SARCOMA 180 INHIBITION SCREENING DATA1 C. Chester Stock, … · SARCOMA 180 INHIBITION SCREENING DATA1 C. Chester Stock, Donald A. Clarke, Fredericks. Philips and Ralph K. Barclay

SARCOMA 180 INHIBITION SCREENING DATA1

C. Chester Stock, Donald A. Clarke, Fredericks. Philipsand Ralph K. Barclay

Division of Experimental ChemotherapySloan-Ketter ing Institute and

Sloan-Kettering Division ofCornell University Medical College

The following method of screening materials for ability to inhibit the

growth of Sarcoma 180 in mice has been employed:

1. Weigh the mice. Swiss females, 18-22 gms., from the Blue Spruce,

Carworth, Harpaul, Millerton Research, and Rockland Farms and from Joseph

E. Stocker have been used. They have been given Purina Laboratory Chow and

water ad lib.

2. Transplant tumor pieces by trocar subcutaneously into the axillary

region. The tumor fragments, approximately 1.5 mm in any dimension, are

cut from non-necrotic portions of the donor tumor and samples of each tumor

cultured for detection of any possible bacterial contamination.

3. Twenty-four hours later start intraperitoneal injections of compounds

in maximum tolerated doses on a repeated basis. In nearly all cases the toxi-

cities of the compounds were determined by either of two methods. The max

imum tolerated doses by intraperitoneal injections repeated daily for five days

have been deter mined or the approximate LD50 for a single dose has been found.

1. The screening program for anti-tumor activity has been supported since 1947by institutional grants from the American Cancer Society. There also hasbeen support in part by a grant-in-aid (CH-22) from the American CancerSociety upon recommendation of the Committee on Growth of the NationalResearch Council.

2. The toxicities of most of the compounds included in this report and manyother compounds were obtained by support in part by a research grant(C-415)from the National Cancer Institute of the National Institutes of Health, U. S.Public Health Service. The data are on file at the Chemical-BiologicalCoordination Center, National Research Council, Washington 25, D. C.

179

on April 12, 2020. © 1955 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

http://cancerres.aacrjournals.org/

180 CancerResearch Stock et al.

Although exceptions have been encountered, in general, one-fourth to one-third

the single dose LD50 has been found to be a dose satisfactorily approximating

the maximum tolerated on repeated injection. In later studies an arbitrarily se

lected dose of 125 mg/K/day has proven adequately satisfactory as an initial

dose without prior toxicity data. In the tables the doses are reported in mg/K

except for many of the liquids which have been measured by volume and are

listed in cmm/K.

4. Injections are continued twice daily for seven days. In some instances

single injections have been given daily. These include materials prepared fresh

daily or in propylene glycol solution.

5. The test is repeated at the same or a different level depending upon the

result of the first trial. If the first dose has been too toxic, a lower dose is

tried; if the first dose appears to be well tolerated, a higher one may be tried.

For each compound reported herein as negative there are additional supporting

data at lower or higher dose levels or both; however, most of the compounds

have not been tested at dose levels higher than 500 mg/K/day.

Results of testing materials have been evaluated as follows:

No effect, when the average diameter was 3/4 or more

of the average diameter of the control tumors.

+ Slight inhibition, when the average diameter was 1/4 to

3/4 of the average diameter of the control tumors.

+ Marked inhibition, when the diameter was 1/4 or less

of that of the control tumors; actually, the volume of

such a tumor would be 1/64 or less of the control if

tumors may be considered spherical.

Over 13,000 compounds and nearly an equal number of materials of

natural origin have been screened for ability to inhibit Sarcoma 180. Thirteen

compounds have met the requirements for the grading of +. They are:



Stock et al. Negative Cancer CÃ¬imiotlierapyData 181

2,4,6-tris-ethyleneimino-s-triazine

4-aminopteroylglutamic acid

4-amino-N10-methylpteroylglutamic acid

4-aminopteroylaspartic acid (DL)

4-amino-9-methylpteroylglutamic acid

4-aminopteroylthreonine

4-amino-9, 10-dimethylpteroylglutamic acid

4-aminopteroyltriglutamic acid

3-bis(ÃŸ-chloroethyl)aminomethyl-4-methoxymethyl

-S-hydroxy-o-methylpyridine dihydrochloride

N, N', N"-triethylenephosphoramide

phosphoric acid, diethylamide diethyleneimide

N-pentamethylene-N1, N"-diethylenephosphoramide

O-diazoacetyl-L-serine

Most of them have already been reported. Annals of the New York

Academy of Sciences 52^ 1360-78 (1950); Cancer Research JJ., 432-36 (1951);

Proc. Soc. Exp. Bioi. Med. 78, 299-305 (1951); Cancer J^ 144-52 (1952);

Naturels, 71 (1954).

Approximately 200 compounds are in the - category. Included are 6-

mercaptopurine, 6-chloropurine, thioguanine, purine, actidione, N-methyl-

formamide, urethane, HN2 and certain other nitrogen mustards, some 2,4-

diaminopyrimidines and some anti-folic acids not as effective as those listed

above. The rest of the - compounds are being studied as possible leads to more

effective, related compounds. All of the othtr compounds wehave tested against

Sarcoma 180 have thus far been negative but many require retesting at higher

dose levels.

In the accompanying tabulated data the solvents have been coded as follows:

UK.. ,.



182 Camer Research Stock et al.

Solvent Coding

Code No. Solvent

1. saline

2. carboxymethylcellulose (Cellulose gum) high viscosity,

Type 120, Hercules Powder Co., 0.5% in saline

3. gum acacia (gum arabic) 1% or 10% in saline

4. propylene glycol

5. butyl Buccinate

6. peanut oil

It is a pleasure to acknowledge the many sources of the compounds we

have used. All of the cooperating laboratories have been most helpful in at

tempting to provide adequate supplies of compounds many of which would not

otherwise have been available to us. The sources of the compounds have been

designated in the tables as listed below:

C Parke, Davis and Company

D Dr. Max Tishler, Merck and Company

Dl Dr. Karl Folkers, "

D2 Dr. Karl Pfister, " "

D3 Dr. Lewis H. Sarett" "

E Eastman Kodak Company

F Dr. F. E. Ray, Cancer Research Laboratory, University

of Florida

G Southern Research Institute

HI Sterling-Winthrop Research Institute

H Winthrop Stearns, Inc.

la Dr. H. L. Haller, Insecticide Investigations, U. S. Department

of Agriculture, Beltsville, Maryland



Stock et al. Negative Cancer Chemotherapy Data 183

II Dr. Thomas D. Fontaine, Biologically-Active Compounds

Division, U. S. Department of Agriculture

13 Dr. Monroe E. Wall, Biochemical Division, U. S. Department

of Agriculture

17 Dr. Aaron M. Altschul, Oilseed Division, Southern Regional

Research Laboratory, U. S. Department of Agriculture

J Smith, Kline, and French Laboratories

L Monsanto Chemical Company

M Bound Brook Division of American Cyanamid Company

M2 Dr. R. O. Roblin, American Cyanamid Company

N Lilly Research Laboratories

P Eaton Laboratories, Inc.

Q E.I. duPont de Nemours and Company

S S. B. Penick and Company

W Abbott Research Laboratories

Z William S. Merrell Company

AA B. F. Goodrich Chemical Company

AE National Research Council, Chemical-Biological Coordination Center

AG Lederle Laboratories Division of American Cyanamid Company

AM The Squibb Institute for Medical Research

AN National Aniline Division of Allied Chemical and Dye Corporation

AP Esso Laboratories, Standard Oil Company

AQ Endo Products, Incorporated

AR Commercial Solvents Corporation

AT Dr. William Doering, Hickrill Chemical Research FoundationAW Sloan-Ketter ing Institute personnel or related sources:

AW-1 Dr. Liebe Cavalieri

AW-4 Dr. George Brown




AW-5 Dr. Ralph Barclay

AW-7 Dr. Earl Balis

AW-13 Dr. Leonlda SantamarÃa

AW-20 Dr. F. DiCarlo

AW-21 Dr. V. Bellavita

AZ Dr. Kenneth M. Campbell, Mead-Johnson and Company

BA Dr. C. K. Cain, McNeil Laboratories

BB Charles Pfizer and Company

BD Dr. Karl Dittmer, Department of Chemistry,

Florida State University

BE Dr. George Hitchings, Wellcome Research Laboratories

BG Socony Vacuum Oil Company, Inc.

BH The Quaker Oats Company

BJ Dr. Ernst A. H. Friedheim

BL Dr. Frederic R. Benson, Remington Rand, Inc.

BP Sharpies Chemicals, Inc.

BX Bristol Laboratories

BY Upjohn Laboratories

CA Dr. N. H. Cromwell, Department of Chemistry,

University of Nebraska

CB Dr. Henry A. Rutter

CC G. D. Bearle and Company

CG Dow Chemical Company

CI General Aniline and Film Corporation

CUI Dr. Donald C. Lewis, Mellon Institute (Carbide and Carbon

Chemicals)

CW Dr. Hoke S. Green, Department of Chemistry,

University of Cincinnati




CY Dr. Carl T. Bahner, Department of Chemistry,

Carson-Newman College

DB Virginia-Carolina Chemical Corporation

DI Armour Laboratories

DK Dr. Louis H. Goodson, Midwest Research Institute

DN Dr. W. T. Sumerford, Mead-Johnson and Company

DP Warner-Chilcott Laboratories

DQ Dr. Irving Kaye, Department of Chemistry, Brooklyn College

DU Dr. Jack Nobis, National Distillers Chemical Corporation

DV Dr. C. G. Overberger, Institute of Polymer Research,

Polytechnic Institute of Brooklyn

EA Delta Chemical Works

EC Rohm and Haas Company

EG Dr. Jerry Milionis, Department of Chemistry,

Purdue University

EH N. V. Organon

El Dr. Wilson M. Whaley, Pabst Laboratories

EJ Dr. Marvin D. Armstrong, University of Utah,

College of Medicine

EO Dr. Carl M. Stevens, The State College of Washington

ES Minnesota Mining and Manufacturing Company

EV Linde Air Products

EW Dr. D. S. Tarbell, Department of Chemistry,

University of Rochester

EX Wallace and Tle r nan Products

EZ Dr. Richard H. Wiley, Department of Chemistry,

University of Louisville



186 Cancer Research Stocketal.

FC Dr. E. R. Weidlein, Jr., Mellon Institute of Industrial Research

Parke, Davis and Company, Fellowships in Medicinal Chemistry at

Mellon Institute:

FC1 Dr. Marcus Morgan

FC2 Dr. Horace DeWald

FC3 Dr. Robert Tipson

FC4 Dr. Alice Renfrew

FE Prof. Dr. F. Bustinza, University of Madrid

FH Dr. Charles F. Geschickter

FK Dr. Patrick J. Hannan, Fungus Control Section Materials

Branch, Engineer Research and Development Laboratories,

Fort Belvoir, Virginia

FM Dr. H. R. Snyder, Department of Chemistry,

University of Illinois

FO The Atlantic Refining Company

FQ Prof. Dr. med. H. Oettel, Badische Anilin and Soda-Fabrik

FR U. S. Industrial Chemicals Company

FU Dr. T. Lloyd Fletcher, School of Medicine,

University of Washington

F W Dr. Ng. Ph. Buu-Hoi, Radium Institute, Paris

GA Dr. Donald Visser, School of Medicine,

University of Southern California

GC Dr. Glenn S. Skinner, Department of Organic Chemistry,

University of Delaware

GD Dr. Ralph L. Shriner, Department of Chemistry,

State University of Iowa

GJ Ethyl Corporation Research Laboratories

GK Dr. E. C. Taylor, University of Illinois




GL Antara Chemicals

GM Dr. Henry Gil man, Department of Chemistry,

Iowa State College

GN Dr. G. M. Kosolapoff, Alabama Polytechnic Institute

GO United States Rubber Company

GQ Heyden Chemical Corporation

JI Dr. J. C. Calandra, Northwestern University

JK Dr. D. M. Carney, University of Detroit

JL Prof. E. D. Armstreetz, Lehigh University

JN General Chemical Company

JO W. J. Strange Company

The Sarcoma 180 studies were carried on effectively through the carefulwork at various times since 1947 of the following: in the toxiclty assay program,Alicia Arnold, Rhoda Baskin, Barbara Bond, Marie Borgatta, Carol Cooklin,Margrit Fehlmann, Ann de Blieux Geisler, Beatrice Nissen Greene, CorinneRoss LacÃ³n, Marie McClure, Aileen Mulvey, Ruth Osato and Barbara Wheelock;and in the Sarcoma 180 screening program, Dolores Anderson, Barbara Averill,Marguerite Bagg, Virginia Bailey, Marie Dunn Bartnett, Angela Boryczka,Dorothy Burnham, FranÃ§oise Costa, Isabel Lincoln Elmer, Robert Eisner,Barbara Jones Gibson, Jacqueline Grundstein, Janet Hacker, Patricia Hagan,Eleanor Hutcheson, Col innÃ©InnÃ©s,Mar gar et Jeter, Helen Karp, Marcia Katzman,Margaret Keeve, Suzanne Knecht, Lorraine Kraus, Joan Leuchten, Edith Lindner,Margaret Lippay, Barbara MacCallum, Lois Montgomery, Annemarie Muller,Mary Helen Nisum, Sheelagh O'Connor, JeanO'Laughlin, Patricia Oley-Dufresne,Angeleine Pagliaro, Joseph Patti, Peggy Pentz, Frances Pepper, Matthew Rudden,Netta Sanow, Lydia Sargent, Elsie Sata, Jean Scoma, Anne Snipes, BarletteSolow, Elizabeth Sprague, Joanna Stein, Arlene Steinberger, Louise Taichert,Anne Tracy, Marie Waite, Robert Wallbrun, Alice Wick, Joan Wiehl, DorothyFong Wong and Joan Cozens Youmans; and for numerous administrative details,Mrs. Sophronia A. Myron.




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1955;15:179-331. Cancer Res C. Chester Stock, Donald A. Clarke, Frederick S. Philips, et al. Sarcoma 180 Inhibition Screening Data

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SARCOMA 180 INHIBITION SCREENING DATA1 C. Chester Stock, … · SARCOMA 180 INHIBITION SCREENING DATA1 C. Chester Stock, Donald A. Clarke, Fredericks. Philips and Ralph K. Barclay