Showing papers in "National Cancer Institute monograph in 1978"

Prostate carcinoma: tissue culture cell lines.

Abstract: The successful isolation of a malignant human, prostatic epithelial cell line, PC-3, is reported. A partial characterization and ultrastructural analysis is included.

Control of cellular proliferation by the fibroblast and epidermal growth factors.

Abstract: Recent studies on the effect of the fibroblast and epidermal growth factors (FGF and EGF, respectively) on the proliferation of ovarian cells and vascular endothelial cells are reviewed. During the ovarian cycle, luteal cells are derived from granulosa cells by a process of cytomorphosis. These two cell types thus allow a study of the changes that occur in growth control when one cell type is converted into another. Also described is the control of vascular endothelial cell proliferation by FGF (but not by EGF). We discuss the effects of FGF and EGF on cells derived from the embryonic ectoderm, mesoderm, and endoderm and examine the hypothesis that cellular specificity for various growth factors is conferred during embryo development. Finally, since antagonists of growth factors are probably as important as the mitogens in the overall control of cell proliferation, we review certain mechanisms and agents through which the mitogenic effect of FGF can be repressed, i.e., cell-cell interaction at confluence, trophic hormones, and a diffusible factor(s) from cartilage.

Experimental ultraviolet photocarcinogenesis: wavelength interactions and time-dose relationships.

Abstract: Tumors were induced in the skin of SKH hairless mice by exposure to fluorescent FS sun lamps or to a long-arc xenon solar simulator. Tumores developed about equally well with varying amounts of UV-A radiation (lambda greater than 320 nm) given simultaneously. In contrast, incremental changes in the UV-B region (lambda less than 320 nm) led to substantial increases in carcinogenic effectiveness. A tumor-"initiating" dose of UV-B (4-10 wk of daily FS lamp exposures) was rendered less effective by subsequent exposures of the mice to UV-A (6 hr/day, F-40 T12BL lamps). The mechanism for this effect is not known. Most tumors induced by a short course (10 wk) of FS lamp exposure grew slowly or regressed, whereas mice exposed for a longer period (30 wk) developed more tumors, and many of those that appeared early grew aggressively. Effects of daily dose fractionation were less clear, and the subject requires further study. These and other variables are being tested in a program designed to yield useful information on the effects of changing spectrum, dose, and dose delivery rates on sunlight-induced cancer.

Photocarcinogenesis: a review.

Abstract: Clinical observations and epidemiologic studies indicate that the sun is the primary stimus for most human skin can formation. However, investigations directly confirming this association as well as defining the action spectra, time-dose relationships, energy level requirements, etc., have been confined to animal experimentation. Studies in which gross methods are used indicate that the experimental carcinogenic action spectrum falls primarily between 280 and 320 nm. Quantitative studies and tumor promotion investigations indicate that UV-induced cancer formation begins with the initial exposure. Heat, wind, and moisture stimulate UV carcinogenesis. Also, exogenous chemicals may influence carcinogenesis as photosensitizers such as 8-MOP, as additive carcinogens as noted with DMBA, or as promoters as described for Croton oil, retinoic acid, and BCNU. Qualitative studies indicate that progressive alterations occur in the epidermal-dermal basement membrane and dermal conncecive tissue and mucopolysaccharides associated with the progressive development of epidermal cancers. Malignant melanomas have also been induced experimentally in hairless mice with UV energy. Mechanistically, immunologic alterations and effects on DNA have received the most attention. Tumor-specific antigenicity as well as antigen deletion has been demonstrated. Immune suppression by antilymphocyte serum and certain chemicals has led to stimulation of tumor development. Perhaps the most exciting new information relates to the demonstration that chronically UV-irradiated mice have not rejected highly antigenic UV-induced cancers. This indicated that UV irradiation specifically altered the immunologic responses of the animals to these tumors. Within recent years, the influence of DNA injury and repair on cutaneous carcinogenesis has received a great deal of attention. This has been partly due to the demonstration of defective repair of UV-induced DNA damage in patients with XP. The primary photosensitive problem in these patients is an inordinate sensitivity to the carcinogenic effects of sunlight. However, correlation of DNA injury and repair directly with cancer formation has not been accomplished.

Skin cancer epidemiology: research needs.

Abstract: The basis data currently being used to estimate and evaluate the dose-response relationship of UV-B and skin cancer are from a 6-month survey for four areas that participated in the TNCS, 1971-1972. Although most investigators from various fields of interest outside of cancer research, i.e. aviation, environmental ecology, physics, chemistry, and photobiology, etc., may admit an association between nonmelanoma skin cancer and UV-B exists, they point out that 1) the epidemiologic data currently available are too sparse and lack certain detail, such as exposure patterns and skin types, and 2) more data of this type are needed over a broad geographical range to allow for more precise measurements of the effects of stratospheric ozone depletion. They argue that the present relationships could change drastically with the addition even of a few more points (geographical locations) and that location-specific and demographic factors should be evaluated. Therefore, these data need to be updated and expanded to include more locations over a longer study period. The National Cancer Institute and the Environmental Protection Agency undertook a special skin cancer study from June 1, 1977 to May 31, 1978. The objectives of this study were: 1) to determine the incidence of nonmelanoma skin cancer (basal cell and squamous cell carcinomas) in various population groups within the United States, and 2) to ascertain and measure epidemiologic factors that may contribute toward the excess risk of nonmelanoma skin cancer in specific population groups.

Multiplication-stimulating activity (MSA): a somatomedin-like polypeptide from cultured rat liver cells.

Abstract: Multiplication-stimulating activity (MSA) has been purified to homogeneity with the use of Dowex chromatography. Sephadex gel filtration, and preparative disc gel electrophoresis. A molecular weight of 8,700 was determined for both native and reduced and alkylated MSA by chromatography on a 6% agarose column in 6 M guanidine HCl. Amino acid analysis of performic acid-oxidized MSA revealed 2--3 cysteic acid residues, and reduction and alkylation resulted in loss of biologic residues, and reduction and alkylation resulted in loss of biologic activity. These results suggested the presence on one intrachain disulfide bond, which is required for biologic activity. Specific receptors for MSA have been identified on chick embryo fibroblasts, human skin fibroblasts, a rat liver cell line, and purified rat liver plasma membranes. The closely related peptides, acid ethanol-soluble nonsuppressible insulin-like activity (NSILA-S) and somatomedin-A, competed for MSA tracer binding to these MSA receptors, whereas unrelated peptides did not compete. MSA receptors were divided into two types based on their reactivity with insulin and proinsulin. Insulin and proinsulin competed potently for MSA binding to chick embryo and human skin fibroblasts (type II) but did not compete for MSA tracer binding to rat liver cells and purified rat liver membranes (type I). In chick embryo fibroblasts, the concentrations of MSA, insulin, proinsulin, and somatomedin-A, which inhibited [125I]MSA binding by 50%, also gave half-maximal stimulation of DNA synthesis, consistent with the MSA receptor being a mediator of DNA synthesis. MSA tracer has also been shown to bind specifically to rat serum proteins. The MSA binding profile on Sephadex G-200 was shown to be growth hormone dependent. Since the serum half-life of somatomedin activity in the rat was also growth hormone dependent, these results suggest that growth hormone induces the binding protein for somatomedin and thereby governs the half-life of somatomedin. Finally, the ability of two rat liver cells lines to multiply in serum-free medium did not depend upon the level of MSA in the conditioned medium.

Life history and histopathology of ultraviolet light-induced skin tumors.

Abstract: The life history and histopathology of UV light-induced skin tumors were studied in NMR rats, outbred female Swiss mice, and Syrian golden hamsters. High intensity UV light of medium wavelengths produced hyperplasia and papillomas, as well as a dysplastic, intermediary solar keratosis-like stage, with distinct cellular atypia leading to several types of squamous cell carcinomas. High doses of UV irradiation of short duration caused scars, which developed into fibromas and fibrosarcomas composed of "light" and "dark" cells. Carcinomas with neoplastic squamous and fibrous components were uncommon; however, collision tumors with two components were occasionally seen. Angiomas and angiosarcomas with a proliferating endothelial structure were observed, but adnexal tumors, with follicular or sebaceous differentiation, and basal cell carcinomas were infrequent. Pigment cell tumors were found only rarely. The number of tumors and tumor-bearing animals at different stages of the experiment were also studied. Tumors were compared with lesions induced by chemical carcinogens in different systems. UV carcinogenesis was characterized by many tumor-bearing animals, but with a low total tumor count and a high mortality, thereby decreasing the number of animals-at-risk. The tumor types, their progression from on type to another, and the distribution of certain biologic characteristics were also analyzed. We concluded that UV irradiation is an effective tumor inducer in animal skin, and the type of tumor, its behavior, and location depend on the experimental conditions.

Adjuvant immunotherapy in superficial bladder cancer.

Abstract: The use of BCG as an intracavitary form of immunotherapy in human bladder cancers is discussed The result of a clinical trial in which BCG is administered in the treatment of human bladder cancers is reported Possible uses of this tumor model in the study of immunotherapy employing BCG are suggested

Specificity of cell membrane antigens in prostate cancer

Abstract: Male CD2F1 mice bearing an MCAM-7 transplant in the right leg underwent surgical excision of the tumor and showed specific resistance to subsequent challenges with that identical tumor line. An in vivo response to tumor-specific antigens (MCAM-7 antigen) solubilized by hypertonic potassium chloride was measured by 24-hour footpad swelling response in male CD2F1 mice immunized to the tumor from which the antigens were extracted. These observations suggested that the transplantable MCAM-7 fibrosarcoma could produce immunity toward the solubilized MCAM-7 tumors antigens and that this tumor immunity could be measured by footpad swelling response to injection of the solubilized antigens, an indication of cell-mediated immunity. The footpad swelling response was also monitored in relation to the extent of tumor growth. Similar techniques have been applied to patients bearing adenocarcinoma of the prostate for whom skin testing was substituted for the measurement of footpad swelling in animals. Four of 10 patients, who had known prostate carcinoma and were given intradermal injections of soluble tumor antigens extracted from their tumors, exhibited a cutaneous, delayed type hypersensitivity response to the injected autologous tumor extracts. No positive reactions were observed in response to solubilized components of control tissues, including BPH. These observations suggest that some patients bearing adenocarcinoma of the prostate can exhibit an immunologic response to specific antigens present in their neoplasms.

Inhibition of skin carcinogenesis in vivo by caffeine and other agents.

Abstract: The induction of skin cancer in mice of the Swiss (Carshalton) strain, by repeated irradiation with UV-light, was strikingly reduced by the local application of caffeine prior to each exposure. Theophylline displayed the same activity. These two substances have been selected as probable inhibitors of error-prone, postreplicative DNA repair. Conversely, reductone and chloroquine, which are considered as inhibitors of the error-free, prereplicative excision repair, did not modify the incidence of the tumors. Special emphasis has been given to the histologic behavior of radiolabeled caffeine in the normal and UV-irradiated epidermis of the mouse in vivo and to the ability of mouse epidermal cells in vitro to repair DNA after UV irradiation.

Immunochemical determination of human chorionic gonadotropin and alpha-fetoprotein in sera and tumors of patients with testicular cancer.

Abstract: In several prospective studies during the past 5 years, we evaluated 400 patients with nonseminomatous and 60 with seminomatous testicular tumors with the use of serum and cellular AFP and HCG at the NCI. Ninety percent of the patients with nonseminomatous testicular tumors had elevated levels of either HCG and/or AFP that have been useful in detection, staging, prognosis, and monitoring the efficacy of the therapeutic modalities. Although 5% of the patients with pure seminoma had an elevated level of serum HCG, one must search for elements of nonseminomatous testicular tumor in these patients by serial section of the seminoma specimen. Elevated serum AFP in patients with designations of seminoma indicates the presence of an element of embryonal carcinoma and/or teratoma. We have localized these markers in various tumor cells by using the technique of indirect immunoperoxidase. The HCG is localized in syncytiotrophoblastic component of choriocarcinoma and syncytiotrophoblastic giant cells occasionally found in association with embryonal carcinoma, teratoma, and seminoma. The AFP is localized in embryonal and endodermal sinus tumor.

Hepatocyte growth control: in vitro approach to problems of liver regeneration and function.

Abstract: Primary monolayer fetal and adult rat hepatocyte culture systems, which are being used to help analyze in vivo mechanisms controlling liver regeneration, proliferation, and differentiation are described. With results from animal studies of normal or genetically altered rats subjected to partial hepatectomy, to chemical infusions, or to specific dietary deficiency regimens, an apparently complex growth regulatory pattern has emerged. The data suggest a working hypothesis postulating interactions among hormone, nutritional, lipoprotein, and novel nucleotide factors at multiple regulatory sites. These findings may provide some conceptual and experimental basis for future research regarding the development of hepatic cancer, as it may arise spontaneously or from exposure to environmental carcinogens.

A radioimmunoassay for prostatic acid phosphatase.

Abstract: A solid phase radioimmunoassay for human prostatic acid phosphatase has demonstrated substantially greater biochemical sensitivity than a standard enzymatic method for which p-nitrophenylphosphate was used as substrate. Preliminary data indicate that the radioimmunochemical approach can precisely classify 43% stage I-II and 94% stage III-IV prostate cancers. In contrast, the standard enzymatic methods correctly classified only 9% stage I-II and 46% stage III-IV cancers. It is clinically apparent that a radioimmunochemical approach for the measurement of human prostatic phosphatase may have distinct potential in the clinical diagnosis of prostate cancer.

Action spectrum for ultraviolet carcinogenesis.

Abstract: Previous observations and experiments have shown that the potent carcinogenic wavelengths for skin cancer in man are found in the 290- to 320-nm range, although shorter and longer wavelengths can also have an effect. The short wavelength limit (290 nm) is determined by thesolar emission reaching the earth's surface, a parameter that varies greatly with season, time, and atmopheric conditions. The long wavelength limit (320 nm) was based on observations of the effect of window glass filtration and on comparison of the effect of mid and long UV radiation. It provide little information as to the efficacy of wavelengths in this range. We performed a series of experiments to provide more specific comparative data by testing the hypothesis that the action spectrum for carcinogenesis parallel that for erythema. Albino mice were exposed the emission of a diffraction grating monochromator (5 nm half power bandwidth) at 290, 300, 310, and 320 nm. Energy levels were proportional to valves for the erythema spectrum of untanned Caucasian human skin. Exposures were given thrice weekly until 50% of the mice had developed tumors. Squamous cell carcinomas developed at approximately the same rate and frequency when the UV exposure was proportional to that for erythema, which indicated a decreasing potency from 300 to 310 to 320 nm. No tumors occurred in mice exposed to 290 nm.

Genesis of a virus-transforming gene.

Abstract: The gene src responsible for neoplastic transformation of fibroblasts by avian sarcoma viruses was apparently derived from highly conserved nucleotide sequences in the normal avian genome. The cellular homologue of src is unlinked to the genome of an endogenous virus in chicken cells and functions in an unknown manner during normal cell metabolism.

Influence of heat, wind, and humidity on ultraviolet radiation injury.

Abstract: We investigated the influence of heat, wind, and humidity on UVR-induced acute and chronic skin damage of experimental animals housed in environmental chambers and irradiated under controlled conditions. Hairless mice (strain HRS/J) irradiated after an increase of 10 degrees F in skin temperature had more skin damage than irradiated controls. Significantly more Swiss albino mice irradiated for 400 days while maintained at 90 degrees F developed tumors than did those receiving the same amount of UVR but maintained at room temperature. Mice exposed to UVR daily for 4 weeks while kept in wind of 7 mph had greater damage and slower recovery than animals irradiated but protected from wind. Wind also accelerated tumorigenesis in mice than received chronic UVR. Mice kept at 80% relative humidity and given a single dose of UVR had greater skin injury than animals irradiated while at 5% relative humidity. High midity also appears to accelerate skin cancer formation in animals that were exposed to chronic UVR.

Plenary lecture: lymphocytic infiltration in relationship to urologic tumors.

Abstract: In summary, it may be said that, to date, among urologic tumors, seminoma is the only one in which lymphocytic and/or plasmacytic infiltration is known to improve the prognosis, and the available information on tumors of bladder, kidney, and prostate do not yet permit any statement relative to prognostic significance of inflammatory cell infiltration. When studying the relationship of lymphocytic and/or plasmacytic infiltration to tumors, it is essential for one to distinguish between cases in which the infiltration is in intimate relationship to the tumor cells and/or where the tumor cells show definite degenerative changes, e.g., seminoma, from those cases in which the inflammation is present at some distance from the tumor, e.g., chronic prostatis, and from those in which the inflammation is preexisting, e.g., schistosomiasis. Claims made about the prognostic significance of such infiltration should have adequate controls.

Immunologic aspects of tumor induction by ultraviolet radiation.

Abstract: Chronic treatment of mice with UVR not only induced skin cancer but also produced a systemic change that interfered with host resistance against these tumors. The studies leading to the this conclusion were prompted by the discovery that most tumors induced in C3H mice by chronic UV irradiation were immunologically rejected following transplatation to normal syngeneic recipients. This raised the question of why these tumors were able to grow progressively in the autochthonous host without being destroyed immunologically. We found that after a short course of UV treatment, the UV-irradiated mice lost their ability to reject transplanted UV-irradiated mice lost their ability to reject transplanted UV-induced tumors, even though such transplants were rejected by unirradiated animals. The growth of the transplanted tumors in UV-treated mice resulted from a systemic alteration in the animals that was induced by UV irradiation of the skin.

Poly I:C immunotherapy in patients with papillomas or superficial carcinomas of the bladder.

Abstract: A randomized prospective therapeutic trial of poly I:C immunotherapy in patients with papillomas or superficial carcinomas of the bladder is presented. Poly I:C had no beneficial effect on the recurrence rate of superficial bladder tumors.

Immunoglobulin production by lymphosarcomas induced by Abelson virus in mice.

Abstract: A brief review of the origin and tumor-inducing properties of Abelson murine leukemia virus is given. The most common neoplasm induced by this virus in vivo is a nonthymic lymphocytic tumor of bone marrow and lymph node origin. Two morphologic types of lymphosarcomas are the undifferentiated lymphosarcoma (LS) and the plasmacytic lymphosarcoma (PL). With the electron microscope, both tumor cell types may be mixed and contain undifferentiated cells or cells with a moderate amount of rough endoplasmic reticulum and polysomes. PL tumors are composed predominantly of the latter. In biosynthetic studies, PL tumors produce more immunoglobulin (Ig) than LS and more of the Ig-heavy chain, which is thought to be the murine counterpart of IgD. PL-cells sensitized with rabbit antisera to mouse kappa chains formed rosettes with formalinized protein-A producing Staphylococcus aureus Cowan I strain. The rabbit antisera were specific for kappa chains by absorption. The failure of lymphosarcoma cells to secrete Ig indicates their differentiation is blocked by the transformation process. Lymphosarcoma cells appear then to be derived from B-lymphocytes.

The somatomedin group of peptide growth factors.

Abstract: The somatomedins, a group of serum growth factors, have in common the ability to stimulate proteoglycan synthesis in cartilage. All are growth hormone dependent and have insulinomimetic properties in extraskeletal tissues. All stimulate DNA synthesis and mitosis in a variety of cell lines. Somatomedin-A and multiplication-stimulating activity are neutral peptides of 7,000--10,000 daltons, whereas nonsuppressible insulin-like activity and somatomedin-C are basic peptides of 5,700--7,000 daltons. Whether some of these substances are identical remains to be established. By use of a highly specific radioimmunoassay for somatomedin-C and less specific radioreceptor assays for insulin-like activity and somatomedin-C, evidence has been obtained for the existence of two major classes of somatomedins: neutral somatomedin, which is more insulin-like, and basic somatomedin, which is more rigorously growth hormone dependent, and which, in some systems, is s more powerful stimulant of growth.

Role of platelet factors in the growth of cells in culture.

Abstract: The studies reported suggest that the principal mitogen(s) present in sera responsible for the proliferation of diploid cells in culture is derived from the physiologic response of platelet adherence, aggregation, and release upon their exposure to factors present in serum, such as thrombin, or in tissue, such as collagen. Since it is impossible to make whole blood serum without platelet release, all sera contain platelet mitogenic factor(s). In contrast, serum made from platelet-free plasma lacks mitogenic activity and permits maintenance of cells in culture in a quiescent state for long periods if the cells are routinely fed. The platelet factor(s) appears to be a heat-stable, basic polypeptide or protein, that upon exposure to the cells recruits them into the cell cycle, DNA synthesis, and mitosis. The factor(s) has been shown to act not only in cell culture but in vivo as well. Maintaining cells in a culture medium containing platelet-free, plasma-derived serum may be more analogous to the quiescence of adult cells in vivo, since quiescent cells in adult tissues are normally exposed to interstitial fluid that is probably more like a filtrate of plasma or lymph rather than to whole blood serum. In contrast, growth of cells in a culture medium containing whole blood serum would be more analogous to the pathologic situation that occurs during tissue injury accompanied by hemorrhage.

In vitro carcinogenesis with cells in early passage.

Abstract: A well-documented rationale exists for the study of the induction of cancer at the cellular level. Transformation can be quantitated; its frequency follows a linear relationship with dose and is consistent with a "one-hit" phenomenon. Transformed colonies do produce transformed lines with attributes of neoplastic cells including the production of tumors; in vitro activity correlates with in vivo activity to provide evidence that chemically induced carcinogenesis can be studied in vitro. In vitro techniques utilizing mammalian cells in culture have made possible the rapid evaluation of carcinogenicity of agents in man's environment. Neoplastic transformation is inductive and not the result of the selection of preexisting tumor cells. The addition of a host-mediated step in the bioassay makes it possible to decrease the number of false negatives, which may result from the requirement for metabolic activation of the chemical. Thus the in vitro studies described have a high probability of providing practical methods for determining which chemicals in use have a potential of producing cancer. Furthermore, the nature of the cell-target insult interaction can be determined, as well as the chemical nature of the ultimate carcinogen, the degree to which any agent acts alone, be it a chemical, a virus, or irradiation, and the extent to which one agent interacts with another from the same or a different category of carcinogens. Sequential treatment involving chemicals, viruses, and radiation are important, since combinations of various agents may be responsible for an increased risk of cancer in laboratory animals and human populations. The use of multiple agents may also lead to different but specific new types of assays to use for surveillance of our environment for carcinogenic agents. Pretreatment of Syrian golden hamster embryo cells with either X-irradiation or methyl methanesulfonate, but not UV-irradiation, increases the frequency of chemical transformation as does posttreatment with caffeine. Most, if not all, chemical carcinogens will increase the sensitivity of hamster embryo cells to transformation by a carcinogenic simian adenovirus SA7. The enhancement of virus transformation is related to both the length of chemical treatment and the interval between chemical and viral addition. The mechanism of transformation enhancement by various agents has yet to be explained. They may affect a number of molecular processes or cause a modification of existing DNA and thus provide an explanation for carcinogenesis; in fact, in some systems some of these agents may also show mutagenic activity and produce chromosomal aberrations, However, although DNA is the critical site for a mutagen, the critical target(s) of chemical carcinogens is still unknown.

Why cell biologists should be aware of genetically transmitted viruses.

Abstract: Retrovirus genomes exist as endogenous genetic elements in the cells of many species used in biomedical research. Many cell lines spontaneously release virus, and other cells are induced to do so by procedures commonly used in research laboratories. The expression of endogenous retroviruses can affect the results of seemingly unrelated experiments. Some retroviruses endogenous to animals grow avidly in human cells. They are not known to be hazardous to man, but further studies are necessary.

Growth factors derived from human serum, platelets, and pituitary: properties and immunologic cross-reactivity.

Abstract: A cationic polypeptide growth factor, isolated from human serum and purified to homogeneity, has stimulated the replication of density-inhibited BALB/c 3T3 cells. It has a molecular weight of 1.3 x 10(4) daltons and an isoelectric point of 9.7. Trypsin or chymotrypsin digestion reduces the growth-stimulatory activity by 75%, whereas 2-mercaptoehanol completely abolishes it. The growth factor is heat-stable (100 degrees C X 10 min) and free of insulin-like activity. The highly purified serum growth factor has been labeled with 125I, and an antiserum to the growth factor was produced in the rabbit. A specific, highly sensitive radioimmunoassay has been developed. Factors with growth-stimulating activity have also been detected in human platelets and human pituitary gland extracts. Platelets and pituitary glands have antigenic determinants that are recognized by antibodies to the serum growth factor. The platelet and pituitary gland growth factors are also cationic and heat stable, and are destroyed by 2-mercaptoethanol. Thus the human serum, platelet, and pituitary gland growth factors have similar properties.