B
253
N4O2C4H3.H2O
B
63P
N3O2C2H5
A
20
2273
HC1
mustard
Methanesulfonic acid, 2-chloroethyl
ester; CB—l
506
@
@
68404
19893
68405
221 85
Uracil, 5—fluoro—
nun,
1 , 1 ‘-@(methylethanliinitril,
sulfate
sesqui.hydrate;
methylglyoxal
bis(guanylhydrazone)
68406
23519
Uracil,
5-diazo-,
5-d.tazouradil
68407
23909
Urea,
68408
24517
Pteridine,2,4—diamino—6,7dimethyl
N6C8H10
C
331A
68409
24818
Podophyllotoxin;naphtho@2,3-d]1 , 3-dioxole-6-carboxylic
acid,
5 ,6 ,7 ,8-tetrahydro-8-hydroxy
7-(hydroxymethyl)-5-(3
,4, 5-tn
xy,
y-lactone
O8C22H22
C
140F
68410
26271
2ff-1,3,2-Oxazaphosphorine,
2-[bis(2-chloroethyl)amino]tr,
2-oxide,
hydrate;
Cytoxan
N2O2PC12C,H15
.H30
A
243
684 1 1
27 640
N305 PC@
1
A
21 7P
68412
29422
9ff—Punine—6—thlol, 2—amino—9—@—D— N5O4SC1 0H1
E
20
D
32
A
254A
nid.t,
1—methyl—1—n.ttroso—
2 ‘
-deoxy-5-fluoro-
nibofunanosyl-
68413
30909
hydrate;
,
; thioguanosine
p-Dioxane, tra,@,e—2,5-bIs[hydroxy— N2O8Hg2C5H10
un,
din.ttnate;
d.t,
2 , 5-bis [(nitnato
mencuni)methyl]68414
60339
Terephthalanilide,
2-chloro4' 1 4―—d.i—2—imidazolin—2—yl
N602C1C26H23
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
2
Cancer Chemotherapy Screening Data
DAVIS et al.
9
TABLE 1
(Continued)
EXPLANATION OF CODES
VEHICLES
Code
Vehicle
A
B
C
D
E
F
0.85% saline solution
Distilled
water
0 . 5% sodium carboxymethylcellulose
2% sodium bicarbonate
solution
Dilute sodium hydroxide
solution
5% ethyl alcohol
SOURCEOF COMPOUNDS
Code
1
Source
Code
Chemical-Biological
Coordination
Center
National Academy of Science
National Research Council
2101 ConstitutionAvenue
Washington,
D. C.
4
Dr. George
Director
Sharp
and
Research
Dohme
1 7A
20
New Jersey
of Experimental
Sciences,
07065
Dr. George Hitchings
Research
Director
Chemotherapy
Division
Wellcome
Research
Laboratories
1 Scarsdale
Road
Tuckahoe, NewYork
49
Research Laboratories
211 Wh.ttmoreLaboratory
University
ar,
Pennsylvania
Eastman Kodak Company
Rochester4,
New York
27P
Parke, Davis and Company
Ann Arbor, Michigan
32
Dr. Leon Goodan,
Chairman
Bio-Organic
Chemistry
Department
Stanford Research
Institute
Menlo Park, California
94025
“P―
following
a source
code number
50
Francis Earle Laboratories
Peekskill,
New York
62A
Prof. Roland K. Robins
Department
of Chemistry
University
of Utah
Salt Lake City, Utah
indicates
63
63P
that the compound
10707
Dr. C. F. H. Allen
The Pennsylvania State University
Dr. Frank M .
, Jr.
Director,
Chemotherapy
Research
Southern Research
Institute
2000 Ninth
, South
Birmingham,
Alabama
35205
U.S.S.R.
Pathology
Moscow, U.S.S.R.
Research
Prof. Clarence
I . Noll
College of Science
of Medical
Institute
Bolsha.ta , Pirogovska.ta
Laboratories
Rahway,
Academy
Therapy of Cancer
37
37P
E . Boxer
of Cancer
I
36
Source
84112
Dr. S. M. Mann
Nutritional
Biochemicals
Corp.
21010 Miles Avenue
Cleveland,
Ohio
44128
was purchased
by.
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
and
10
Cancer Research
Vol. 26, February 1966, Part 2
TABLE 1
(Continued)
SOURCEOF COMPOUNDS
Code
66B
Source
Code
Dr. Ronald
Breslow
Department
of Chemistry
21 7P
Hoffmann-La
Nutley,
Havemeyer
Hall
Columbia University
218
New York, New York
Source
10027
74A
Dr. Everette L . May
Room 110, Building4
National
Institutes
of Health
Bethesda,
Maryland
20014
97
Dr. Kenyon Hayes
Director of Chemical
Research
Development
Norwich Pharmacal
Company
Roche,
Inc.
New Jersey
Yoshio
ur,
Pharm . D.
Chief of Division
Cancer Chemotherapy
Division
Cancer Institute
Nishisugamo,
2-Chome , Toshima-ku
Tokyo, Japan
229A
and
Dr. Andrew S . Tomcufclk
Cancer Chemotherapy
Group
Organic Chemical
Research
Section
Lederle Laboratories
Pearl River, New York
10965
Box 191
rwi,
1 30
New York
Dr. Edward
I
13815
243
Dr. Kenneth N . Campbell
Director,
Medicinal
Chemistry
Research Laboratories
Mead Johnson and Company
Evansville,
Indiana
47721
253
Mr . Frederic
J . Modest
Laboratories
of
Chemistry
Children's
Cancer
35 Binney Street
Organic
Research
Boston, Massachusetts
Foundation
02115
A. French
Cancer Research Laboratories
140F
Dr. Jonathan L. Hartwell
Cancer Chemotherapy
National
Service Center
National
Cancer Institute
National
Institutes
of Health
Wisconsin
, Room 1 04B
Bethesda, Maryland
20014
Mount Zion Hospital
1600 Divisadero Street
San Francisco,
254A
California
94115
Dr. J. Schmutz
Research
Institute
Dr. A. Wander, S.A.
Berne , Switzerland
201
213A
Dr. Ronald Ross
Cancer Chemotherapy
National
Service Center
National
Qancer Institute
National
Institues
of Health
Bethesda
14, Maryland
273
Sachio Hirneno
Secretariate
Takeda Chemical Industries , Ltd.
27 Doshomachi
Osaka,
Nichome
, Higashiku
Japan
Dr. W. C. J. Ross
Chester Beatty Research Institute
Institute
of Cancer
Royal Cancer
“Pu'following
Cyclo Chemical
Corp.
Los Angeles , California
318P
Arapahoe Chemicals, Inc.
Hospital
Fulham Road
Lo,
31 7P
Research
S .W. 3 , England
a source
code
number
Boulder,
indicates
that
the
compound
was
Colorado
purchased
by
CCNSC.
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
DAVIS
et al.
Cancer
Chemotherapy
Screening
Data
11
TABLE1
(Concluded)
SOURCEOF COMPOUNDS
Code
331A
Source
Code
Dr. Charles F. Kade, Jr.
Vice President
and Director of
Research
McNeil
abori,
Inc .
Camp Hill Road
Fort Washington
, Pennsylvania
401
Source
Prof. L. Vargha
Research
Institute
of the Pharmaceutical
Industry
Rottenbiller
U . 26
Budapest Sill, Hungary
19034
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
12
Cancer Research
Vol. 26, February 1966, Part 2
TABLE2
Toxicity
NSC
No.DOSE
629
740
743
747
749
of 45 Compounds
(mg/kg)SCHEDULE*AVERAGE
12
9.4
2.0
1.0
150
150
120
60
20
751
753
754
755
10
400
200
1000
60
40
20
1000
0.5
0.25
0.25
0.125
1026
1393
50
24
12
1578
800
2066
80
40
2083
800
2107
80
300
60
30
3051
3061
3069
3073
1000
3080
100
30
3088
20
15
3425
MCA-Induced
Mammary
Tumors
BODY
DAY--1101442
WEIGHT (gm)
750
756
762
in Rats with
10
1800
a
a
d
d
a
a
d
d
a
a
a
a
a
d
d
d
a
d
d
a
d
a
d
d
a
d
d
d
a
a
d
d
a
a
d
d
d
d
a
ON
ON DAY--SURVIVORS
186
183
174
178
197
176
184
185
178
153
163
186
178
185
188
0
6
3
6
5
6
6
6
0
6
3
6
5
6
6
6
167
159
177
172
173
184
189
189
171
3
6
5
6
5
6
6
6
0
1
5
6
5
6
5
6
183
178
177
165
178
192
184
187
188
185
128
168
160
176
178
172
194
191
5
3
6
6
6
6
2
5
6
5
3
6
6
6
5
2
5
6
181
194
184
183
188
185
183
196
200
176
185
174
191
6
6
6
5
6
6
6
6
6
5
5
5
6
6
174
177
186
197
182
185
175
182
176
186
181
175
175
178
194
185
196
188
188
173
3
3
6
0
6
0
6
0
6
0
6
6
6
6
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
DAVIS et al.
Cancer
Che@notherapy
Screening
Data
13
TABLE 2
(Concluded)
NSC
No.DOSE
BODY
DAY--1 (gm)
WEIGHT
ON DAY--SURVIVORS
(mg/kg)SCHEDULE*AVERAGE
ON
101442
4911
6396
9698
9706
10107
14210
14574
17663
18016
19893
22185
23519
23909
24517
24818
26271
27640
29422
30909
60339
300
5.0
2.5
20
0.33
a
d
d
a
a
189
184
186
178
173
185
137
187
164
151
6
0
6
6
6
6
0
6
6
6
d
d
194
196
—
152
0
5
0
5
10
5.0
113
3.0
12.5
60
40
40
30
20
d
d
a
a
a
a
a
d
d
d
183
188
183
170
185
180
167
182
192
179
—
179
153
162
191
127
139
138
165
183
0
6
5
6
6
0
3
0
2
6
0
6
4
6
6
0
2
0
2
6
60
8.0
25
200
2.3
a
a
a
a
a
183
175
182
180
179
179
157
157
166
173
3
6
6
6
6
3
6
6
5
6
40
40
d
a
182
170
137
158
4
5
2
3
30
d
186
188
6
5
d
a
d
d
d
d
179
176
189
189
176
180
178
160
192
199
156
143
6
4
6
6
4
4
6
4
6
5
3
4
d
200
201
6
6
60
30
20
110
8.0
4.0
12.5
40
20
*
Five
(Days
intraperitoneal
injections
were
1, 3, 5, 7, and 9); d--one
given
injection
by
2 treatment
daily
(Days
schedules:
a--one
injection
every
other
day
1-5).
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
14
Cancer Research
Vol. 26, February 1966, Part 2
TABLE 3
ControlsDAYNUMBER
Growth of MCA-Induced
Rat Tumors In Untreated
Controls
and Ovariectomized
TUMORSADDITIONAL
TUMORSTOTAL
WEIGHT
volume
per rat
(gm)INITIAL SURVIVORSNumber
(ml)
TUMOR
VOLUME
TUMOR-FREE
PER RAT
(ml)NUMBEROF
-UNTREATED
@ =_____MEANBODY
-TotalNumbe
OF RATS
per rat
-Mean
CONTROLS.118185210.30000.300718186210.8260.330.8801418188212.24120.672.7202118192213.57170.944.3402818194206.27191.067.531351819
CONTROLS112182130.30000.300712187130.3010.080.3401412198100.4020.170.4622112212100.4420.170.4622812224100.5120.170.582351222680.
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
Cancer Chemotherapy Screening Data
DAVIS et al.
15
TABLE 4
Summary of Drug Evaluation
Data
TUMORSTUMOR-FREENSCDOSESCHEDULE*(ml)
TOTALTUMOR VOLUMEADDITIONAL
RATRATS,No
PER RATPER
.(mg/kg)ON
DAY--ON
DAY--SURVIVORS
42)14421442
629
740
743
747
749
9.4
2.0
1.0
150
150
120
60
a
2.74
d
d
a
a
d
d
7.30
2.65
0.94
3.56
1.59
0.84
0.78
1.59
1.59
4.79
6.51
750
10
a
751
400
a
753
754
755
200
1000
60
40
a
a
d
d
d
20
756
762
1026
1393
1578
2066
1000
0.5
0.25
0.25
0.125
50
24
12
80d
80
40
a
d
a
d
d
a
d
d
a
d
d
d
(Day
13.04
17.43
0.67
6.22
15.28
17.16
11.06
13.87
0.17
0.40
1.17
0.50
0
0.73
0
23.53
16.63
18.11
6.89
6.86
1 .30
0.17
1.00
0.17
0 . 20
0.33
0 . 50
0.17
3.31
6.57
2.73
0.94
0.32
0.17
0.09
4.22
3.29
25.95
25.94
11.08
3.83
2.39
0.65
8.19
8.13
11 .09
1.40
0
0
0.17
0.33
0
0
0.40
0 . 50
0.83
1.00
1.83
0.20
0.50
0.40
2.00
3.51
14.29
0.33
1.67
1.67
5.86
2.20
21 .28
13.81
0 . 50
1.67
1 .00
1.60
37.70
6.72
6.67
38.33
1.00
0.17
3.40
0.67
2.50
0.50
1.33
2.26
0.33
1.50
0.67
0.67
1.60
1.00
1 .67
1/6
0/3
0/6
1/5
0/6
0/6
0/6
0
2.20
1.00
0.80
1.50
1.00
1.50
1/1
0/5
0/6
0/5
1/6
0/5
1/6
2.80
0/5
1/3
1/6
0/6
0/6
1/5
2.33
0.33
2083
2l07@
800
80
3051
300
60
30
a
d
d
7.80
a
a
2.51
17.36
0.33
0.33
4.27
30.46
0.33
3.17
3080
1000
100
15
0
3088
10
0.25
2.00
0.17
3061
3069
3073
a
3425
1800
d
d
a
4911
300
6396
9698
9706
10107
1.91
2.29
2.21
9.21
3.66
26.08
3.69
3.73
0.17
0
a
0.84
6.34
0.17
2.5
20
0.33
d
1.98
0.13
26.57
1.32
0.69
30
d
9.02
24.79
0.33
0.33
0.33
a
a
0.28
0
2.00
1.17
1.50
0
0.67
1.20
0/2
1/5
0/6
0/6
0/6
1/5
0/5
0/5
0/6
0/6
1/3
0/6
1/6
0/6
0/6
1/6
0/6
1/6
1/6
1/5
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
16
Cancer Research
Vol. 26, February 1966, Part 2
TABLE 4
(Concluded)
TOTAL TUMOR VOLUMEADDITIONAL
PER RAT
RAT
ON DAY--PER
ON DAY --RATS!
TUMORSTUMOR-FREENSC
SURVIVORS
NoDOSE
(m /k)SCHEDULE*(ml)
42)14421442142105.0d0.2311.930.331.830/614574113a0.050.800.401.500/4176633.0a1.1817.920.330.501/61801612.5
(Day
d
0
0
0.34
30
11.79
0/2
d0.01
20a
01.00
0.270.06
3.430
0.500/2
2/62218560a1.719.5201.000/3235198.0a0.220.9600.502/62390925a0.3712.940.173.501/624517200a0.875.720.831.000/5248182.3
40
30
20
110
0.14
3.87
0.59
0.493.52
1.91
10.14
20.42
20.000.25
0
0.33
0.17
0.250.50
0.67
1.00
1.50
2.000/2
4.0d
d1.86
5.946.23
0/53090912.5d7.3221.171.001.670/36033940
18.800.17
0.330.67
1.170/6
20.300
00.50
1.000/4
2764040•d
0/4294228.0
a
d
d
a0.16
d0.90
20d
*
Five
Intraperitoneal
d--one
injection
injections
were
given
15.2418.58
by
2 treatment
schedules:
a--one
Injection
every
other
0/3
0/5
0/6
0/6
day;
daily.
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
Cancer Chemotherapy Screening Data
DAVIS et al.
17
TABLE 5
Effect of 45 Compounds
Tumor Growth
Against
MCA-Induced
In Untreated
tDay
NSC
No.DOSE (mg/kg)SCHEDULE*TOTAL
Controls
Mammary Tumors In Rats Compared
and Ovariectomized
TUMOR VOLUME (ml)
PER RATtADDITIONAL
42T/CI 14Day
With
Controls
TUMORS PER RAT
42Day
14Day
TbT/CTbT/CTbTICT/O
629
740
743
747
749
750
751
753
754
755
756
762
9.4
1.0
150
150
120
60
10
400
200
1000
60
40
20
1000
0.25
0.25
1026
1393
1578
2066
2083
2107
3051
3061
3069
3073
3080
3088
3425
4911
6396
9698
9706
10107
14210
14574
17663
0.125
50
12
800
1.01
5.96
5.76
a
0.97
0.35+
1.31
d
d
0 .31+
a
d
a
0.58
a
0.29+
a
a
0.58
a
d
d
d
0.58
1.76
2.39
0.83
0.27+
a
1.22
a
1.00
d
d
a
d
0.35+
0.12+
0.06+
1.55
1.21
a
60
30
d
d
d
a
a
d
d
1000
100
15
10
1800
a
a
d
d
a
0.81
a
d
a
a
d
0 . 31+
0.73
0.05+
0.25+
0.10+
d
0 . 08+
0.02+
0 .43÷
80
40
800
80
300
300
2.5
20
0.33
30
5.0
113
18016
3.0
12.5
19893
20
a
a
a
d
1.29
0.61
2.15
0.81
0.70
0.84
2.87
1.57
1.35
1.37
1.32
0.10+
2.04
7.74
3.46
1.83
1.70
3.46
3.46
10.41
14.15
1.19
0.57
1.40
1.57
1.01
1.27
4.91
1.59
0 . 12+
7.20
5.93
2.37
1.07
0.35+
0.22+
0.06+
2.04
.1.00
0.25+
0.60
1.75
0.75
0 . 00+
0.25+
2.15
1.52
1.66
0.63
0.63
0.70
0.37÷
9.17
11.54
5.51
13.52
15.19
9.79
12.27
20.82
14.72
16.03
6.10
6.07
1.15
22.96
9.81
3.39
2.12
0.58
1.49
0.25+
3.94
1.00
2.35
6.88
1.23
0.55
2.94
1.31
1.91
0.82
0 . 00+
1.37
1.00
5.88
1.80
0.82
0.66
1.23
0.50+
0.75
0.25+
2.94
1.00
0.82
4.00
1.23
6.00
2.09
0 . 00+
8.24
0.00+
1.00
1.94
0.00+
2.30
0.68
0.82
11.20
3.32
0 . 30+
0.25+
0.50+
0 . 00+
0.60
0.75
7.32
0.80
2.35
0.33+
2.94
1.64
1.60
8.00
7.19
9.81
7.63
3.63
12.74
4.78
1.31
0.50+
1.94
0.75
1.49
2.94
1.37
1.37
3.45
12.65
18.83
12.22
33.36
4.15
0.61
5.95
0.25+
5.88
5.88
1.00
2.79
1.64
4.98
16.96
0. 61
3.50
5.90
33.92
2.78
26.96
8.15
23.08
2.38
0.34+
1.00
3.94
2.04
0.75
2.94
1.09
6.68
6.68
6.40
13.60
8.00
10.00
5.32
0.50+
1.94
0.00+
1.00
0.00+
2.60
0.20÷
1.64
0.14+
12.68
1.00
8.00
0.68
1.00
1.94
1.94
1.94
0.00+
0.96
1.94
2.35
1.94
6.88
0 . 00+
1.50
1.23
1.49
0.00+
0.25+
0.00+
5.61
23.51
1.15
7.98
21.94
0.25+
0 .50+
1.64
10.56
0.71
15.86
2.30
22.24
1.75
0 .00+
1.83
0.58
4.30
2.43
0.28÷
0.12+
0.82
1.50
0.61
3.30
2.27
0.50+
1.09
0.11+
2.57
7.80
0 . 59
0.07+
0.31+
3.04
4.00
0.16÷
1.01
0.84
3.20
6.00
1.50
0.74
9.28
4.80
7.96
8.02
8.80
4.00
1.00
1.18
1.94
7.15
1.95
1.26
6.00
2.68
6.40
9.32
4.00
6.68
0.50+
0.50÷
0.50+
0.00+
0.60
0.50÷
1.31
1.23
0.00+
0.55
0.98
0.41+
2.60
0.41+
4.68
6.00
0 . OOi
2.68
4.80
7.32
6.00
2.00
12.68
2.00
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
18
Cancer Research
Vol. 26, February 1966, Part 2
TABLE 5
(Concluded)
TUMORVOLUME (ml)@D@ONAL
RAIl'Day
TUMORS PER
S
No .S
(mg/kg)SCHEDULE*TOTAL
42T/CT/OTICT/OTICT/OT/CT/O22185
14Day
14Day
42Day
23519
23909
24517
24818
8.0
25
200
2.3
a
a
a
a
0.08+
0.14+
0.32+
0.84
26271
30
20
110
8.0
4.0
12.5
40
d
d
a
d
d
d
d
1.42
0.22+
0.18+
0.68
2.18
2.69
0.33+
d——
5.60——33.13——
1.86——17.96——
0.00+——
0.00+——
0.82—— 4.00
27640
29422
30909
6033960
20a
*
Five
d--one
intraperitoneal
injection
injections
were
given
0.48+
0.80
1.89
4.96
8.41
1.28
1.07
4.04
12.91
15.91
1.96
by
2
treatment
0.09+
1.18
0.52
0.88
0.85
11.45
5.06
8.50
0.00+
0.25+
1.24
0.25+
0.00+
1.00
4.88
1.00
0.41+
2.87
0.82
0.55
2.00
14.00
4.00
2.68
0.93
1.87
1.83
0.57
1.72
8.97
18.07
17.70
5.51
16.64
0.50+
0.25+
0.37+
0.25÷
0.50+
1.49
0.00+
1.94
1.00
1.47
1.00
1.94
5.88
0.00+
0.82
1.23
1.64
0.55
0.96
4.00
6.00
8.00
2.68
4.68
——
1.70
——
16.44
schedules:
a--one
injection
——
——
0.41+
every
other
daily.
t Valuesfollowedby (+)areconsideredpositive (<0.5).
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1966 American Association for Cancer Research.
2.00
day;
Evaluation of Chemotherapeutic Agents in Mammary Carcinoma
Induced by 3-Methylcholanthrene in Wistar Rats
A. P. Davis, M. Gruenstein and M. B. Shimkin
Cancer Res 1966;26:1-18.
Updated version
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