Cancer Chemotherapy and Selective Drug Development : Proceedings of the 10th Anniversary Meeting of the Coordinating Committee for Human Tumour Investigations, Brighton, England, October 24–28, 1983

Over the past 30 years many significant advances have been made in the management of a number of disseminated malignant diseases. The prognosis for diseases such as childhood leukaemia, choriocarcinoma and Hodgkin's disease has gradually been transformed as better anti tumour agents have become available and their clinical use has been refined. During the past 10 years the advent of new agents, particularly cisplatin, bleomycin and the podophyllotoxins, has allowed the cure of disseminated testicular tumours. This degree of success has not, however, been achieved in the case of a number of other common cancers. Ovarian carcinoma is tantalisingly chemo-sensitive and although there are long term survivors from disseminated disease, these are only a small proportion of the total. Breast cancer, although "sensitive" to a multitude of drugs appears to have yielded neither survival benefit, nor cure to the efforts of therapists, while tumours such as those of the colon remain stubbornly unresponsive. Against this backcloth it is apparent that additional more selective treatments are needed if further impact is to be made on the problem of cancer. The development of such agents requires the integration of a multidisciplinary effort encompassing the fields of chemistry, biology and medicine. This symposium provided a forum for clinical and preclinical sCientists, where current aspects of cancer treatment were reviewed and approaches to the development of a new generation of more selective anticancer drugs discussed. Front Matter....Pages i-xxv Front Matter....Pages 1-1 Clinical Drug Resistance....Pages 5-11 New Therapies With Old Drugs....Pages 13-17 Antimetabolite Combinations Possessing Enhanced Efficacy....Pages 19-32 Mismatched Bone Marrow Transplantation....Pages 33-41 Prospects for Immunotherapy....Pages 43-45 Platinum Analogs....Pages 49-53 Mitoxantrone: A Promising New Agent for the Treatment of Human Cancer....Pages 55-63 Current Clinical Progress — Podophyllotoxins....Pages 65-69 Pharmacology of Nitrosourea Anticancer Agents....Pages 71-75 Current Clinical Progress with New Agents: Alkylating Agents....Pages 77-82 Interferon....Pages 83-87 Chemotherapy of Lung Cancer....Pages 91-94 Hormone-Chemotherapy in Treatment of Advanced Breast Cancer....Pages 95-104 Chemotherapy of Ovarian Cancer....Pages 105-109 Obstacles to Improved End-Results in Head and Neck Cancer....Pages 111-115 Treatment of Disseminated Malignant Lymphoma....Pages 117-122 Malignant Disease in Childhood....Pages 123-133 Chemotherapy of Disseminated Testicular Cancer....Pages 135-139 Rational Approach to the Management of Febrile Granulocytopenic Patients....Pages 141-144 Front Matter....Pages 145-145 Effective Use of Narcotic Analgesics....Pages 147-151 Front Matter....Pages 145-145 A Double Blind Cross-Over Study of Two Oral Formulations of Morphine....Pages 153-158 Non-Narcotics and Co-Analgesics....Pages 159-163 Advanced Cancer: Oncologist, Family Doctor, or Hospice?....Pages 165-171 Why Do Cancer Patients Vomit?....Pages 173-176 Cancer, Vomiting, and Gut Motility....Pages 177-182 The Medical Management of Malignant Bowel Obstruction....Pages 183-188 Etiology of Chemotherapy-Induced Vomiting....Pages 189-193 The Management of Nausea and Vomiting Caused by Anticancer Chemotherapy....Pages 195-203 Front Matter....Pages 205-205 Experimental Models and their Predictive Value in New Drug Development: A Critical Appraisal: I. Toxicity Models.....Pages 209-214 In Vivo Antitumor Models and Drug Development....Pages 215-219 Assays for Clonogenic Human Tumour Cells in Experimental and Clinical Chemotherapy....Pages 221-225 Mechanisms of Resistance to Anticancer Agents....Pages 227-230 The Role of Pharmacokinetics in Drug Design and Use....Pages 231-233 Novel Structures in Development....Pages 235-239 Hypoxia-Mediated Drugs for Radio- and Chemotherapy....Pages 241-247 Induction of Cell Differentiation as a Target for Cancer Therapy....Pages 251-255 Complement Lysis of Tumour Cells Induced by Univalent Antibodies....Pages 257-262 Antibody-Toxin Conjugates as Anti-Cancer Agents....Pages 263-267 Biological Response Modifiers as Anticancer Agents....Pages 271-276 Prostaglandins and Cancer — Therapeutic Potential....Pages 277-281 Front Matter....Pages 205-205 The Therapeutic Potential of Lymphokines in Human Cancer....Pages 283-287 The Interleukins....Pages 289-293 The Role of Polyamines in Cell Differentiation....Pages 295-299 Polyamines, Immune Response and Tumour Growth Control....Pages 301-305 Potential Use of Retinoids in Cancer Prevention and Treatment....Pages 307-311 Front Matter....Pages 313-313 Inosine 5’-Phosphate Dehydrogenase as a Target for Cancer Chemotherapy. Results with 3-Deazaguanine, Tiazofurin and 2- β -D-Ribofuranosylselenazole-4-Carboxamide (PD-111232)....Pages 315-320 Antitumour Activity and Pharmacology of CCRG 81010 (NSC 353451, M&B 39565, 8-carbamoyl-3-(1-chloroethyl)imidazo [5,1-d]-1,1,3,5-tetrazin-4(3H)-one)....Pages 321-325 New Pyrimidine Nucleosides with Potent Antiviral Activity....Pages 327-331 Lipophilic Inhibitors of Dihydrofolate Reductase....Pages 333-337 Review of Phase I-II Clinical Trials with Vinzolidine (VZL), A New Orally Active Semisynthetic Vinblastine Derivative....Pages 339-343 New Developments in Anthracyclines....Pages 345-349 Nitrosoureas-Still a Challenge for Developmental Cancer Chemotherapy....Pages 351-356 Further Objectives in the Development of Platinum Drugs....Pages 357-362 Front Matter....Pages 363-363 The Structure of Active Genes and HMG Proteins in Normal and Transformed Cells....Pages 365-369 Pretreatment of Human Colon Tumor Cells with DNA Methylating Agents Inhibits their Ability to Prevent Chloroethylnitrosourea-Induced DNA Interstrand Crosslinking....Pages 371-375 Structural Requirements for DNA Intercalation and their Relevance to Drug Design....Pages 377-381 Dialkanesulphonates and Chromatin....Pages 383-387 DNA Repair Characteristics of Walker Rat Carcinoma Cells Sensitive and Resistant to Cis -Diamminedichloroplatinum(II) (Cisplatin) and Difunctional Alkylating Agents....Pages 389-394 Is Alkylating Agent “Priming” a DNA Repair Phenomenon?....Pages 395-400 DTIC Induces Damage in Melanoma DNA During Semi-Conservative DNA Synthesis....Pages 401-405 Front Matter....Pages 363-363 The Non-Random Binding of Chlorambucil to DNA in Chromatin....Pages 407-411 Alkylating Antitumour Agents Decrease Histone Acetylation in Ehrlich-Ascites Tumour Cells....Pages 413-417 Influence of the Nuclear Matrix on Nuclear Structure and Response to Anticancer Drugs....Pages 419-424 Cytotoxicity of a Steroid-Linked Mustard (Estramustine) through Non-DNA Targets....Pages 425-429 Potentiation of Cytotoxicity by Inhibitors of Nuclear ADP-Ribosyl Transferase....Pages 431-435 Front Matter....Pages 437-437 Adjuvant Tamoxifen Treatment in Operable Breast Cancer. Should the Treatment Continue for Many Years?....Pages 439-444 Adjuvant Hormonal Therapy of Breast Cancer....Pages 445-449 New Approaches to the Use of Endocrine Therapy in Breast Cancer....Pages 451-455 The Pharmacology of a New Antiestrogen....Pages 457-461 In Vitro Systems for Evaluating Anti-Endocrine Agents....Pages 463-468 Experience of the LHRH Analogue, ICI 118,430, in Carcinoma of the Prostate....Pages 469-473 Complete Androgen Neutralization is Most Important in the Treatment of Prostate Cancer....Pages 475-479 Aminoglutethimide (Orimeten R ): The Present and the Future....Pages 481-483 The Development of New Anti-Endocrine Type Drugs....Pages 485-489 Antiestrogenic Action of Tamoxifen Derivatives in the Human Mammary Carcinoma Cell Line MCF-7....Pages 491-496 Nuclear Estrogen Receptors in Human Tumours of Breast and Uterus....Pages 497-501 Activation and Translocation of Estradiol Receptors in Nitrosomethylurea-Induced Mammary Carcinomas of Rats....Pages 503-507 Hormone Receptors in Gynecological Tumours and their Relevance for Therapeutic Management....Pages 509-511 Front Matter....Pages 513-513 Pretherapeutic in Vitro Prediction of Human Tumour Drug Response....Pages 517-517 Continuous Cell Lines as an Experimental Model for Bladder Cancer Chemotherapy....Pages 517-517 Front Matter....Pages 513-513 Chemical and Biological Properties and Mode of Action of 8-Carbamoyl-3-(2-Chloroethyl)Imidazo [5,1-d]-1,2,3,5-Tetrazin-4(3H)-One, A Novel Broad Spectrum Antitumour Agent....Pages 518-518 Lycurim in Combination Chemotherapy with 3,4,5-Trihydroxybenzo Hydroxamic Acid in Vitro....Pages 518-518 Phenotypic and Genotypic Changes Induced by Thioproline in Cancer Cells in Tissue Culture. Guidelines for Clinical Studies of the Drug....Pages 519-519 Use of Mesna in Reducing Bladder Toxicity....Pages 519-519 Normal Tissue Protection during High-Dose Chemo/Radiotherapy by a “Priming Dose” of Cyclophosphamide....Pages 520-520 5-Acetoxy-2-(4-Acetoxyphenyl)-1-Ethyl-3-Methylindole (D 16726): Preclinical Evaluation of a New Mammary Tumour Inhibiting Drug....Pages 520-520 Rolin Enhancing Effect Upon in Vitro PHA-Proliferation Of Normal Human Peripheral Blood Lymphocytes....Pages 521-521 DTIC: Towards an Appropriate Alternative....Pages 521-521 Drug Resistance of Human Glioma Cell Lines in Culture — The Role of Membrane Transport....Pages 522-522 Lethal and Kinetic Effects of AMSA in a Range of Human Tumour Cell Lines and its Value in Overcoming Induced Drug Resistance in a Series of Murine L5178Y Lymphoma Sublines in Vitro ....Pages 522-522 A Novel HPLC Procedure for Measurement of 6-Mercaptopurine in Plasma....Pages 523-523 Potentiation of the Cytotoxicity of Antibody-Toxin a Chain Conjugates....Pages 523-523 The Effect of Inhibitors of Poly(ADP-Ribose)Polymerase Activity on the Cytotoxic Action of Bifunctional Alkylating Agents and Radiation....Pages 524-524 Characterisation of a Murine Renal Cell Carcinoma Model Potentially Useful in Selecting New Chemotherapeutic Agents....Pages 524-524 Perturbation of S-Adenosylhomocysteine (SAH) and S-Adenosylmethionine (SAM) Levels Following 2’-Deoxycoformycin (dCf) and 2’-Deoxyadenosine (AdR) Administration....Pages 525-525 The Development of Resistance to Methotrexate in a Human Leukaemia (AML) Growing in Nude Mice....Pages 525-525 Inhibitors of Thymidine (TdR) Salvage....Pages 526-526 Studies on the Mechanism of CB 3717 Induced Hepatotoxicity....Pages 526-526 Studies Relating to the Reversal of the Cytotoxicity of the Thymidylate Synthetase Inhibitor CB 3717....Pages 527-527 Studies with Mutant L1210 Cell Lines that have Acquired Resistance to CB 3717....Pages 527-527 Front Matter....Pages 513-513 PAC Polychemotherapy of Stage III + IV Ovarian Carcinoma....Pages 531-531 Weekly Low Dose 4 Epi-Adriamycin-Effective Single Agent Chemotherapy for Advanced Breast Cancer with Low Toxicity....Pages 531-531 Combination Treatment of Malignant Gliomas with Dibromodulcitol (DBD)....Pages 532-532 Initial Clinical Sudies with Iproplatin (CHIP, JM9)....Pages 532-532 Tamoxifen Induced Fluorescence: Spectrofluorimetric Study and Clinical Applications of the Ion-Pair Eosin Tamoxifen....Pages 533-533 EB-Virus Antibody Titers in Two Sisters with Nasopharyngeal Carcinoma and in Several Members of their Family....Pages 533-533 Loco-Regional Chemotherapy with Adriamycin — Intravesical, Intrapleural, and Intrahepatic Administration....Pages 534-534 Etoposide (VP 16–213) as a Fourth Drug in Combination with BVP for Treating Metastatic Germ Cell Tumours....Pages 534-534 Investigations on Leucovorin Rescue after Methotrexate Treatment of Human Osteosarcoma Cells in vitro ....Pages 535-535 Early Clinical Studies with CB 3717 (N-(4-(N-((2-Amino-4-Hydroxy-6-Quinazolinyl)Methyl)Prop-2-Ynylamino)Benzoyl)-L-Glutamic Acid) at the Royal Marsden Hospital....Pages 535-535 DNA Repair Enzymes and Crosslinks: Prevention of BCNU Inter-Strand Crosslinking in vitro by 06-Methyltransferase....Pages 539-539 CIS-Diamminedichloroplatinum Toxicity and DNA Crosslinking in Human Melanoma and Lymphoblast Cells....Pages 539-539 Experimental Trial of New Alkylating Hexitols....Pages 540-540 Sites and Extents of Alkylation in Tumour Cell DNA and their Relation to Antitumour Effects of Dibromodulcitol and Dianhydrogalactitol....Pages 540-540 Hexamethylmelamine: Metabolic Activation and Cytotoxicity....Pages 541-541 Melanogenesis in Human Malignant Melanoma Xenografts....Pages 541-541 DNA Cross-Linking and Cytotoxicity in Normal and Transformed Human Cells Treated in vitro with M&B 39565....Pages 542-542 In Vivo Pharmacokinetics of Daunorubicin in Bone Marrow in Adult Acute Nonlymphocytic Leukaemia....Pages 545-545 Pharmacologic Characterization of Teroxirone (Henkel Compound) in Animals and Humans....Pages 545-545 Pharmacokinetics and Toxicity of VP 16 (Etoposide) in Patients with Gestational Choriocarcinoma and Malignant Teratoma....Pages 546-546 Front Matter....Pages 513-513 Tissue Distribution and Myelotoxicity of Daunomycin in Normal and Leukemic Rats: Rapid Bolus Injection versus Continuous Infusion....Pages 546-546 Metabolism of 4-Hydroxyandrostene-3, 17-Dione by Rat Liver....Pages 547-547 Enzyme Inhibition Studies with Derivatives of Aminoglutethimide....Pages 547-547 The Species Dependent Pharmacokinetics of DTIC....Pages 548-548 Preliminary Studies on the Metabolism and Pharmacokinetics of the Dialkylphenyltriazenes....Pages 548-548 The Role of Glutathione and Glutathione S-Transferases in Acquired Drug Resistance....Pages 549-549 Disposition of Tricyclic Nucleoside 5’-Phosphate (TCN-P, NSC 280594) in Man and Rat....Pages 549-549 Circadian Variation in the Pharmacokinetics of Some Cytotoxic Drugs and Synthetic Steroids....Pages 550-550 Antitumour and Pharmacokinetic Studies with Platinum Coordination Complexes Following Oral Administration....Pages 550-550 Back Matter....Pages 551-585