ADVANCES IN CANCER RESEARCH VOLUME 46 Interferon Treatment of Human Neoplasia This Page Intentionally Left Blank ADVANCES IN CANCER RESEARCH Edited by GEORGE KLEIN SIDNEY WEINHOUSE Department of Tumor Biology Karolinska lnstitutet Stockholm, Sweden Fels Research Institute Temple University Medical School Philadelphia, Pennsylvania Volume 46 Interferon Treatment of Human Neoplasia By HANS STRANDER Radiumhemmet Karolinska Hospital S-104 01 Stockholm 60, Sweden 1986 ACADEMIC PRESS, INC Harcourt Brace Jovanovich, Publishers Orlando San Diego New York Austin London Montreal Sydney Tokyo Toronto COPYRIGHT @ 1986 BY ACADEMIC PRESS INC ALL RIGHTS RESERVED NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL INCLUDING PHOTOCOPY RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER ACADEMIC PRESS, INC Orlando Florida 321187 United Kingdom Edition published by ACADEMIC PRESS INC ( L O N D O N ) LTD 24-28 Oval Road London NWI 7DX LIBRARY OF CONGRESS CATALOG CARD N U M B E R 52-13360 : ISBN 0-12-006646-7 PRINTCD IN THE UNlTtD STATkS (IF AMtHlCA Hh 87 88 89 Y X h S J l ? l CONTENTS PREFACE ix Chapter Interferons (IFNs) I Introduction I1 Types 111 Production and Purification IV Induction and Production Control V Genetics Chapter General Action I Action on Cells in General I1 Action on the Cell Surface 111 Tumor Viruses and Oncogenes IV Biological Response Modifiers V IFNs and Prostaglandins 10 15 16 18 19 Chapter Anti-Growth Effects I The Anti-Growth Concept I1 Anti-Growth Effects in Tissue Culture 111 Colony Techniques IV Theory behind the Anti-Growth Concept V Nude Mouse Experiments 20 21 28 30 32 Chapter Effects on the Immune System I General Effects I1 IFNs and NK Cells 111 Other Effector Systems IV Immunoregulatory Circuits V 36 44 54 55 vi CONTENTS Chapter Effects on Other Parameters I Receptors and Somatic Antigens I1 Tumor Cell Antigens and Other Markers 111 Various Laboratory Parameters 58 60 61 Chapter Pharmacology and Toxicity I IFN Effects in Animals-General Implications I1 Animal Toxici ty 111 IFN Titrations and Pharmacokinetics IV Anti-IFN Antibodies V Side Effects and Toxicity VI IFN and Disease 66 67 68 71 72 81 Chapter Animal Tumor Models Text 88 Chapter Treatment of Human Papillomavirus-Associated Tumors I Local Treatment of Human Papillomavirus-AssociatedTumors I1 IFN Treatment of Juvenile Laryngeal Papillomatosis I11 Systemic IFN Treatment of Other HPV-Associated Tumors 99 102 106 Chapter Regional Treatment of Other Tumors I I1 I11 IV V VI VII VIII IX Intra- and Peritumoral IFN Therapy Local Treatment of Malignant Melanoma Local Treatment of Breast Cancer Local Treatment of Cancer of the Uterine Cervix Local Treatment of Neurological Tumors Local Treatment of Head and Neck Tumors Local Treatment of Lung Tumors Local Treatment of Bladder Tumors Intraarterial IFN Therapy 108 109 112 112 113 115 116 117 118 Chapter 10 Systemic Therapy of Indignant Disease I I1 I11 IV V VI Systemic IFN Therapy of Tumors-Screening Trials Systemic Treatment of Leukemias Systemic Treatment of Lymphomas., Systemic Treatment of Myelomatosis Systemic Treatment of Kaposi's Sarcoma Systemic Treatment of Soft Tissue Sarcomas 119 134 141 146 149 152 vi i CONTENTS VII Systemic Treatment of Osteosarcomas VIII Systemic Treatment of Malignant Melanoma IX Systemic Treatment of Renal Cell Carcinoma X Systemic Treatment of Lung Cancer XI Systemic Treatment of Gastric Cancer XI1 Systemic Treatment of Colorectal Carcinoma XI11 Systemic and Intraarterial IFN Treatment of Liver Cancer XIV Systemic Treatment of Carcinoids xv Systemic Treatment of Nasopharyngeal Carcinoma XVI Systemic Treatment of Brain Tumors XVII Systemic Treatment of Neuroblastoma XVIII Systemic Treatment of Prostate Carcinoma XIX Systemic Treatment of Carcinoma of the Uterine Cervix Systemic Treatment of Ovarian Carcinoma XXI Systemic Treatment of Breast Cancer xx 152 156 160 167 170 170 172 172 173 173 177 178 178 179 180 Chapter 11 Inducers Text 183 Chapter 12 Other Forms of IFN Therapy I IFN as an Antiviral Agent in Tumor Patients I1 Additional Uses of IFN Therapy 185 189 Chapter 13 Conclusions I General Discussion and Future Prospects I1 Addendum 191 202 BIBLI~C~L~PHY 204 INDEX 257 This Page Intentionally Left Blank PREFACE Information concerning the effects of interferons (IFNs) in the treatment of tumors-especially at the clinical level-has been compiled and presented in this volume A rather complete survey is included of what has happened in just a few years of intensive international I F N research in this area Since so many data have accumulated from both experimental and clinical oncology sources, references to information gathered before 1979 will be limited Included are data presented at symposia and references that are difficult to obtain from general sources The volume is almost entirely devoted to data on humans, but some mention is made of animal experimentation The book contains chapters dealing with experimental I F N effects, with special emphasis on the types of IFNs and their actions that cause regression of tumors The volume starts with a survey of the various IFNs, how they are produced, and how they act Their pharmacology and toxicity are discussed A short chapter on animal tumor models used for possible application to human tumor disease follows The book then deals with the treatment of benign tumor diseases I F N treatment of malignant diseases is also discussed I F N inducers and other forms of I F N therapy are mentioned Concluding the volume is a chapter summarizing the present situation and suggestions for future research Readers most likely to find this book of particular interest will be investigators actively involved in I F N effects and the possible mechanisms underlying the effects achieved with human tumors This book will also be of interest to oncologists and other specialists working with I F N at the clinical level It should also fulfill the needs of investigators interested in a broad introduction to the area It is clear that IFNs have become a permanent part of the armamentarium used in the treatment of tumor disease in man and thus should be of general interest to all engaged in clinical oncological research This work was made possible by grants from the Swedish Cancer Association, The Cancer Society of Stockholm, The Albert and Mary Lasker Foundation, and the Karolinska Hospital I want to thank ix 252 BIBLIOGRAPHY Tovey, M G (1980) PQthOl B i d 26, 631-634 Tovey, M G., and Gresser, I (1982).In “The Clinical Potential of Interferons” (R Kono and J Vileek, eds.), pp 311-319 Univ of Tokyo Press, Tokyo Tovey, M., Dron, M., Mogensen, K E., Lebleu, B., Mechti, N., and Begon-ZoursGuymarho, J (1983).J Gen Virol 64,2649-2653 Toy, J L (1983a) Clin E x p Immunol 54, 1-13 Toy, J (1983b) In “The Biology of the Interferon System” (E De Maeyer, G Galasso, and H Schellekens, eds.), pp 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Elsevier, New York Zor, U., Ben-Don, R., Maoz, I., Wallach, D., and Gurari-Rotman, D (1982) J Gen Vtrol 63, 359-363 Zschiesche, W (1980) Dtsch Gesundhettswesen 35, 1609-1618 Zur Hausen, H (1978) Curr Top Microbiol Immunol 78, 1-30 INDEX A (2’-5’)A synthetase, interferon and action on cells, 13 animal toxicity, 66, 67 animal tumor models, 91, 97 anti-growth effects, 23 HPV-associated tumors, 106 immune system, 43 laboratory parameters, 61, 62 nude mouse experiments, 32 Acute granulocytic leukemia (AGL), systemic treatment of, 134, 135 Acute lymphocytic leukemia (ALL), 134, 136, 147, 183, 194 Acute myelogenous leukemia, 128, 136, Anti-growth effects, interferon and colony techniques, 28-30 concept, 20, 21 nude mouse experiments, 32-35 theory, 30,31 in tissue culture, 21-27 Antiproliferative properties, interferon and animal tumor models, 97 anti-growth effects, 21, 23-26, 31 colony techniques, 29 production, systemic treatment, 149 Antiviral agents, interferon and, 185-189 Astrocytomas, interferon and, 113, 114, 175 184, 193,201 Adenocarcinoma, systemic treatment of, 167, 170, 171 Adriamycin, interferon and, 35, 152, 155 AIDS, interferon and, 189, 190 animal tumor models, 93 purification, systemic therapy, 150, 151 toxicity, 86 Anorexia, interferon and, 74, 78, 163, 181 Antibody-dependent cellular cytotoxicity (ADCC), interferon and, 196 breast cancer, 180, 181 disease, 84 immune system, 37, 39-41,43,51 lymphoma, 141, 142 Antigens, interferon and, 1, 192, 196, 197 EBV, 17 expression, 196 immune system, 43,44,54,56 somatic, 58-60 systemic therapy, 129, 142, 168 tumor cells, 60,61 257 B cells, interferon and, 196 anti-growth effects, 24 EBV-transformed, 36 immune system, 46.54 leukemia, 138, 141 lymphoma, 141 B lymphocytes, interferon and, 37, 81 Biological response modifiers, interferon and, 18, 19 Bladder carcinoma, interferon and, 23, 96, 117, 118, 120, 131, 134, 193, 199 Brain tumors, systemic treatment of, 173- 177 Breast carcinoma, interferon and, 29, 30, 109, 112, 116, 119-126, 129, 131133, 180-182, 193, 194, 199, 200 Burkitt’s lymphoma, interferon and, 197 antigens, 58,60 anti-growth effects, 21-23, 26 immune system, 37 258 INDEX C Carcinoids, systemic treahiient of, 172, 173 cDNA, interferon and, 4, 7, 10 Cell-mediated cytotoxicity, interferon and, 45, 47, 84 Central nervous system toxicity, interferon and, 74, 75, 79, 80, 83 Cervical cancer, interferon and, 108, 112, 113, 120, 132, 133, 178 Chemotherapy, interferon and, 191, 199, 20 animal tumor models, 89, 94-96 anti-growth effects, 23, 35 immune system, 39, 51, 53 regional treatment, 112, 114, 115, 117 systemic treatment of brain tnmors, 175, 177 of breast cancer, 180, 182 of Kaposi’s sarcoma, 150, 151 of leukemias, 134, 135, 137, 138 of lung cancer, 169 of lymphomas, 141, 142, 145 of melanoma, 156, 158 of myelomatosis, 146-148 of nasopharyngeal carcinoma, 173 of neuroblastoma, 177 of osteosarconw, 152, 153, 155 of ovarian carcinoma, 179 of renal cell carcinoma, 161, 163 of soft tissue sarcoma, 152 of tumors, 121, 124, 128, 129 toxicity, 79-82 Chronic granulocytic leukeniia (CGL), systemic treatment of; 134 Chronic lymphocytic leukemia (CLL), interferon and immune system, 46,47 systemic therapy of leukemias, 138, 139 of lymphomas, 141 of tumors, 122, 127, 129, 130 toxicity, 84 Chronic niyelogenous leukemia (CML), interferon and, 2, 136-138, 197 Cimetidine, interferon and, 59, 93, 110112, 157, 159, 160 Colon carcinoma, interferon and, 193, 194 colony techniques, 30 systemic therapy, 127, 128, 132, 133, 170 Colony techniqnes, interferon and, 2830 Colorectal cancer, interferon and, 120, 121, 123, 125, 170-172, 199 Computed tomography (CT) scanning, interferon and, 114, 174, 175 Condylomata acuminata, interferon and, 2, 100, 101, 106, 108 Confusion, interferon and, 76, 77, 163, 181 Corynebucteritrtn puruum, interferon and, 82,93, 119 Cyclophosphamide, interferon and animal tumor models, 94-96 anti-growth effects, 23, 26, 35 immune system, 57 systemic therapy, 155, 177, 182 toxicity, 80 Cyclosporine A, interferon and, Cysteine, interferon and pharmacokinetics, 70 production, toxicity, 78 Cytoniegalovirus infection, interferon and, 186-188 Cytotoxicity, interferon and, 199, 201 animal tumor models, Yo, 93, 96, 97 colony techniques, 28 immnne system, 36, 39, 41, 44-49, 51, 52, 54, 56 laboratory parmaeters, 62 pharmacology, 83.84 systemic therapy, 128, 180, 181 D Daudi cells, interferon and, 21, 23-27, 31 Degradation, interferon and, 10, 71 Delayed-type hypersensitivity, interferon and antigens, 59 anti-growth effects, 26 systemic therapy, 129 259 INDEX Dexamethasone, interferon and, 19 Differentiation, interferon and, 196 action on cells, 11-14 animal tumor models, 89 antigens, 61 anti-growth effects, 20, 21 colony techniques, 28 systemic therapy, 141 Diffuse histiocytic lymphoma (DHL), 142, 144 Diffuse lymphocytic poorly differentiated lymphoma (DLPL), 142, 144 DNA, interferon and, 86, 102, 201, see also Recombinant DNA DNA synthesis, interferon and, 31, 55 Down’s syndrome, interferon and, 85, 136 E Electroencephalogram (EEG), interferon and systemic therapy, 168 toxicity, 75, 78, 80 Encephalomyocarditis (EMC) infection, interferon and, Epstein-Barr virus, interferon and antigens, 58 antiviral agents, 185 inimune system, 36, 37, 47, 54 oncogenes, 17 pharmacology, 81 Erythroleukemia, interferon and, 89, 90 Escherichiu coli, interferon and anti-growth effects, 24 production, purification, systemic therapy, 33 toxicity, 76 Estradiol, interferon and, 63 F Fatigue, interferon and, 74-79, 157, 158, 163, 168, 175, 178, 182 Fibroblasts, interferon and, 165 animal tumor models, 95 antigens, 58 anti-growth effects, 20, 22, 24, 26, 27 immune system, 47 production, systemic therapy, 128 toxicity, 77 Friend leukemia, interferon and, 90 G Gastric cancer, systemic treshnent of, 170, 195 Gene expression, interferon and, 8, 11, 16 Genetics, interferon and, 8, Glioblastomas, interferon and, 114, 174176 Gliomas, interferon and, 34, 113, 114, 176 Glycose, interferon and, Glycosylation, interferon and inhibition, 13 pharmacokinetics, 69 production, Granulocytes, interferon and action on cells, 12 immune system, 38 laboratory parameters, 62 toxicity, 73 Granulocytopenia, interferon and, 75, 78, 147, 161 H Hairy cell leukemia, interferon and, 2, 140, 141, 197 Head tumors, interferon local treahnent of, 115, 116 systemic therapy, 129 Headache, interferon and, 1, 74 Helper T cells, interferon and, Hepatitis, interferon and, 33, 187 Hepatoma, interferon and nude mouse experiments, 32 systemic therapy, 123 Hepatotoxicity, interferon and, 76, 179 Herpes simplex virus, interferon and, 186, 187 High-density lipoprotein cholesterol (HDLC), interferon and, 63, 64 260 INDEX Hodgkin’s disease, interferon and, 121, 122, 125, 141, 142, 190 HPV, see Human papillomavirus Human papillomavirus (HPV), interferon and, 86.87, 198 associated tumors local treatment of, 99-101 systemic treatment of, 106, 107 juvenile laryngeal papillomatosis, 102-105 I Immune system, interferon and, effects on effector systems, 54,55 general effects, 36-44 immunoregulatory circuits, 55-57 natural killer cells, 44-54 Immunoregulatory circuits, interferon and, 55-57 Indomethacin, interferon and immune system, 55 prostaglandins, 19 systemic therapy, 137 Inducers, interferon and, 183, 184, 192, 200 Inducibility, interferon and action on cells, 11 animal tumor models, 89 anti-growth elrects, 20 Induction, interferon and, 1, 7, 8, 192 action on cells, 12, 13, 15 animals, 66, 67 antigens, 60 anti-growth effects, 21 diterpene esters, immune system, 36, 43, 47, 48, 55 laboratory parameters, 62 pharmacology, 85 systemic therapy, 159 Inhibition, interferon and, 202 action on cells, 13-15 animals, 66, 89, 91, 94 anti-growth effects, 20, 21, 24, 25, 27, 30,31 antiviral agents, 185 biological response modifiers, 18, 19 colony techniques, 28, 29 HPV-associated tumors, 99 immune system, 36-38, 40, 44 nnde mouse experiments, 33, 34 prostaglandins, 19 tumor viruses, 17 Interleukin 1, interferon and immune system, 38 toxicity, 78 Interleukin 2, interferon and animal tumor models, 97 immune system, 36,46,55-57 toxicity, 78 Inh-aarterial interferon therapy, 118 J Juvenile laryngeal papilloniatosis, interferon and, 2, 102-105, 183, 184, 194 K Kaposi’s sarcoma, interferon and, 2, 86, 121, 149-151, 189, 193 L Laryngeal carcinoma, interferon and, 32, 183 Lectin-dependent cellular cytotoxicity (LDCC), interferon and, 37 Leukemia, interferon and, see also specific leukemias animal tumor models, 88, 89, $1.3 94 immune systems, 47, 50 systemic therapy, 120, 123, 134-141 toxicity, 75, 79, 85 Leukemic cells, interferon and action on cells, 11-13 anti-growth eflects, 20 systemic treatment, 134 Leukocyte interferon, 1, 194, 196, 198 action on cell surface, 16 antigens, 58, 59 anti-growth concept, 30, 31 anti-interferon antibodies, 71, 72 antiviral agents, 185-188 colony techniques, 30 H PV-associated tumors, 99- 105 immune system, 37, 39, 42, 44, 48, SO, 54, 55 lahoratory parameters, 62, 63 INDEX monoclonal antibodies, pharmacokinetics, 69 regional treatment, 108, 109, 112, 113, 115- 117 side effects, 72, 74, 76, 80, 84 systemic therapy of brain tumors, 176 of breast cancer, 180, 182 of cervical cancer, 178 of Kaposi’s sarcoma, 149, 150 of leukemias, 134, 137 of lung cancer, 167 of lymphonias, 141-143, 145 of melanoma, 159 of myelomatosis, 146, 147 of neuroblastoma, 177 of osteosarconias, 152-155 of ovarian carcinoma, 179 of renal cell carcinoma, 161, 162 of tumors, 119-121, 125-127 Leukocytes, interferon and, 1, 61, 65 animals, 67 anti-growth et’f’ects, 26 breast cancer, 181 colony techniques, 28 EBV, 17 immune system, 48,W lymphoma, 144 pharmacology, 82,85 production, 4, Leukopenia, interferon and colony techniques, 28 disease, 83 immune system, 50 systemic therapy, 121, 130, 147, 161, 163 Liposarcoma, interferon and, 95 Liver cancer, systemic treatment of, 172 Low-density lipoprotein cholesterol, interferon and, 64 Lung carcinoma, interferon and, 193 nude mouse experiments, 32 systemic therapy, 121, 127, 133, 167169 Lung tumors, local treatment of, 116, 117 Lymphoblastoid cells, interferon and anti-growth effects, 22, 23, 25 inhibition, 19 systemic therapy, 119 26 I Lymphoblastoid interferon, 198, 201 action on cells, 11 antigens, 58,5Y anti-growth effects, 24, 31 biological response modifiers, 18 HPV-associated tumors, 103, 105, 106 immune system, 139, 141, 144, 150, 151 laboratory parameters, 62, 64 lymphoma cells, nude mouse experiments, 33,35 pharniacokinetics, 69 production, regional treatment, 110 systemic therapy of brain tumors, 175 of breast cancer, 180, 181 of cervical cancer, 178 of colorectal carcinoma, 170 of gastric cancer, 170 of Kaposi’s sarcoma, 151 of leukemias, 136 of lung cancer, 169 of lymphomas, 145 of melanoma, 156, 158 of myelomatosis, 149 of ovarian carcinoma, 179 of renal cell carcinoma, 162-165 of tumors, 121-124 toxicity, 74-76, 79, 80 Lymphocytes, interferon and, 201, see also B lymphocytes; T lymphocytes action on cells, 10, 11, 14, 15 antigens, 58 anti-growth effects, 25 HPV-associated tumors, 105 immune system, 36, 37, 40, 43, 46, 47, 49, 51, 54, 55 peripheral blood, 61 pharmacokinetics, 70 production, regional treatment, 108-110 systemic therapy, 124, 133, 137, 139, 140 toxicity, 73, 84, 85 Lymphokines, interferon and, 189, 190, 192 antigens, 59,60 antiviral agents, 186 biological response modifiers, 18 262 INDEX imniune system, 36, 56 production, Lymphoma, interferon anti, 190, 193195, 197, see U ~ S OBnrkitt's lymphoma; Nodular lyniphocytic poorly tliflertwtiated lymphoma animal tiniior models, 88, 8s) 04 anti-growth efl'ects, 25, 26 imniunotlepressioii, 81 systemic therapy, 141-146 of tumors, 119-121 123, 125-127, 131, 132 toxicity, 78, 79 Lymphoma cell s, i nterferon and antigens, 61 anti-growth effects, 24, 26 prodnction, 5, Lyinphotoxins, interfitron and, 192, 2OU anti-growth eflects, 30 immune system, 56 production, systemic therapy, 151 toxicity, 78 M &Macroglobulins, interferon and, 58 Macrophages, interferon and, 189 action o n cells, 12 animals, effects in, 67 antigens, 59, 60 ininiune system, 38, 55, 56 regional treatment, 108, 109 Malaise, interferon and, 1, 74, 83, 117, 163,168 Medulloblastoiiia, interferon and, 114, 174- 177 Melanomas, interferon and, 64, 192-194 animal tumor models, 92, 93 antigens, 59, 61 anti-growth eflects, 21, 31 in tissue culture, 25-27 biological response modifiers, 18 colony techniques, 29, 30 HPV-associated tumors, 100 imniune system, 43, 45, 47-49, 54 laboratory parameters, 62 nude mouse experiments, 30 regional treatnient, 107-1 12, 118 systemic therapy, 156- 160 of tuinors, 121, 125, 127, 130, 132, 133 PL-iiiicroglobulins, intrrli.ron antl, 65 antigens, 58, 59, 61 systemic therapy, 124, 168, 180 toxicity, 78 Mitogelis, interferon and, 1, 189 immune system, 39,44, 55 systemic therapy, 142 Moloney sarcoma virus (MSV)-transformed cells, interfernn and, 14 Monoclonal antihodirs, iiiterft-ron ancl, 192,201 antigens, 60 antiviral agents, 188 immnne system, 41, 43, 44, 56 leukocytes, nude mouse experiments 35 phannacology, 71 production, systemic therapy, 128, 145, 156 Monocytes, interfcron and imniune system, 36, 38, 41, 42, 54 production, toxicity, 73, 85 mRNA, interferon a n d action on cells, 10, 13 antigens, 58, 59 Multiple sclerosis, interferon and, 84, 85, 189 Myeloid leukemic cells, interferon antl action on cells, 11 colony technicliltas, 28 immune system, 47 xenografts, 32 Myeloma, interferon and, 193, 196 colony techniqnes, 28, 30 immune system, 37, 49 intliicers, 183 systemic treatment, 146-14'3, 158 of lymphomas, 141, 142 of tumors, 119-123, 125, 127, 129, 130 N Nasopharyngeal carcinoma, iiiterfcvwn and, 195 263 INDEX animal tumor models, 97 EBV and, 17 nude mouse experiments, 32 systemic therapy, 119, 129, 132, 173, 176 Natural killer cells, interferon and, 198, 20 action on cells, 10, 11 animals effects in, 66, 67 tumor models, 91, 92, 96 antiviral agents, 185 immune system, 36-54 laboratory parameters, 62 nude mouse experiments, 32, 33 production, systemic therapy of breast cancer, 180, 181 of carcinoids, 173 of leukemias, 137, 138 of lung cancer, 168 of lymphomas, 141, 142, 144 of tumors, 125, 129, 130 toxicity, 77, 84, 85 Nausea, interferon and, 74, 181 Neck tumors, interferon and local treatment of, 115, 116 systemic therapy, 129 Neoplasia, interferon and, 2, 198 Neuroblastoma, interferon and, 94, 95, 109, 113, 128, 177, 195 Nodular lymphocytic poorly differentiated lymphoma (NLPDL), 126, 142144 Oncogenes, interferon and, 16, 17, 138 Osteosarcoma, interferon and, 197, 201 animal tumor models, 91.92 anti-growth effects, 23, 24 anti-interferon antibodies, 71 immune system, 55 nude mouse experiments, 34 side effects, 173 systemic therapy, 128, 152-156 Ovarian carcinoma, interferon and, 193 nude mouse experiments, 32 systemic therapy, 124, 126, 128, 179 P Papillomaviruses, interferon and, 17, see also Human papillomavirus; Juvenile laryngeal papillomatosis Peripheral blood mononuclear cells (PBMCs), interferon and, 61 laboratory parameters, 62, 65 natural killer cells, 47, 51, 53 toxicity, 82, 84, 85 Pharmacokinetics, interferon and, 68-70, 122, 125, 130, 139, I95 Pharmacology, interferon and animals, 66-68 anti-interferon antibodies, 71, 72 disease, 81-87 pharmacokinetics, 68-71 side eflects, 72-81 Prednisolone, interferon and, 19, 146, 147 Production, interferon and, 4-7, 13 Production control, interferon and, 7, Progesterone, interferon and, 63 Proliferation, interferon and, 198 action on cells, 13, 15 anti-growth effects, 20, 30 colony techniques, 28 Daudi cells, 24 disease, 84 immune system, 36.55-57 systemic, 138, 175 Prostaglandins, interferon and, 19, 196 immune system, 48.55 toxicity, 80, 82, 85 Prostate carcinoma, systemic treatment of, 178 Purification, interferon and, 2, 3, 5-7, 11 Pyrexia, interferon and, 74, 147 R Radioresistance, interferon and, 91, 14I Receptors, interferon and, 58-60, 84 Recombinant DNA, interferon and, action on cell surface, 16 anti-growth effects, 29, 31 antiviral agents, 188 production, INDEX Recombinant interferon, 4, 193, 195, 198 action on cells, 13 animal toxicity, 67, 68 antigens, 59, 60 anti-growth effects, 25 anti-viral agents, 188 biological response modifiers, 18 colony effects, 28, 30 immune system, 37.41-44,50-52,54, 55 induction, 11 laboratory parmeters, 62, 64 pharmacokinetics, 68, 69 production, purification, regional treatment, 110, 117 systemic therapy of brain tumors, 176 of breast cancer, 181, 182 of cervical cancer, 178 of Kaposi’s sarcoma, 149-151 of lung cancer, 167 of lymphomas, 141, 143, 145 of melanoma, 157, 159 of renal cell carcinoma, 165-167 of tumors, 124-128, 132, 133 toxicity, 72, 75-80, 84, 88 Rectum, cancer of, see Colorectal cancer Renal cell carcinoma, interferon and, 2, 193 colony techniques, 29 immune system, 38,55 laboratory parameters, 62 systemic therapy, 120-123, 126, 127, 131-134, 160-167 Renal transplantation, interferon and, 81, 82, 129, 188 Resistance, interferon and, 47 RNA, interferon and, 10, 183, 184 RNA viruses, interferon and, 33 Sendai virus, interferon and, 5, 85 Sensitivity, interferon and, 11 Serum glutamic pyriivic transaminase, interferon and, 158 Soft tissue sarcomas, systemic treatment of, 152 Squamous cell carcinoma, interferon and, 120, 176 Steroids, interferon and, 137, 139 Synergistic effects, interferon and, 201 action on cells, 11 animal tumor models, 94 anti-growth effects, 27 antiviral agents, 185 colony techniques, 29, 30 systemic therapy, 160 Systemic interferon treatment, 106, 107 of brain tumors, 173-177 of breast cancer, 180-182 of carcinoids, 172, 173 of cervical cancer, 178 of colorectal carcinoma, 170 of gastric cancer, 170 of Kaposi’s sarcoma, 149-151 of leukemias, 131-141 of liver cancer, 172 of lung cancer, 167-169 of lymphomas, 141-146 of melanoma, 156-160 of myelomatosis, 146-149 of neuroblastoma, 177 of osteosarcomas, 152-156 of ovarian carcinoma, 179 of prostate carcinoma, 178 of renal cell carcinoma, 160-167 of soft tissue sarcoma, 152 of tumors, 119-131 Systemic lupus erythematosis, interferon and, 68, 83, 84, 86 S T Sarcolectins, interferon and, 18, 19 Sarcoma, interferon and action on cells, 14 animal tumor models, 88, 91, 93 immune systems, 52 systemic therapy, 121, 126, 132 toxicity, 87 T cells, interferon and, 196 antigens, 58 anti-growth effects, 24 cytotoxic, 54, 93, 97 immune system, 41, 43, 50, 54-57 production control, systemic therapy, 125, 142 265 INDEX toxicity, 84 tumor viruses, 16 T cell leukemia, systemic of, 139, 141, 145 T cell lymphoma, interferon and HPV-associated tumors, 100 nude mouse experiments, 32 systemic therapy, 126, 127, 145 T lymphocytes, interferon and, 189 immune system, 37,56 Toxicity, interferon and, 196 animals, 66-68 anti-interferon antibodies, 71, 72 disease, 84 HPV-associated tumors, 104 inducers, 183, 184 intraarterial interferon therapy, 118 natural killer cells, 50 pharmacokinetics, 68-71 side effects, 72-81 systemic therapy of breast cancer, 180, 181 of colorectal carcinoma, 170 of Kaposi’s sarcoma, 150, 151 of leukemias, 137 of lung cancer, 169 of lymphomas, 141, 142, 144, 145 of melanoma, 157, 158 of myelomatosis, 147 of ovarian Carcinoma, 179 of renal cell carcinoma, 161, 163, 164, 166 of soft tissue sarcoma, 152 of tumors, 120-122, 130 Transcription, interferon and, Transformation, interferon and animal tumor models, 88 fibroblasts, 26 immune system, 54 systemic therapy, 128, 138 tumor viruses, 17 Translocation, interferon and, Trisomy 21, interferon and, 2, 85, see also Down’s syndrome U Uterine cervix, carcinoma of, see Cervical cancer v Vaginal flat condylomata, interferon and, 101 Vesicular stomatitis virus, interferon and, 11 Vincristine, interferon and, 137, 162, 177 W Waldenshom’s macroglobulinemia, interferon and, 126, 143, 147 World Health Organization (WHO), interferon and, 2, 191 X Xenografts, interferon and, 32-35, 201 This Page Intentionally Left Blank [...]... devoid of this activity (Zor et al., 1982) Other prostaglandin synthetase inhibitors, including indomethacin and aspirin, did not alter IFN production, although prostaglandin synthesis was abolished These investigators concluded that while the induction of IFN and prostaglandin E may be the consequence of the same initial cellular event, prostaglandin E does not have a regulatory effect on IFN synthesis... treatment In embryonal carcinoma cells, IFNs are able to induce a partial antivi20 ANTI-GROWTH EFFECTS IN TISSUE CULTURE 21 ral state in which the induced antiviral proteins can interfere with the replication of only some viruses (Nilsen et al., 1980) It is interesting that malignant embryonal carcinoma cells can neither produce nor respond to IFNs, whereas differentiated cells obtained from embryonal carcinoma... populations Of nine osteosarcoma cell lines tested in uitro, all were found to be inhibited in their growth by human natural IFN-a in tissue culture (Strander and Einhorn, 1977).What was especially interesting in the tissue culture work was the fact that cells could be affected at concentrations that can b e obtained in the serum of IFNtreated patients (see also Chapter 3, Section I) Rubin and Gupta found... itself induce the differentiation, but it did augment induction by several other substances IFN could, however, induce lysozyme activity in these cells and behaved in a synergistic manner with other inducers in this re- 12 2 GENERAL ACTION spect It is interesting that the induction of differentiation in this system can also be achieved with hormone preparations Tomida et al further demonstrated in 1982... interactions between the I F N and prostaglandin systems are an intriguing subject, especially since elevated prostaglandin production seems to be a marker of high metastatic potential in the neoplastic cells of breast cancer (Rolland et al., 1980).Hydrocortisone and dexamethasone, inhibitors of prostaglandin E synthesis, decreased the induction of both prostaglandin and IFN in IFN-pretreated cells, while various... Dahlstrom, Stefan Einhorn, Eva Gripenholm, Amy Klion, Edward Rye, and Gerd Stridh I am also indebted to the investigators who kindly submitted unpublished results and manuscripts HANSSTRANUEH CHAPTER 1 INTERFERONS (IFNs) “The writing of an article helps to make the writer better informed on the subject he discusses.” Morris Fishbein (1938) I Introduction Interferons (IFNs) are proteins or glycoproteins able... prostaglandins in IFN-sensitive and IFN-resistant cells They found that IFN stimulated prostaglandin synthesis and that this enhanced synthesis could be inhibited by prednisolone or indomethacin These results suggested that IFN stimulates prostaglandin synthesis by promoting the release of arachidonic acid from phospholipids It is of interest that prednisolone and indomethacin partially inhibited the... Produced in E coli; lysine at position 23; deletion at position 44 Produced in E coli; 29 amino acid variations from aA From cultured lymphoma cells in oitro or in hamsters Can be purified; made from fibroblasts or SV40-transformed cells Cysteine at position 17 Serine at position 17 More impure in earlier trials Probably different from natural y 4 1 INTERFERONS (IFNS) portant in this respect Recombinant... is in comparison to an induced protein kinase and other affected pathways in the cell The kinase is also likely to play a role, however, since the same conditions that activate the (2’-5’)A system trigger the kinase Munoz et al (1983) suggested that under some circumstances degradation of cellular RNA upon virus infection does not take place in IFN-treated cells The important point at the moment, in. .. actions IFNs can, in fact, regulate the growth of many cells, including melanoma cells in culture (Creasey et al., 1983).The clinical importance of target cell receptor down-regulation by circulating peptide hormones has been emphasized (see King and Cuatrecasas, 1981) It will be interesting to see if the IFN system follows the same principles Relationships between IFNs and neuroendocrine hormones have .. .ADVANCES IN CANCER RESEARCH VOLUME 46 Interferon Treatment of Human Neoplasia This Page Intentionally Left Blank ADVANCES IN CANCER RESEARCH Edited by GEORGE KLEIN SIDNEY WEINHOUSE Department... osteosarcoma cell lines tested in uitro, all were found to be inhibited in their growth by human natural IFN-a in tissue culture (Strander and Einhorn, 1977).What was especially interesting in the tissue... impure in earlier trials Produced in E coli; arginine at position 23; deletion at position 44 Produced in E coli; lysine at position 23; deletion at position 44 Produced in E coli; 29 amino acid