Cancer : Experiments and Concepts

This book really ought to be read on vacation, just for enjoyment. Granted, cancer is, literally, a deadly serious matter, and cancer research is primarily a part of medicine with Hippocrates in its back­ ground. Yet, cancer research is also natural science, and as such it yields the joys and sorrows of any science. The cancer problem is also a brain teaser, a challenge for the curious. This introductory report on experimental cancer research is there­ fore directed to curious students of many disciplines: naturally to medical students, but also to chemists and physicists who have an interest in biological phenomena; biology students will surely en­ counter pr9blems peculiar to their field in what is supposedly a medi­ cal one. We have attempted to write without assumptions to a certain degree, for a chemist is essentially in over his head in medicine, and a physician has only the slightest idea of the chemical problems im­ portant in cancer research. We had no intention of giving a complete view of the field, and from the large number of different lines of development we have chosen only a few. Chemotherapy, as an ex­ ample, has been treated quite cursorily, along with RNA tumor viruses, although it is possible that just these subjects are especially important for human tumors. Tumor induction via radiation could only be mentioned in passing, in spite of its great practical significance; similarly the role of hormones was only intimated.

The impetus for experimental cancer research.- Melancholia carcinogenica.- Cigarette smoking and lung cancer.- Our daily carcinogens.- The Turkey disaster and the anatoxin story.- Pesticides or humanicides.- Asbestos lung cancer.- “Morality” and genital cancer.- Nuns have an increased risk of breast cancer.- Stomach cancer in the poor.- The cancer staircase again.- Summary and prognosis.- A first step: elucidation of tar cancer.- Experimental tumor research before Yamagiwa.- Yamagiwa and Ichikawa induce the first experimental tumors.- A few grams of 3,4-benzpyrene from two tons of tar.- Polycyclic hydrocarbons can induce other than skin tumors.- Theories on the chemical mechanism of hydrocarbon carcinogenesis.- Polycyclic hydrocarbons are bound to protein.- Proteins could be growth regulators.- Polycyclic hydrocarbons also react with DNA.- Summary.- Aromatic amines: activation through metabolism.- Aniline cancer: aniline itself is not to blame.- Butter yellow and the carcinogenic azo dyes.- Acetylaminofluorene, an aborted insecticide.- Not all aminoazo dyes are carcinogenic.- Aromatic amines must be converted to carcinogens via metabolism.- Ortho ring-hydroxylation: increase in carcinogenicity.- N-Hydroxylation, a necessary but not always sufficient step for activation of aromatic amines.- Aminoazo dyes also form N-hydroxy derivatives.- Azo dyes react with methionine.- N-Hydroxy esters as final steps in the activation to the actual carcinogen (“ultimate carcinogens”).- Which esters are the “ultimate carcinogens”?.- The N-Hydroxylation hypothesis has its difficulties.- Carcinogenic aromatic amines are bound to protein.- The stronger the carcinogen, the better the binding to protein.- Carcinogenic aromatic amines are bound preferentially to h2-proteins.- H2-Proteins are greatly reduced in hepatomas.- H2-Proteins inhibit the growth of cell cultures (in vitro).- Summary.- A closer look at chemical carcinogenesis: quantitative aspects.- The Iball index.- Dose-response curves.- Carcinogenic effects are irreversible.- Carcinogenesis as an accelerated process.- There are no subthreshold carcinogenic doses.- Carcinogens differ in their acceleration behavior.- Biological significance of acceleration.- Latent periods and tumor yields are not necessarily coupled.- Summary.- Multiple step hypothesis of chemical carcinogenesis.- The Berenblum-Mottram experiment: two steps lead to papillomas.- Not only croton oil can promote.- Irritation and carcinogenesis.- Rous discovers the two-step process in the rabbit’s ear.- Croton oil is not a “chemical cork borer”.- Two steps are an insufficient description.- Promotion is reversible.- Initiation is irreversible.- The general validity of the two-step hypothesis is questionable.- Syncarcinogenesis: carcinogens can substitute for each other.- Syncarcinogenesis and cocarcinogenesis: more than a question of semantics.- Summary.- Host factors in tumor induction.- The path to the inner sanctum.- Activation of carcinogens as a limiting step in chemical carcinogenesis.- Danger for carcinogens: detoxication reactions.- Reactivation of glucuronides in the urine: bladder cancer.- Phase rule of carcinogenesis.- Tumor cells can be dormant.- Paradoxical influences of nutrition.- Hormone-dependent tumor growth.- Tumor cells must slip past the immune response.- The pattern of metastases is also determined by the host.- Summary: Host factors, or the “game plan” of tumor development.- Tissue-specific growth regulation (“chalones”).- Cybernetic model of tissue-specific growth regulation.- Regulation of liver regeneration by humoral inhibitoi.- Skin as a regenerating system (“wound healing”).- Stress hormones suppress mitoses.- Epidermal chalone in an in vitro experiment.- Tentative characterization of the epidermal chalone.- Chalones can block mitosis directly.- Alternatives to the chalone theory: wound hormones.- Chalones as repressors.- Tumor cells as dialone mutants.- Substitution therapy of chalone-deficient tumors.- Chalones, a general principle?.- “Visible” regulation fields.- Summary.- Carcinogenesis and cell organelles.- The inner architecture of a cell.- Isolation of cell organelles in the ultracentrifuge.- The cell as a chemical factory.- The nucleus and carcinogenesis.- Lysosomes.- Carcinogenic hydrocarbons are taken up by lysosomes.- Lysosomal DNases as carcinogens.- Cell membranes, cell sociology, and carcinogenesis.- Cell sociology in tissue culture.- Membrane changes in tumor cells.- Neuraminic acid and phospholipids “negativize” cell membranes.- Binding forces betwen cells.- Cell contacts are specific.- Normal cells can regulate tumor cells.- Carcinogenesis from the membrane perspective.- A small natural philosophy of cell membranes.- Is there really a “contact inhibition”? Growth factors vs. contact inhibition.- Inhibitors guarantee “contact inhibition”.- Membranes regulate cell growth.- Summary.- The mitochondria and Warburg’s cancer theory.- Energy production in the respiratory chain.- Glycolysis.- Warburg’s manometric methods for measurement of respiration and glycolysis.- Cancer cells glycolyze.- Carcinogens damage respiration.- Omne granum e grano.- Path to the tumor cell: selection of cells capable of glycolysis.- Glycolytic energy is “inferior”.- Oxygen deficiency in tumor tissue.- Tumor development in two phases.- Cancer prevention by support of respiration.- Not all tumors show the Warburg effect.- Glycolysis and growth rate of a tumor are correlated.- Summary.- Tumor immunology: basics of a host-specific tumor defense.- Donor-recipient relationships in transplantations.- Transplantable tumors.- Early hopes for a protective injection against tumors.- Tumor-specific antigens in genetically identical animals.- Immune animals can only handle a few cells.- The defense against tumor cells can be pretransferred to a test tube.- Individual tumors have individual antigens.- Virus-induced tumors also have tumor-specific antigens.- Tumor-specific antigens evoke a true immune reaction.- The rejection of syngenic tumor transplants as a model for defense against primary tumors.- A rat can mobilize defenses against its own primary tumor.- Do tumor-specific antigens necessarily belong to tumor growth?.- Are there really tumor-specific antigens?.- Antilymphocytic serum promotes tumor growth.- Chemical carcinogens are immunosuppressives.- The double effect of chemical carcinogens.- Immune therapy.- Enhancement: The paradoxical increase in tumor growth by immunization.- Summary.- Natural history of some tumor viruses.- Chicken leukemias.- Rous sarcoma virus (RSV).- Shope papilloma virus in rabbits.- Bittner’s milk factor.- Polyoma.- Mouse leukemia and mouse sarcoma viruses.- Human medical digression.- Human and monkey viruses: adenoviruses and SV-40.- Classification of animal viruses.- Summary.- DNA tumor viruses in tissue culture.- Counting live viruses in the plaque test.- Transformation in vitro.- Transformation and cell death.- The cell can choose between production and transformation.- Masked viruses.- On the trail of masked tumor viruses-virus-specific antigens.- On the trail of masked DNA tumor viruses: virus-specific ribonucleic acids.- Virus DNA is retained in transformed cells.- Unmasking of the tumor virus: cell fusion forces virus production.- The virus DNA is responsible for transformation.- A DNA tumor virus has only a few genes.- Which genes are suspected of transformation?.- The role of the cell once more.- A side glance at RNA tumor viruses.- Summary.- Genetics and cancer.- Chromosome alterations in tumor cells: the Philadelphia chromosome.- Inheritance factors in tumor induction: animal strains with guaranteed tumor incidence.- Tumor induction by species crossing: tumor-bearing hybrids.- “Artificial” carcinogenesis and heredity.- Mutagenic and carcinogenic activity can be correlated.- Mutation hypothesis as a theoretical necessity.- Objections to the mutation theory.- Concluding words on the mutation theory.- Summary.- DNA and carcinogenesis.- Tumor DNA as a carcinogen.- Infectious tumor virus DNA, a potent “chemical carcinogen”.- Carcinogens disturb DNA synthesis.- Carcinogens disturb the formation of adaptive enzymes.- Chemical carcinogens react with the cell DNA.- Covalent bonds between carcinogens and guanine.- Eventual consequences of the reactions with guanine.- Cells can repair defective DNA.- Neoplastic transformations work better with proliferating cells.- Binding without bonds: intercalation.- Summary.- A few models for tumor chemotherapy.- Alkylating agents.- Nitrogen mustard with a fuse.- Direct attack on tumor DNA.- Antimetabolites in tumor therapy.- Immunosuppressive side effects.- Asparaginase starves tumor cells.- Labilization of tumor cells by excessive acid.- Many tumor cells are especially heat-sensitive.- Multistep therapy.- Chain reactions lead to a “natural” cell death.- Virus tumor therapy?.- A new star?.- Summary.- Dogmas of tumor induction.- Not all tumor cells grow faster.- Dogma of transformation.- Dogma of selection.- Dogma of isolation.- Transplantability does not have to be a criterion of a tumor.- Dogma of irreversibility.- Dogma of the reprogramed tumor cell.- Summary.- Tumor theories in dialogue.- Summary: a program for a computer.- Appendix: morphological glossary.- Reference works.