Table Of ContentRecent Results 94
in Cancer Research
Founding Editor
P. Rentchnick, Geneva
Managing Editors
Ch. Herfarth, Heidelberg· H. 1. Senn, St. Gallen
Associate Editors
M. Baum, London· C. von Essen, Villigen
V. Diehl, Koln . W. Hitzig, Zurich
M. F. Rajewsky, Essen· C. Thomas, Marburg
Predictive Drug
Testing on
Human Tumor Cells
Edited by
V. Hofmann M.E. Berens G. Martz
With 87 Figures and 107 Tables
Springer-Verlag
Berlin Heidelberg New York Tokyo 1984
Priv. Doz. Dr. Victor Hofmann
Universitatsspital Zurich
Departement fur Innere Medizin
Abteilung fur Onkologie
Ramistrasse 100, 8091 Zurich, Switzerland
MichaelE. Berens, Ph. D.
Department of Obstetrics Gynecology
Bowman Gray, School of Medicine
300 S. Hawthorne, Winston Salem NC 27103, USA
Professor Dr. Georg Martz
Universitatsspital Zurich
Departement fur Innere Medizin
Abteilung fur Onkologie
Ramistrasse 100, 8091 Zurich, Switzerland
Sponsored by the Swiss League against Cancer
ISBN-13: 978-3-642-82297-1 e-ISBN-13: 978-3-642-82295-7
DOl: 10.1007/978-3-642-82295-7
Library of Congress Cataloging 'n Publication Data. Main entry under title: Predictive drug
testing on human tumor cells. (Re 'ent results in cancer research; 94) Includes bibliographical
references and index. 1. Antineoplastic agents-Testing. 2. Cancer cells-Growth-Regulation.
3. Cloning. 4. Cancer-Chemotherapy-Evaluation. I. Hofmann, V. (Victor). 1948- .
II. Berens, M. E. (Michael E.). 1953- . III. Martz, G. IV. Series: Recent results in
cancer research. v. 94 [DNLM: I. Antineoplastic Agents-pharmacodynamics. 2. Colony
FormingUnitsAssay.3. Neoplasms-drugtherapy. 4. TumorStem Cell Assay. W1 RE 106Pv. 94/
QZ 267 P923] RC261.R35 vol. 94 616.99'4s 84-5599 [RC271.C5] [616.99'2061]
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© Springer-Verlag Berlin Heidelberg 1984
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2125/3140-543210
Preface
Predictive drug testing on human tumor cells in order to define the
appropriate chemotherapy will remain imperative as long as the
anticancer agents available are few in number and show only limited
activity. The advantages of an effective test would lie in obviating the
need for testing antineoplastic agents on large cohorts of patients for
assessment of drug activity (phase II studies) and in allowing
determination of optimal use of anticancer agents (phase III trials).
Such an in vitro test could help to better define dose and schedule of
drugs preclinically. The additive value of individual drugs could be
determined on tumor cells in vitro in order to define the best
combination chemotherapy in vivo.
Test-directed therapy would avoid unnecessary drug-related morbidity
in patients with refractory tumors. Chemotherapy treatment would be
more than justified even with side effects if palliation or even prolonged
survival could be anticipated as a result. The benefits of predictive drug
testing on human tumor cells would extend beyond improvement of
individual patient treatment if the testing helped to identify new active
agents. This spectrum of benefits to the entire field of oncology pro
vides tremendous motivation for the development of such testing.
Although a number of chemosensitivity tests have been proposed
since the advent of modern anticancer chemotherapy, interest has
been renewed by the possibility of cloning human tumor cells on agar
plates, with a view to testing drug activity on cells with high pro
liferation capacity.
Other tests, referred to as nonclonogenic assays, measure the effects of
the drugs on all the cells comprising the tumor.
After the initial optimism concerning immediate application of
such tests, this book, arising from an international conference held in
Zurich in July 1983, provides the reader with a more realistic
perspective on the achievements to date in this rapidly moving field.
It is fair to say that test-directed treatment of individual patients is
not yet a reality, although some initial studies suggest that patients
treated according to in vitro results may fare better. Now that the
number of chemosensitivity-testing laboratories has dramatically
VI Preface
expanded throughout the world, it is hoped that predictive tests will
improve step by step and find their place in clinical oncology
practice.
Zurich, July 1984 The Editors
Contents
Clonogenic Assays for Solid Tumors 1
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Mo Rozencweig, Vo Hofmann, C. Sanders, Wo Rombaut, Uo Fruh,
and Go Martz:
In Vitro Growth of Human Malignancies in a Cloning Assay 1
So Eo Salmon:
Development and Applications of a Human Tumor Colony
Assay for Chemosensitivity Testing 8
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Vo Do Courtenay:
A Replenishable Soft Agar Colony Assay for Human Tumor
Sensitivity Testing 17
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Vo Hofmann, Mo E. Berens, and Uo Fruh:
Analysis of Malignant Effusions by Cellular Composition,
Proliferation Kinetics, and In Vitro Clonogenicity 35
0 0 0 0 0 0 0 0 0
R. Fo Ozols, Wo Mo Hogan, and R. C. Young:
Direct Cloning of Human Ovarian Cancer in Soft Agar:
Clinical Limitations and Pharmacologic Applications 41
0 0 0 0 0 0 0
Mo Mo Lieber:
Technical Problems with Soft Agar Colony Formation Assays
for In Vitro Chemotherapy Sensitivity Testing of Human Solid
Tumors: Mayo Clinic Experience 51
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
C. Cillo and N. Odartchenko:
Cloning of Human Tumor Cells in Methylcellulose-Containing
Medium 56
000000000000000000000000000000000000000
H.-Po Honegger, Ao von Hochstetter, Po Groscurth,
Vo Hofmann, and Mo Cserhati:
The Effect of Chemotherapy on Human Bone Sarcomas:
A Clinical and Experimental Study 65
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
VIII Contents
Predictive Tests for Hematological Malignancies. . . . . . . . . . 76
E. A. McCulloch:
Experimental Approaches to Outcome Prediction in Acute
Myeloblastic Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
B. G. M. Durie:
Experimental Approaches to Drug Testing and Clonogenic
Growth: Results in Multiple Myeloma and Acute Myelogenous
Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
H. D. PreislerandA. Raza:
In Vitro Assessment of Drug Sensitivity in Acute
Nonlymphocytic Leukemia ......................... 102
J. D. Schwarzmeier, R. Pirker, and E. Paietta:
Short-Term In Vitro Sensitivity Testing in Acute Leukemia 116
Non-Clonogenic Assays for Drug Testing . . . . . . . . . . . . . .. 127
o. Sanfilippo, M. G. Daidone, N. Zaffaroni, and R. Silvestrini:
Development of a Nucleotide Precursor Incorporation Assay
for Testing Drug Sensitivity of Human Tumors . . . . . . . . . .. 127
R. Silvestrini, o. Sanfilippo, M. G. Daidone, and N. Zaffaroni:
Predictive Relevance for Clinical Outcome of In Vitro
Sensitivity Evaluated Through Antimetabolic Assay. . . . .. 140
M. Kaufmann:
Biochemical Short-Term Predictive Assay.
Results of Correlative Trials in Comparison to Other Assays 151
L. M. Weisenthal, R. H. Shoemaker, J. A. Marsden, P. L. Dill,
J. A. Baker, and E. M. Moran:
In Vitro Chemosensitivity Assay Based on the Concept of Total
Tumor Cell Kill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Evaluation onn Vitro Results .... . . . . . . . . . . . . . . . . . .. 174
M. Rozencweig and M. Staquet:
Predictive Tests and Infrequent Events in Cancer
Chemotherapy .................................. 174
D. S. Alberts, J. Einspahr, R. Ludwig, and S. E. Salmon:
Pharmacologic Pitfalls in the Human Tumor Clonogenic Assay 184
P. Schlag and D. Flentje:
Heterogeneity and Variability of Test Results 11s Limiting
Factors for Predictive Assays . . . . . . . . . . . . . . . . . . . . . . .. 191
v. Hofmann, E. E. Holdener, M. Muller, and U. Fruh:
Interlaboratory Comparison of In Vitro Cloning of Fresh
Human Tumor Cells from Malignant Effusions ........... 197
Contents IX
Pharmacology, Phase II Studies and New Drug Development 202
R. Ludwig, D. S. Alberts, and S. E. Salmon:
Evaluation of Schedule Dependency of Anticancer Drugs in
the Human Tumor Clonogenic Assay . . . . . . . . . . . . . . . . .. 202
E. E. Holdener, P. Schnell, P. Spieler, and H. Senn:
In Vitro Effect of Interferon-a on Human GranulocytelMacro
phage Progenitor Cells and Human Clonogenic Tumor Cells. 205
C. U. Ludwig, B. G. M. Durie, S. E. Salmon, and T. E. Moon:
Effect of Leukocyte Interferons on Cell Proliferation of Human
Tumors in Vitro ................................. 220
M. S.Aapro:
Drug Combination Testing with In Vitro Clonal Cultures . . .. 224
C. Sauter, M. Cogoli, S. Arrenbrecht, and C. Marti:
Neutralization of cis-Dichlorodiammineplatinum II
and Nitrogen Mustard by Thiols . . . . . . . . . . . . . . . . . . . . .. 232
B. F. Issell, J. J. Catino, and E. C. Bradley:
Usefulness of the Human Tumor Colony Forming Assay for
New Drug Development ........................... 237
U. Eppenberger, W. Kung, R. Loser, and W. Roos:
In Vitro Characterization of New Antiestrogens in Human
Mammary Tumor Cells .......... . . . . . . . . . . . . . . . . .. 245
Modulation of Tumor Growth by Non.Chemotherapeutic
Intervention . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . .. 253
G. Spitzer, F. Baker, G. Umbach, V. Hug, B. Xomasovic,
J. Ajani, M. Haynes, and S. K. Sahu:
Growth Factor Enhancement of the In Vitro Stem Cell Assay 253
J. F. Eliason, A. Fekete, and N. Odartchenko:
Improving Techniques for Clonogenic Assays . . . . . . . . . . .. 267
G. A. Losa and G. J. M. Maestroni:
Relationship of Steroid Hormone Receptors to the Cloning of
Fresh Breast Cancer Tissues ........................ 276
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 283
List of Contributors *
Aapro, M. S. 2241 Issell, B. F. 237
Ajani, J. 253 Kaufmann, M. 151
Alberts, D. S.· 184,202 Kung, W. 245
Arrenbrecht, S. 232 Lieber, M. M. 51
Baker, F. 253 Loser, R. 245
Baker, J. A. 161 Losa, G. A. 276
Berens, M. E. 35 Ludwig, C. U. 220
Bradley, E. C. 237 Ludwig, R. 184,202
Catino, J. J. 237 Maestroni, G. J. M. 276
Cillo, C. 56 Marsden, J. A. 161
Cogoli, M. 232 Marti, C. 232
Courtenay, V. D. 17 Martz, G. 1
Cserhati, M. 65 McCulloch, E. A. 76
Daidone, M. G. 127,140 Moon, T. E. 220
Dill, P. L. 161 Moran, E. M. 161
Durie, B. G. M. 93,220 MUller, M. 197
Einspahr, J. 184 Odartchenko, N. 56,267
Eliason, J. F. 267 Ozols, R. F. 41
Eppenberger, U. 245 Paietta, E. 116
Fekete, A. 267 Pirker, R. 116
Flentje, D. 191 Preisler, H. D. 102
Fruh,U. 1,35,197 Raza,A. 102
Groscurth, P. 65 Rombaut, W. 1
Haynes, M. 253 Roos, W. 245
Hochstetter von, A. 65 Rozencweig, M. 1,174
Hofmann, V. 1,35,65,197 Sahu, S. K. 253
Hogan, W. M. 41 Salmon, S. E. 8, 184, 202, 220
Holdener, E. E. 197,205 Sanders, C. 1
Honegger, H.-P. 65 Sanfilippo, O. 127,140
Hug, V. 253 Sauter, C. 232
* The address of the principal author is given on the first page of each
contribution
1 Page on which contribution begins
XII List of Contributors
Schlag, P. 191 Spitzer, G. 253
Schnell, P. 205 Staquet, M. 174
Schwarzmeier, J. D. 116 Tomasovic, B. 253
Senn,H. 205 Umbach, G. 253
Shoemaker, R. H. 161 Weisenthal, L. M. 161
Silvestrini, R. 127, 140 Young, R. C. 41
Spieler, P. 205 Zaffaroni, N. 127,140
