Cancer Chemotherapy and Selective Drug Development

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.

I: Advances in Cancer Treatment.- 1. New Approaches to Old Problems.- Clinical drug resistance.- New therapies with old drugs.- Antimetabolite combinations possessing enhanced efficacy.- Mismatched bone marrow transplantation.- Prospects for immunotherapy.- 2. Current Clinical Progress with New Agents.- Platinum analogs.- Mitoxantrone: A promising new agent for the treatment of human cancer.- Current clinical progress ― podophyllotoxins.- Pharmacology of nitrosourea anticancer agents.- Current clinical progress with new agents: alkylating agents.- Interferon.- 3. Drug Treatment of Specific Cancers.- Chemotherapy of lung cancer.- Hormone-chemotherapy in treatment of advanced breast cancer.- Chemotherapy of ovarian cancer.- Obstacles to improved end-results in head and neck cancer.- Treatment of disseminated malignant lymphoma.- Malignant disease in childhood.- Chemotherapy of disseminated testicular cancer.- Rational approach to the management of febrile granulocytopenic patients.- II: Control of Pain and Vomiting in Cancer Patients.- Effective use of narcotic analgesics.- A double-blind cross-over study of two oral formulations of morphine.- Non-narcotics and co-analgesics.- Advanced cancer: Oncologist, family doctor or hospice?.- Why do cancer patients vomit?.- Cancer, vomiting and gut motility.- The medical management of malignant bowel obstruction.- Etiology of chemotherapy-induced vomiting.- The management of nausea and vomiting caused by anticancer chemotherapy.- III: Perspective in New Drug Development.- 1. Problems in Achieving Drug Selectivity.- Experimental models and their predictive value in new drug development: A critical appraisals I. Toxicity models.- In vivo antitumour models and drug development.- Assays for clonogenic human tumour cells in experimental and clinical chemotherapy.- Mechanisms of resistance to anticancer agents.- The role of pharmacokinetics in drug design and use.- Novel structures in development.- Hypoxia-mediated drugs for radio- and chemotherapy.- 2. Targetted Chemotherapy.- Induction of cell differentiation as a target for cancer therapy.- Complement lysis of tumour cells induced by univalent antibodies.- Antibody-toxin conjugates as anticancer agents.- 3. Regulatory Molecules in Chemotheraphy.- Biological response modifiers as anticancer agents.- Prostaglandins and cancer ― therapeutic potential.- The therapeutic potential of lymphokines in human cancer.- The interleukins.- The role of polyamines in cell differentiation.- Polyamines, immune response and tumour growth control.- Potential use of retinoids in cancer prevention and treatment.- IV: Design and Development of New Drugs.- Inosine 5’-phosphate dehydrogenase as a target for cancer chemotherapy.- Antitumour activity and pharmacology of CCRG 81010.- New pyrimidine nucleosides with potent antiviral activity.- Lipophilic inhibitors of dihydrofolate reductase.- Review of phase I–II clinical trials with vinzolidine (VZL), a new orally active semisynthetic vinblastine derivative.- New developments in anthracyclines.- Nitrosoureas ― still a challenge for developmental cancer chemotherapy.- Further objectives in the development of platinum drugs.- V: Chromatin as a Target in Cancer Chemotherapy.- The structure of active genes and HMG proteins in normal and transformed cells.- Pretreatment of human colon tumour cells with DNA methylating agents inhibits their ability to prevent chloroethylnitrosourea-induced DNA interstrand crosslinking.- Structural requirements for DNA intercalation and their relevance to drug design.- Dialkanesulphonates and chromatin.- DNA repair characteristics of Walker rat carcinoma cells sensitive and resistant to cis-diamminedichloroplatinum(II) (cisplatin) and difunctional alkylating agents.- Is alkylating agent “Priming” a DNA repair phenomenon?.- DTIC induces damage in melanoma DNA during semi-conservative DNA synthesis.- The non-random binding of chlorambucil to DNA in chromatin.- Alkylating antitumour agents decrease histone acetylation in Ehrlich ascites tumour cells.- Influence of the nuclear matrix on nuclear structure and response to anticancer drugs.- Cytotoxicity of a steroid-linked mustard (Estramustine) through non-DNA targets.- Potentiation of cytotoxicity by inhibitors of nuclear ADP-ribosyl transferase.- VI: Endocrine Therapy.- Adjuvant tamoxifen treatment in operable breast cancer. Should the treatment continue for many years?.- Adjuvant hormonal therapy of breast cancer.- New approaches to the use of endocrine therapy in breast cancer.- The pharmacology of a new antiestrogen.- In vitro systems for evaluating anti-endocrine agents.- Experience of the LHRH analogue, ICI 118,430, in carcinoma of the prostate.- Complete androgen neutralization is most important in the treatment of prostate cancer.- Aminoglutethimide (OrimetenR): The present and the future.- The development of new anti-endocrine type drugs.- Antiestrogenic action of tamoxifen derivatives in the human mammary carcinoma cell line MCF-7.- Nuclear estrogen receptors in human tumours of breast and uterus.- Activation and translocation of estradiol receptors in nitrosomethylurea-induced mammary carcinomas of rats.- Hormone receptors in gynecological tumours and their relevance for therapeutic management.- Abstracts of Proffered Papers and Posters.- 1. New Agents: Experimental Studies.- Pretherapeutic in vitro prediction of human tumour drug response.- Continuous cell lines as an experimental model for bladder cancer chemotherapy.- 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.- Lycurim in combination chemotherapy with 3,4,5-trihydroxybenzo hydroxamic acid in vitro.- Phenotypic and genotypic changes induced by thioproline in cancer cells in tissue culture.- Use of MESNA in reducing bladder toxicity.- Normal tissue protection during high-dose chemo/radiotherapy by a “priming dose” of cyclophosphamide.- 5-Acetoxy-2-(4-acetoxyphenyl)-1-ethyl-3-methylindole (D 16726): Preclinical evaluation of a new mammary tumour inhibiting drug.- Rolin enhancing effect upon in vitro PHA-proliferation of normal human peripheral blood lymphocytes.- DTIC: Towards an appropriate alternative.- Drug resistance of human glioma cell lines in culture ― the role of membrane transport.- 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.- A novel HPLC procedure for measurement of 6-mercaptopurine in plasma.- Potentiation of the cytotoxicity of antibody-Toxin A chain conjugates.- The effect of inhibitors of poly(ADP-ribose)polymerase activity on the cytotoxic action of bifunctional alkylating agents and radiation.- Characterisation of a murine renal cell carcinoma model potentially useful in selecting new chemotherapeutic agents.- Perturbation of S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM) levels following 2?-deoxycoformycin (dCf) and 2’-deoxyadenosine (AdR) administration.- The development of resistance to methotrexate in human leukaemia (AML) growing in nude mice.- Inhibitors of thymidine (TdR) salvage.- Studies on the mechanism of CB 3717 induced hepatotoxicity.- Studies relating to the reversal of the cytotoxicity of the thymidylate synthetase inhibitor CB 3717.- Studies with mutant L1210 cell lines that have acquired resistance to CB 3717.- 2. New Agents/Combinations: Clinical Studies.- PAC polychemotherapy of stage III + IV ovarian carcinoma.- Weekly low dose 4 epi-adriamycin-effective single agent chemotherapy for advanced breast cancer with low toxicity.- Combination treatment of malignant gliomas with dibromodulcitol.- Initial clinical studies with iproplatin (CHIP, JM9).- Tamoxifen induced fluorescence: Spectrofluorimetric study and clinical applications of the ion-pair eosin tamoxifen.- EB-virus antibody titers in two sisters with nasopharyngeal carcinoma and in several members of their family.- Loco-regional chemotherapy with adriamycin - intravesical, intrapleural and intrahepatic administration.- Etoposide (VP 16–213) as a fourth drug in combination with BVP for treating metastatic germ cell tumours.- Investigations on leucovorin rescue after methotrexate treatment of human osteosarcoma cells in vitro.- Early clinical studies with CB 3717 at the Royal Marsden Hospital.- 3. New Agents: Cytotoxic Mechanisms.- DNA repair enzymes and crosslinks: Prevention of BCNU inter-strand crosslinking in vitro by 06-methyltransferase.- Cis-diamminedichloroplatinum toxicity and DNA crosslinking in human melanoma and lymphoblast cells.- Experimental trial of new alkylating hexitols.- Sites and extents of alkylation in tumour cell DNA and their relation to antitumour effects of dibromodulcitol and dianhydrogalactitol.- Hexamethylmelamine: Metabolic activation and cytotoxicity.- Melanogenesis in human malignant melanoma xenografts.- DNA cross-linking and cytotoxicity in normal and transformed human cells treated in vitro with M&B 39565.- 4. New Agents: Metabolism and Pharmacokinetics.- In vivo pharmacokinetics of daunorubicin in bone marrow in adult acute nonlymphocytic leukaemia.- Pharmacologic characterisation of teroxirone (Henkel compound) in animals and humans.- Pharmacokinetics and toxicity of VP16 (etoposide) in patients with gestational choriocarcinoma and malignant teratoma.- Tissue distribution and myelotoxicity of daunomycin in normal and leukaemic rats: Rapid bolus injection versus continuous infusion.- Metabolism of 4-hydroxyandrostene-3,17-dione by rat liver.- Enzyme inhibition studies with derivatives of aminoglutethimide.- The species dependent pharmacokinetics of DTIC.- Preliminary studies on the metabolism and pharmacokinetics of the dialkylphenyltriazenes.- The role of glutathione and glutathione S-transferases in acquired drug resistance.- Disposition of tricyclic nucleoside 5?-phosphate (TCN-P, NSC 280594) in man and rat.- Circadian variation in the pharmacokinetics of some cytotoxic drugs and synthetic steroids.- Antitumour and pharmacokinetics studies with platinum coordination complexes following oral administration.- Author Index.