Showing papers on "Carcinogenesis published in 1977"

A Potent Pancreatic Carcinogen in Syrian Hamsters: N-Nitrosobis(2-oxopropyl)amine

Abstract: N-Nitrosobis(2-oxopropyl)amine (BOP), a further postulated beta-metabolite of di-n-propylnitrosamine, induced a high incidence of pancreatic duct adenomas and adenocarcinomas as early as 13 weeks in Syrian hamsters receiving weekly sc injections for life and a few pancreatic adenomas, after 28 weeks, in those given a single sc dose. Compared to related compounds, N-nitrosobis(2-hydroxypropyl)amine and N-nitrosobis(2-acetoxy-propyl)amine which are also pancreatic carcinogens, BOP induced only a few neoplasms of the lung, liver, and kidney and none in the nasal cavity, larynx, and trachea. The results therefore indicate progress in developing a more specific model for pancreatic carcinogenesis studies.

Induction of morphological transformation in mouse C3H/10T1/2 clone 8 cells and chromosomal damage in hamster A(T1)C1-3 cells by cancer chemotherapeutic agents.

Abstract: Various cancer chemotherapeutic agents including alkylating agents, antimetabolites, and antibiotics or natural products were studied for their ability to produce morphological transformation in the C3H/10T1/2 clone 8 mouse cell line and chromosomal damage in the A(T1)C1-3 hamster cell line following a 24-hr exposure of each agent at different concentrations. Those drugs that were known to be carcinogenic in vivo also produced morphological transformation and chromosomal damage, whereas those agents that have not been shown to be carcinogenic in vivo produced neither transformation nor chromosomal lesions. The concentrations used for these studies were in general similar to those actually reached in the plasma of patients treated with these same drugs for malignant, as well as certain nonmalignant, conditions.

Lymphoma in cotton-top marmosets after inoculation with Epstein-Barr virus: tumor incidence, histologic spectrum antibody responses, demonstration of viral DNA, and characterization of viruses.

Abstract: 6 of 20 cotton-top tamarins (Saguinus oedipus) inoculated with Epstein-Barr virus (EBV) developed diffuse malignant lymphoma resembling reticulum cell or immunoblastic sarcoma of man. Hyperplastic lymphoreticular lesions were induced in three additional animals; in two instances the hyperplastic lesions regressed. Inapparent infection with development of antibody occured in eight animals. In two animals there was no evidence of EBV infection. One animal died in the first week after inoculation of parasitic infection. 10 animals uninoculated or mock-inoculated developed neither lymphoproliferative disease nor antibody. The malignant lymphoma appeared to arise from a cell with an uncleaved vesicular nucleus found in the center of the germinal follicle. The prominent cytologic features of this cell were extensive formation or rough endoplasmic reticulum and elaboration of the cytoplasmic membrane with microvilli. Cell lines derived from these tumors did not have receptors for complement. IgFc, or sheep erythrocytes, and the cell lines adhered to glass and plastic. EB nuclear antigen was found in imprints of two lymph nodes, one with lymphoma and one with hyperplasia. EB virus DNA was detected directly in the tumors of three animals and in cell lines from two lymphomas. Typical herpes virus particles were found in supernatant fluids from cell lines obtained from lymph nodes with tumors and hyperplasia, as well as in lines derived from blood leukocytes of marmosets with inapparent infection. These virus preparations had the biologic property characteristic of EBV, namely, stimulation of cellular DNA synthesis and immortalization of human lymphocytes. The virus derived from two cell lines was neutralized by reference human sera with EBV antibody and not by antibody-negative human sera. The virus derived from the experimental lesions is thus indistinghishable from human EBV. The marmoset has enhanced susceptibility to oncogenesis by EB virus. Among identified factors which may play a role in the heightened tumorigenicity of EB virus in this species are the increased production of virus by transformed cells and the absence of membrane receptors for complement or IgFc on transformed cells.

Marked Differences in the Tumor-initiating Activity of Optically Pure (+)- and (−)-trans-7,8-Dihydroxy-7,8-dihydrobenzo(a)pyrene on Mouse Skin

Abstract: The ability of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to initiate skin tumors in mice was determined with a two-stage tumorigenesis system A single application of 50 to 200 nmoles of (+)- or (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to the backs of CD-1 mice followed by twice-weekly applications of 12-O-tetradecanoyl-phorbol-13-acetate revealed that the (-)-enantiomer was 5- to 10-fold more potent than was the (+)-enantiomer as a tumor initiator at the three dosage levels tested When the tumor-initiating activities of the (+)0 and (-)-enantiomers of trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene were compared to the activity of benzo(a)pyrene at an equimolar dose, the (-)-enantiomer was more active while the (+)-enantiomer was considerably less active This is the first report of differences in the carcinogenic activity between optical enantiomers

Photosensitizing effects of 8‐methoxypsoralen on the skin of hairless mice—11. train and spectral differences for tumorigenesis

Abstract: — The photosensitizing effects of 8-methoxypsoralen on the skin of two strains of hairless mice were studied using fractionated exposure to UV Spectral dependent differences for tumorigenesis were studied by comparing the tumor responses to three different spectra; the exposure levels for each spectrum here adjusted in proportion to their relative efficiencies for tissue damage and cytokinetic responses. There were no strain differences in the spectral dependent induction of cutaneous damage or estimates of the photomediated interstrand cross-linking of epidermal DNA by 8-methoxypsoralen. Squamous cell carcinomas were induced in the photosensitized skin of both strains of mice after fractionated exposures to emissions at principally 365 nm. Exposures to a broader spectrum of light resulted in the earlier appearance of tumors in the photosensitized skin of the SKH: hairless-1 mice, but produced few or no tumors in the HRS/J/Anl strain. In a second series of experiments; mice were exposed to a fluorescent sun lamp prior to each combined treatment of psoralen and exposure at 365 nm to determine the influence of shorter wavelengths of UV on the tumor response. These treatments resulted in an enhanced expression of tumors in the SKH:hairless-1 mice as compared to the HRS/J/Anl strain. Under the conditions of the experiments, the marked strain and spectral dependent differences for tumorigenesis demonstrated that although treatments that induce psoralen photoadducts also induce tumors. there was no apparent quantitative correlation between the occurrence of DNA cross-links and the incidence of tumors. The results also suggested, first, an interaction between UV (280–400 nm) induced photoproducts and psoralen photoadducts and secondly, a strain difference in the oncogenic effects of this interaction.

Genetic control of radiation leukemia virus-induced tumorigenesis. I. Role of the major murine histocompatibility complex, H-2.

Abstract: Resistance to radiation leukemia virus-induced leukemogenesis is associated with the H-2D region of the H-2 complex, or with closely linked loci. The H-2Dd allele confers resistance ot the disease, while the H-2D-Q and H-2Ds alleles are associated with susceptibility. It is not clear whether Ir genes, or an alternative mechanism are responsible for the observed H-2-linked resistance to the disease.

A test for mutation theory of cancer: carcinogenesis by misrepair of DNA damaged by 4-nitroquinoline 1-oxide.

Abstract: Evidence for a mutation theory of cancer is presented by reviewing the experimental work on 4-nitroquinoline 1-oxide (4NQO) carcinogenesis. 4NQO almost completely mimics u.v. light and produces 4NQO-purine adducts on DNA. When 4NQO-treated cells are held in liquid medium under appropriate conditions, the 4NQO adducts disappear from DNA, in parallel to decrease of premutational damage in Escherichia coli, or pretransformational damage in cultured mouse cells. Post-treatment with caffeine greatly diminishes the yields by 4NQO of mutants in E. coli, malignant transformants in cultured mouse cells and tumour nodules in the lung of mice. Potentially tumourigenized stem cells in the lung remain sensitive to selective killing by caffeine for at least 5 days after 4NQO treatment, in spite of their DNA being apparently replicated, an indication that carcinogen-damaged DNA in the stem cell can be transmitted to its successive daughter stem cells for many generations. This peculiar characteristic is discussed as a possible lead to the crux of the mutation theory of cancer in vivo, and a model for carcinogenesis is proposed.

Malignancy and transformation: expression in somatic cell hybrids and variants.

Abstract: Publisher Summary This chapter reviews the genetic basis for the regulation of the expression of transformed or tumor cells in vitro and in vivo. It focuses on the studies involving somatic cell hybrids and phenotypic revertants derived from transformed cells and cell lines that display temperature-dependent expression of transformed characteristics. The role of genetic factors in tumorigenesis and in vitro transformation is well documented. This association exists for a variety of virological, chemical, and physical agents known to induce tumors. The phenomenon of cell fusion permits the introduction of the entire genome of one cell into another. The capability to generate and select for hybrid cells of appropriate properties offers opportunities to study the genetic regulation of tumor cells. It is also observed that suppression of malignancy can occur in intraspecies cell hybrids between a malignant and a nonmalignant cell. Suppression occurs with a large variety of tumors of different origin and at different initiation events.

Newer insights into the pathogenesis of liver cancer.

Abstract: A new hypothesis leading to a new model of liver carcinogenesis is described; it is based on the acquisition by carcinogen-altered hepatocytes during initiation of a new functional handle--resistance to the cytotoxicity of a carcinogen--and on the ability of such cells to proliferate in an environment that prevents proliferation of normal hepatocytes. The creation of such a differential environment now enables a quantitative analysis for initiation, the beginning synchronization of the putative premalignant hepatocytes for about 15 cell cycles, the study of the pattern of growth of such resistant cells to form nodules that have some resemblance to the organizational pattern of fetal liver, the analysis of the appearance of distinctive positive and negative markers for these cells, and the further investigation of the development of liver cancer from such cells. The remarkable similarity in overall pattern betweeen the development of cancer in the skin and in the liver with chemicals and the possible role of both somatic mutation and neodifferentiation in carcinogenesis are briefly discussed.

Phenotypic markers in human skin fibroblasts as possible diagnostic indices of hereditary adenomatosis of the colon and rectum.

Abstract: Hereditary adenomatosis of the colon and rectum (ACR) and its Gardner's syndrome variant, an autosomal dominant trait, indicate a propensity for neoplasia. The present study describes the growth abnormalities of cultured human skin fibroblasts derived from normal-appearing cutaneous biopsies of ACR genotypes and a portion of the clinically asymptomatic ACR progeny, first filial generation, and their differential susceptibility to transformation by Kirsten murine sarcoma virus. These skin fibroblasts, but not cells derived from unaffected individuals, showed lack of contact inhibition, decreased serum requirement for growth, elevated levels of plasminogen activator, and alterations in the intracellular distribution of actin cables; they did not, however, grow in the absence of anchorage, nor did they form palpable tumors in congenitally athymic BALB/c nu/nu mice, and they were normal with regard to cholesterol feedback regulation. Skin fibroblasts from ACR subjects were 100- to 1000-fold more susceptible to transformation by the Kirsten murine sarcoma virus than were normal cells. The virally transformed skin fibroblasts were anchorage-independent and formed tumors in athymic mice. These growth abnormalities represent steps in the changing phenotypic expression of cells undergoing neoplastic transformation. Identification of abnormal expressions associated with oncogenesis may facilitate their use as diagnostic indices for the detection of latent forms of colon cancer in man.

Developmental decline in DNA repair in neural retina cells of chick embryos: persistent deficiency of repair competence in a cell line derived from late

Abstract: Neural retinas of 6-day-old chick embryos synthesize DNA and are able to carry out DNA excision repair. However, in contrast to the situation in human cells, the maximum rate of repair induced by N-acetoxy acetylaminofluorene (AAAF) is no greater than that induced by methyl methanesulfonate (MMS). With advancing differentiation of the retina in the embryo, cell multiplication and DNA synthesis decline and cease, and concurrently the cells lose the ability to carry out DNA excision repair. Thus, in 15-16-day embryos, in which the level of DNA synthesis is very low, DNA repair is barely detectable. If retinas from 14-day embryos are dissociated with trypsin and the cell suspension is plated in growth- promoting medium, DNA synthesis is reinitiated; however, in these cultures there is no detectable repair of MMS-induced damage, and only low levels of repair are observed after treatment with AAAF. A cell line was produced, by repeated passaging of these cultures, in which the cell population reached a steady state of DNA replication. However, the cell population remained deficient in the ability to repair MMS-induced damage. This cell line most likely predominantly comprises cells of retino-glial origin. Possible correlations between deficiency in DNA repair mechanisms in replicating cells and carcinogenesis in neural tissues are discussed.

α‐Fetoprotein‐containing cells in the early stages of liver carcinogenesis induced by 3′‐methyl‐4‐dimethyl‐aminoazobenzene and 2‐acetylaminofluorene

Abstract: The morphology of rat liver cells containing alpha-feto-protein (AFP) during early stages of carcinogenesis induced by 3'methyl-4-dimethylaminoazobenzene and 2-acetylaminofluorene was investigated. Indirect immunofluorescence was used to detect AFP. AFP was not found in the cells of hyperplastic nodules but was present in the cells located in areas of transitional cell proliferation. A large proportion of the AFP-positive cells formed gland-like structures. The cells containing AFP were at various levels of differentiation according to morphological criteria. Poorly differentiated, small, basophilic cells were predominant amont the AFP-positive population. The most highly differentiated AFP-positive cells had the morphology of hepatocytes.

The viral etiology of cancer: a realistic approach.

Abstract: The etiology of cancer resembles that of many other diseases in that multiple factors may be required. Because of this, the role or viruses in the etiology of human cancers is especially difficult to assess. When animal tumor systems were used as models, the roles of various predisposing characteristics in virus oncogenesis were elucidated. Extrapolation of these findings to the human diseases suggests the importance of genetics, age, hormones, immune competence, and stress in determining susceptibility to tumor development in individuals infected with an oncogenic virus. The importance of cofactors in induction of those human tumors most strongly associated with virus infection, including Burkitt's lymphoma, nasopharyngeal carcinoma, cerviccal carcinoma, acute myelogenous leukemia, and breast cancer, is reviewed. Understanding of the role of these cofactors in virus carcinogenesis may lead to disease prevention through elimination of one or more of the cofactors.

Diaplacental carcinogenesis: tumor localization and tumor incidence in NMRI mice after diaplacental initiation with DMBA and urethane and postnatal promotion and the phorbol ester TPA in a modified 2-stage Berenblum/Mottram experiment.

Abstract: Diaplacental initiation with the carcinogens DMBA or urethane followed by repeated topical treatment of mice of the F1 generation with the tumor promoter TPA leads to the formation of benign and malignant tumors on the skin of the back as well as in other tissues and organs. The tumor yield in this modified 2-stage Berenblum/Mottram experiment considerably exceeds the number of spontaneously formed tumors and of tumors produced by initiation alone. Further differences can be demonstrated in the malignancy rate, the formation of multiple tumors in various organs, additional non-neoplastic alterations and in a reduction of the lifetime of the animals. The effect of the tumor promoter TPA is not restricted to carcinogenesis in the back skin. Obviously, TPA is able to activate inititated tumor cells in internal organs to form tumors. This, in turn, implies the absorption of the substance via the blood vessels and its distribution throughout the body. The preferential occurrence of tumors in the genital tract of female mice (carcinomas and sarcomas of the vaginal wall, granulosa cell tumors of the ovaries) points to a possible hormonal involvement; in this context, relevance to prenatally induced tumors in human pathology is discussed. The results emphasize the important role of prenatal carcinogenesis and indicate the increased risk to man by either prenatal initiation or postnatal promotion.

Cancer: Experiments and Concepts

Abstract: 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.

Immunodiagnostic potential of a virus-coded, tumor-associated antigen (ag-4) in cervical cancer

Abstract: The central theme of this communication is the recognition of an immunodiagnostic potential in a herpes virus antigen, the molecular interrelationship of which with cervical tumor cells is described. In addition to the productive infection caused by herpes simplex virus type 2 (HSV-2) we are confronted by latency and, as suggested by recent studies, by cancer. These different types of virus-host cell interactions are discussed at the host, as well as at the cellular level. A defined level of molecular interaction between host and viral gene products must exist if the virus is to co-exist with the host, as is the case in latency and carcinogenesis. The molecular interpretations posit the presence, in the squamous cervical tumor cells, of a product of the expression of the viral genome that has immunodiagnostic potential. The antigen designated AG-4 fulfills these predictions and appears to have immunodiagnostic potential. AG-4 is present in cervical tumor biopsies, but not in normal cervical tissue. It is a structural component of the HSV-2 virion that, in tissue cultures infected with HSV-2, is synthesized preferentially under conditions that prevent the normal replication of the virus. In view of its structural nature it is most probably virus-coded. AG-4 antibody identified in complement fixation assays with antigen prepared in tissue culture, disappears following successful tumor removal and reappears during cancer recurrence. This antibody also potentially identifies those patients with cervical atypia that are at high risk of neoplastic progression. The clinical benefits of the assay are evident.

Repair of DNA damage induced by ionizing radiation and benzo[a]pyrene in mammalian cells.

Abstract: The biological effects of DNA‐damaging agents are codetermined by the structural characteristics of the lesions, the quality and extent of the local distortion of DNA and chromatin structure, and the mode(s) of damage processing used by a given type of cell. Persistent damage (i.e., damage that is not removed before it is reached by DNA replication) may be mostly responsible for metagenesis and carcinogenesis. To understand the effects of environmental physical and chemical DNA‐damaging agents on human health, the mechanisms of damage processing used by human cells have to be elucidated. We report our studies of the excision of gamma‐ray products of the 5,6‐dihydroxydihydrothymine type (tγ o2) in normal human fibroblasts and in fibroblasts from patients with the hereditary diseases Fanconi's anemia (FA) and ataxia telangiectasia (AT). Both diseases are characterized by chromosomal instability and increased susceptibility for the development of cancer. Decreased capacities of nuclear and whole cell sonicat...

Relationship between differentiation and carcinogenesis.

Abstract: Carcinomas are caricatures of the normal process of tissue renerwal. Malignant stem cells proliferate, and some of their progeny differentiati and form benign functional cells. In teratocarcinoma, it has been demonstrated that the stem cells are the target in carcinogenesis and become malignant stem cells. The normal and malignant stem cells are equally differentiated. Normal stem cells of breast and colon are no more differentiated than their counterparts. If they are the target in carcinogenesis, then the concept of dedifferentiation is bypassed as an explanation for the undifferentiated appearance of tumors. While the focus of this meeting has been on mutation as an explanation for carcinogenesis, in this paper emphasis is placed on electrophilic carcinogens acting on cytoplasmic molecules that control gene expression. A type of gene control in addition to the operon is postulated.

Mammary tumors and mammary tumor virus expression in hybrid mice of strains C57BL and GR.

Abstract: Mammary tumorigenesis in genetic crosses between the high mammary tumor incidence GR and the low incidence C57BL mouse strains is highly correlated with murine mammary tumor virus expression in milk. Although the F1 and first backcross females had a mammary tumor incidence which was consistent with a single dominant gene segregation, the tumor incidence in the critical second backcross segregants disproved the single gene hypothesis. Genetic factors were clearly involved in regulation of virus expression which in turn correlated with both tumor incidence and tumor latency; these complex phenotypes are however best explained as threshold or quasicontinuous characters. As predicted from this model, the age specific incidence of mammary tumors showed a broad peak at 14-19 mo of age with no evidence of an early or late phase. Hematopoietic tumors showed no correlation with virus expression or mammary tumorigenesis suggesting different etiologies for these tumors.

Development of hemangiosarcomas in B6C3F1 mice fed 2‐methyl‐1‐nitroanthraquinone

Abstract: Subcutaneous hemangiosarcomas developed in 97% of 172 B6C3F1 mice of both sexes fed either 0.03% or 0.06% 2-methyl-1-nitroanthraquinone in the diet. There was no significant relationship to dose or sex. In addition, similar vascular tumors occurred in the mesentery of 14 mice. 2-Methyl-1-nitro-anthraquinone is carcinogenic in B6C3F1 mice when given in food. One of 97 control mice had a splenic hemangiosarcoma.

THE MURINE Ah LOCUS AND DYSMORPHOGENESIS

Abstract: Many environmental pollutants and other polycyclic aromatic compounds induce certain cytochrome P-450-mediated monooxygenases which, in turn, metabolize the inducers at increased rates. This induction process, controlled by the Ah locus, is present in almost all tissues of the mouse. Genetic differences that have been shown to be associated with the Ah locus (because of increased steady-state levels of reactive intermediates) include an increased susceptibility to chemical carcinogenesis, mutagenicity, and drug toxicity. There is evidence for the Ah locus in the human. Pregnant mice received a single intraperitoneal injection of 3-methylcholanthrene, 7, 12-dimethyl-benz[a]anthracene, or benzo[a]pyrene on day 7, day 10, or day 12 of gestation, and the uterine contents were examined on day 18. Striking (3- to more than 10-fold) increases in the incidence of stillborns, resorptions, small for gestational age, and malformations were seen in individuals genetically “responsive” at the Ah locus, compared with individuals genetically “nonresponsive” at this locus. These data suggest that a single gene (or small number of genes) controlling the metabolism of foreign compounds in tissues of the individual fetus rather than of the mother may be important in the etiology of certain birth defects.

DNA injuries, their repair, and carcinogenesis.

Abstract: The cancer cell is characterized by a distortion of gene expression that makes it escape normal control of at least some cellular functions, and provides it with survival advantages over many, if not most, cells of the organism. The special properties of the cancer cells are transferred from one generation of cells to the next. The conversion of a normal into a cancer cell is achieved by DNA and RNA viruses, ultraviolet light, ionizing radiation, and chemical carcinogens. This process is usually believed to occur in two stages: initiation and promotion. Although the molecular events responsible for initiation and promotion are not known, it seems logical to assume that the initiation process results from the interaction between the physical, biological, or chemical agent and the genome (for review [316]).

Comparative immunology of carcinogenesis by DNA viruses.

Abstract: Investigations during the last decade have established a definitive role for certain viruses in the induction and maintenance of neoplasia under natural and laboratory conditions. Although the causal relationship between viruses and neoplasia in animals is well established, no viruses have yet been demonstrated to be the direct cause of human cancer. A close association, however, has been made between the DNA-containing herpesvirus, Epstein-Barr virus (EBV), and Burkitt’s lymphoma (BL) and nasopharyngeal carcinoma (NPC) in the human population. DNA-containing tumor viruses differ from one another in morphology, nucleic acid content, host range, mode of replication, and ability to undergo latency and to cause neoplasia in their natural host. These include viruses that cause neoplasia in the host in which they replicate (herpes-, pox-, and papovaviruses) and viruses that induce tumors in heterologous hosts in which they undergo abortive infection (papovaviruses and adenoviruses). These viruses invariably transform both permissive and nonpermissive cells in culture to malignancy. One of the consequences of viral transformation of mammalian cells both in vitro and in vivo is the synthesis of macromolecules by the transformed cells, which are distinctly antigenic in the autochthonous or syngeneic host and to which the host makes both a cellular and a humoral immune response. The new antigens expressed in virally transformed cells may be directly coded by the viral genome integrated into the host chromosome or they may be of cellular origin.

Changes in chromosomal proteins in colon cancer. The complexity and DNA‐binding properties of tumor‐associated proteins and evidence for their association with the malignant state in human colonic epithelium

Abstract: The properties of two classes of nonhistone nuclear proteins (NHNP) whose appearance has been correlated with the process of carcinogenesis in the colonic epithelium of rats given 1,2-dimethylhydrazine (DMH) have been investigated. NHNP isolated from adenocarcinomas of the colon were tested for their binding to homologous DNA. The tumor-specific protein class TNP1 (molecular weight ca. 44,000) shows high affinity for DNA while the second class of tumor-specific proteins (TNP2; molecular weight ca. 62,000) does not bind to DNA. When tumor chromatin is subjected to a limited digestion with DNAse I under conditions that are known to preferentially digest active genes, the TNP1 proteins are selectively released, suggesting that this protein fraction is associated with the actively transcribing portions of the genome. The complexity of both tumor-specific protein classes has also been analyzed by two-dimensional gel electrophoresis. This method reveals a high degree of complexity both in TNP1 and TNP2. Protein classes similar to TNP1 and TNP2 that are also found in human colonic adenocarcinomas are not detectable in polyps from familial polyposis-affected patients at times when no sign of malignancy has yet appeared.