Showing papers in "Cancer and Metastasis Reviews in 1987"
TL;DR: The vascular-extravascular exchange of fluid and solute molecules in a tissue is determined by the transport parameters, which have significant implications in tumor growth, metastasis, detection and treatment.
Abstract: The vascular-extravascular exchange of fluid and solute molecules in a tissue is determined by three transport parameters (vascular permeability, P, hydraulic conductivity, Lp, and reflection coefficient, σ); the surface area for exchange, A; and the transluminal concentration and pressure gradients. The transport parameters and the exchange area for a given molecule are governed by the structure of the vessel wall. In general, tumor vessels have wide interendothelial junctions; large number of fenestrae and transendothelial channels formed by vesicles; and discontinuous or absent basement membrane. While these factors favor movement of molecules across tumor vessels, high interstitial pressure and low microvascular pressure may retard extravasation of molecules and cells, especially in large tumors. These characteristics of the transvascular transport have significant implications in tumor growth, metastasis, detection and treatment.
860 citations
TL;DR: Evidence that radiation resistant hypoxic cells exist in human tumors is considerably more indirect than the evidence for their existence in transplanted tumors, but it is convincing, and evidence that hyp toxic cells are a significant cause of local failure after optimal clinical radiotherapy or chemotherapy regimens is limited and less definitive.
Abstract: The presence of radiation resistant cells in solid human tumors is believed to be a major reason why radiotherapy fails to eradicate some such neoplasms. The presence of unperfused regions containing hypoxic cells may also contribute to resistance to some chemotherapeutic agents. This paper reviews the evidence that radiation resistant hypoxic cells exist in solid tumors, the assumptions and results of the methods used to detect hypoxic cells, and the causes and nature of tumor hypoxia. Evidence that radiation resistant hypoxic cells exist in the vast majority of transplanted rodent tumors and xenografted human tumors is direct and convincing, but problems with the current methodology make quantitative statements about the magnitude of the hypoxic fractions problematic. Evidence that radiation resistant hypoxic cells exist in human tumors is considerably more indirect than the evidence for their existence in transplanted tumors, but it is convincing. However, evidence that hypoxic cells are a significant cause of local failure after optimal clinical radiotherapy or chemotherapy regimens is limited and less definitive. The nature and causes of tumor hypoxia are not definitively known. In particular, it is not certain whether hypoxia is a chronic or a transient state, whether hypoxic cells are proliferating or quiescent, or whether hypoxic cells have the same repair capacity as aerobic cells. A number of new methods for assessing hypoxia are reviewed. While there are still problems with all of the new techniques, some of them have the potential of allowing the assessment of hypoxia in individual human tumors.
396 citations
TL;DR: The results strongly implicate the tumor cell surface lectins in cell adhesion and metastasis and it is proposed that such lectins can increase the ability of tumor cells that enter the blood stream to form aggregates with other tumor cells, or to adhere to host cells or the extracellular matrix and thereby increase their metastatic potential.
Abstract: The formation of secondary tumors by circulating cancer cells (blood-borne metastasis) correlates with an increased tendency of the cells to form emboli by aggregation with other tumor cells or with host cells. Although it is evident that cell-cell recognition and adhesion are mediated by cell surface components, the identity of these molecules is only now being unraveled. Over the last decade an increasing number of studies have demonstrated the presence of endogenous carbohydrate-binding proteins on the surface of various normal cells, and it has been proposed that such lectin-like molecules might be involved in intercellular adhesion. We have shown that various tumor cell lines contain endogenous galactose-specific lectins. Lectin activity was detected at the cell surface by the binding of asialofetuin. This glycoprotein also enhanced the aggregation of the tumor cells. After purification by affinity chromatography on immobilized asialofetuin the lectin activity was associated with two proteins of Mr 14,500 and 34,000. By using polyclonal and monoclonal antilectin antibodies in conjunction with various immunologic techniques we have demonstrated that the endogenous lectins are present on the surface of different tumor cells. Quantitation of cell surface lectins by flow cytometric analyses of antilectin antibody binding revealed that among related tumor cells those exhibiting a higher metastatic potential expressed more lectin on their surface. The binding of monoclonal antilectin antibodies to metastatic cells decreased asialofetuin-induced homotypic aggregation in vitro and suppressed the ability of the cells to form lung metastases after intravenous injection in the tail vein of syngeneic mice. These results strongly implicate the tumor cell surface lectins in cell adhesion and metastasis. We propose that such lectins can increase the ability of tumor cells that enter the blood stream to form aggregates with other tumor cells, or to adhere to host cells or the extracellular matrix and thereby increase their metastatic potential. Other contributing components to tumor cell-host cell interactions are cell surface carbohydrate-binding proteins that have been detected on lymphocytes, platelets, macrophages, hepatocytes, and endothelial cells. These lectin-like molecules might recognize and bind carbohydrates expressed on the surface of tumor cells and enhance emboli formation and organ colonization.
300 citations
TL;DR: Pleural effusion may be a presenting or late sign of cancer, and when recurrent can be a vexing symptomatic problem as mentioned in this paper, which may at times be difficult to diagnose or treat.
Abstract: Pleural effusion is a common and important complication of malignancy which may at times be difficult to diagnose or treat. Its well recognized association with numerous diseases plus the limitations of our usual diagnostic tests may occasionally cause difficulty. In the oncology patient there are a number of common medical problems associated with the development of pleural effusion which frequently coexist with the malignancy. Pleural effusion may be a presenting or late sign of cancer, and when recurrent can be a vexing symptomatic problem. Fortunately, an increasing number of effective diagnostic and therapeutic modalities are available which, when judiciously applied, facilitate our approach.
184 citations
TL;DR: Results, taken together, indicate that certain sialylated Asn-linked oligosaccharides found on metastatic tumor cells are required for expression of the metastatic phenotype.
Abstract: The synthesis and expression of cell surface carbohydrates is a developmentally regulated process that appears to affect a number of cell-cell interactions. To determine whether specific oligosaccharide structures present on highly malignant cells are required for expression of the metastatic phenotype, we have isolated lectin resistant tumor cell mutants with defects in the biosynthesis of oligosaccharides. The mutants selected from the highly aggressive lymphoreticular-like tumor line MDAY-D2 were grouped into genetic complementation classes, compared for metastatic ability and for changes in cell surface glycoconjugates. The Asn-linked oligosaccharides and glycolipids of class 1 mutants were deficient in both sialic acid and galactose and the cells showed a greatly attenuated metastatic phenotype compared to the parental cells. A revertant of the class 1 mutation selected in vitro regained the wild type glycoconjugate profile and the highly metastatic phenotype indicating a direct association between the mutation and the loss of metastatic potential. Class 2 mutants remained highly metastatic and had Asn-linked oligosaccharide structures very similar to those found in the wild type cells with N-glycolylneuraminic acid rather than the N-acetylneuraminic acid. Swainsonine, an inhibitor of golgi α-mannosidase II, blocks the synthesis of complex-type Asn-linked oligosaccharides resulting in the expression of hybrid-type oligosaccharides at the cell surface and the cells display a lectin resistant phenotype. Although swainsonine inhibited neither tumor cell growth in vitro nor solid tumor growth in situ, the drug dramatically reduced the incidence of lung colonies after i.v. inoculation of both MDAY-D2 and B16F10 melanoma cells. These results, taken together, indicate that certain sialylated Asn-linked oligosaccharides found on metastatic tumor cells are required for expression of the metastatic phenotype.
133 citations
TL;DR: For a large number of N-nitroso compounds a comparison of their carcinogenic effects in rats and Syrian golden hamsters has been made, finding that nitrosamines, which require metabolic activation, and nitrosoalkylamides, which do not, produce quite different tumor responses.
Abstract: Since 1956 when the carcinogenic activity of the first N-nitroso compound, nitrosodimethylamine, was reported by Magee and Barnes,(1) there has been growing interest in the biological activity of this group of compounds. Extensive studies of the carcinogenic activity of N-nitroso compounds of various structures have been carried out with the aim of using the differences in activity to suggest possible mechanisms of their carcinogenic action. This approach, which is common in pharmacology, has proved very useful.
109 citations
TL;DR: The bypassing or subversion of the receptor-operated Ca2+/phospholipid breakdown/protein kinase C signalling mechanism is probably the basis of the freeing of cell proliferation from external controls that characterizes all neoplastic transformations.
Abstract: Evidence is steadily mounting that the proto-oncogenes, whose products organize and start the programs that drive normal eukaryotic cells through their chromosome replication/mitosis cycles, are transiently stimulated by sequential signals from a multi-purpose, receptor-operated mechanism (consisting of internal surges of Ca2+ and bursts of protein kinase C activity resulting from phosphatidylinositol 4,5-bisphosphate breakdown and the opening of membrane Ca2+ channels induced by receptor-associated tyrosine-protein kinase activity) and bursts of cyclic AMP-dependent kinase activity. The bypassing or subversion of the receptor-operated Ca2+/phospholipid breakdown/protein kinase C signalling mechanism is probably the basis of the freeing of cell proliferation from external controls that characterizes all neoplastic transformations.
84 citations
TL;DR: New clinical and research opportunities may involve the use of GGT and the placental isozyme of GST (PGST) as markers of preneoplasia and neoplasia in humans as well as factors involved in the genetic expression of these two enzymes.
Abstract: Enzymes of glutathione metabolism, particularly gamma-glutamyltransferase (GGT) and glutathione S-transferase (GST), play a role in multistage hepatocarcinogenesis. The enhanced expression of these enzymes in preneoplastic altered hepatic foci, nodules, and hepatocellular carcinomas has been demonstrated after treatment with a variety of initiating and promoting agents. Glutathione is necessary for the detoxification of xenobiotics and carcinogens and for cell replication. Induction of GGT in altered hepatocytes may permit these cells to utilize extracellular glutathione to preserve their internal glutathione levels. GST induction allows glutathione utilization for the protection of the altered hepatocyte in an environment of exposure to xenobiotics, such as promoting agents. Thus, the combined effects of GGT and GST, in a toxic environment, may provide for the enhanced proliferation observed in preneoplastic hepatocytes. New clinical and research opportunities may involve the use of GGT and the placental isozyme of GST (PGST) as markers of preneoplasia and neoplasia in humans. Many factors, such as hormones, diet, and exposure to initiating and promoting agents, influence GGT and GST expression. The recent cloning of cDNAs to GGT and PGST offers opportunities for the study of factors involved in the genetic expression of these two enzymes. Coupled with the use of hepatocyte culture and transplantation, the factors involved at the molecular level in the creation of hepatocellular neoplasia may be discovered.
81 citations
TL;DR: An interrelationship between the cytoskeleton and cell adhesion is suggested, which can control and uagment the expression of the metastatic phenotype of neoplastic cells.
Abstract: The interaction of metastatic cells with the host environment occurs, to a large extent, through the cell surface, and the cell cytoskeletal system controls the distribution and motility of cell surface receptors. During metastasis, tumor cells migrate from one organ to another, and the dynamic properties and mechanochemical deformability of disseminated cells play a central role in the process. The studies described hereunder suggest an interrelationship between the cytoskeleton and cell adhesion, which can control and uagment the expression of the metastatic phenotype of neoplastic cells.
70 citations
TL;DR: It is suggested that stem cells exist in the rat and human glands that are capable of differentiating to the other major cell types of the mammary parenchyma, and that during the carcinogenic process they generate genetically unstable cells which lose their ability to differentiate and attempt to maximise their intrinsically slow growth rate.
Abstract: Evidence based on immunocytochemical staining and ultrastructure suggests that morphological gradations between epithelial and myoepithelial cells, and possibly between epithelial cells and alveolar-like cells occur in terminal ductal structures of rat and human mammary glands. The benign carcinogen-induced rat and benign human mammary tumors can contain epithelial, myoepithelial-like and alveolar-like cells, whereas the malignant counterparts mainly contain only epithelial-like cells. Clonal epithelial cell lines from normal rat mammary glands, benign tumors, and SV40-transformed human mammary glands can differentiate to either myoepithelial-like or alveolar-like cells. In those of the rat, the differentiation processes occur in steps: intermediate cells along the myoepithelial-like pathway resemble intermediates in terminal ductal structures in vivo, and can also generate certain well-differentiated mesenchymal elements of the original tumours. Differentiation of the benign rat cells to alveolar-like cells with mammatrophic hormones and retinoids in vitro leads to a reduction in their tumor-forming ability in vivo. Cell lines from malignant rat mammary tumors of increasing metastatic potential and from human ductal carcinomas largely fail to yield myoepithelial-like or alveolar-like cells and are relatively slow-growing. Growth of the rat mammary epithelial cells in culture is stimulated by a pituitary-derived mammatrophic growth factor (PMGF), prostaglandin E2, and α-transforming growth factor; the response of the malignant cell lines to PMGF is reduced. It is suggested that stem cells exist in the rat and human glands that are capable of differentiating to the other major cell types of the mammary parenchyma, and that during the carcinogenic process they generate genetically unstable cells which lose their ability to differentiate and attempt to maximise their intrinsically slow growth rate.
70 citations
TL;DR: There has been a search for new treatment or procedures in patients with previously untreated and locally advanced cancer of the head and neck and the results, including studies of combined modality therapy and chemotherapy after surgery, are discussed.
Abstract: The use of chemotherapy in patients with head and neck cancer is increasing. In patients with recurrent head and neck cancer, a large number of chemotherapeutic drugs have shown antitumor activity. These drugs are discussed, and factors which influence response rate and survival are examined. New agents and treatment, including specific agents for combination chemotherapy, are presented. There has been a search for new treatment or procedures in patients with previously untreated and locally advanced cancer of the head and neck. The results, including studies of combined modality therapy and chemotherapy after surgery, are discussed. Chemotherapy in tumor of the salivary glands is briefly discussed, followed by an examination of intraarterial therapy.
TL;DR: The molecular cloning of human DNA repair genes by transfection into drug sensitive rodent cells has been attempted and some success has been achieved but the functions of the cloned genes have yet to be identified.
Abstract: In discussing the role of DNA repair in resistance to cytotoxic drugs used in cancer chemotherapy, several important facts should initially be emphasised. Firstly, a significant number of drugs at present in current use in cancer chemotherapy exert their cytotoxic effect by mechanisms other than direct interaction with DNA; thus the role of DNA repair in development of resistance to such drugs will be minimal. Thus, I exclude from consideration resistance to antimetabolites, the Vinca alkaloids and many of the antitumour antibotics whose mode of action is unknown or for which there is little evidence implicating DNA as the critical intracellular target.
TL;DR: The biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development are reviewed.
Abstract: We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development. Toxicology and clinical data are not discussed. 10-Ethyl-10-deazaaminopterin (10-EdAM) is a classical antifolate, structurally related to methotrexate (MTX) but with greater activity against murine tumors. 10-EdAM has more efficient membrane transport, and relatively greater polyglutamylation in murine tumors than in normal mouse tissues, and these differential effects are greater for 10-EdAM than for other 10-deaza antifolates or for MTX. Trimetrexate and piritrexim are nonclassical antifolates, lacking a glutamate substitution. They are lipophilic, cross cell membranes more rapidly than does MTX, and retain activity against tumors resistant to MTX because of impaired drug transport. These nonclassical antifolates are active against several MTX-insensitive murine tumors, and both have demonstrated clinical anticancer activity. 10-EdAM, trimetrexate and piritrexim all inhibit dihydrofolate reductase (DHFR) as their primary site of action. As such, they deplete cellular thymidylate and purine pools, and inhibit DNA replication. N10-Propargyl-5,8-dideazafolic acid (CB3717) differs from the first three compounds in acting primarily on thymidylate synthase. Like DHFR inhibitors, it blocks DNA replication through depletion of dTTP, but it does not exert an antipurine effect. CB3717 retains activity against transport-defective MTX-resistant cells, and also against cells that overproduce DHFR. 5,10-Dideazatetrahydrofolic acid (DDATHF) is a selective inhibitor of glycinamide ribotide transformylase, and its biochemical pharmacology may differ appreciably from that of the other intifolates under study. DDATHF has strong antitumor activity in several murine systems.
TL;DR: A large body of information has been accumulated over the years regarding the immunogenic properties of the tumor variants obtained following treatment with those xenogenizing agents, and the therapeutic implications of xenogenization in experimental systems of tumor immunotherapy are discussed.
Abstract: Chemical xenogenization occurs when experimental tumors, treated in vivo or in vitro with selected chemicals, become immunogenic, i.e., able to induce a strong rejection response, immunological in nature, in the histocompatible hosts. Unlike modifications induced by haptens, changes in tumor cell immunogenicity associated with chemical xenogenization are heritable as a result of drug interfence with the genetic code. Drugs endowed with potent mutagenic activity are known to be powerful xenogenizing agents, and their mechanism of action is traditionally regarded as involving changes in DNA nucleotide sequence. Triazene and nitrosoguanidini derivatives are among the best known examples of this type of compound, and a large body of information has been accumulated over the years regarding the immunogenic properties of the tumor variants obtained following treatment with those xenogenizing agents. The present paper reviews this information, and also discusses the therapeutic implications of xenogenization in experimental systems of tumor immunotherapy. Xenogenization of murine tumors has also been obtained by means of chemicals devoid of mutagenic activity but capable of affecting gene transcriptional activity. The characteristics of this ‘new’ type of xenogenization are also reviewed and compared to those of triazene xenogenization.
TL;DR: Irrespective of the type of tumor that develops in these experimental animals, all of these models can be successfully used to evaluate the various modifying (risk) factors and biological behaviour of these neoplasms.
Abstract: In order to understand the evolution, histogenesis, and biological behaviour of exocrine pancreatic carcinoma, some reproducible experimental models have been developed in certain rodent species. To date, more than 16 chemicals, many of them structurally unrelated, have been shown to induce pancreatic tumors. Although some of these chemicals appear species specific in their effect on the pancreas, others have been shown to be capable of inducing pancreatic tumors in more than one species. In hamsters, the administration of diisopropylnitrosamine or its oxidized metabolites leads to the development of ductal adenocarcinomas that histologically resemble human pancreatic carcinomas. The histogenesis of the ductal type of adenocarcinoma in hamsters is complex, and appears to involve both the duct cells and dedifferentiated acinar cells. All pancreatic tumors in rats develop from acinar cells showing variable degrees of differentiation, regardless of the type of carcinogen used. The type of pancreatic lesions that develop in mice are also of acinar cell origin. In guinea pigs the tumors are adenocarcinomas of the ductal type and are shown to be derived from dedifferentiated acinar cells that have undergone duct-like transformation. Irrespective of the type of tumor that develops in these experimental animals, all of these models can be successfully used to evaluate the various modifying (risk) factors and biological behaviour of these neoplasms.
TL;DR: Views on mechanisms that may be responsible for the carcinogenicity of metals are updated and analysed, and questions are raised as to the effectiveness of conventional dosimetry in accurately measuring risk from radiopharmaccuticals.
Abstract: Inorganic metals and minerals for which there is evidence of carcinogenicity are identified. The risk of cancer from contact with them in the work place, the general environment, and under conditions of clinical (medical) exposure is discussed. The evidence indicates that minerals and metals most often influence cancer development through their action as cocarcinogens. The relationship between the physical form of mineral fibers, smoking and carcinogenic risk is emphasized. Metals are categorized as established (As, Be, Cr, Ni), suspected (Cd, Pb) and possible carcinogens (Table 6), based on the existing in vitro, animal experimental and human epidemiological data. Cancer risk and possible modes of action of elements in each class are discussed. Views on mechanisms that may be responsible for the carcinogenicity of metals are updated and analysed. Some specific examples of cancer risks associated with the clinical use of potentially carcinogenic metals and from radioactive pharmaceuticals used in therapy and diagnosis are presented. Questions are raised as to the effectiveness of conventional dosimetry in accurately measuring risk from radiopharmaceuticals.
TL;DR: The manipulation of specific idiotypes in anti-tumor immunity is discussed, emphasizing the appropriate consideration of genetic restriction, the choice of idiotype specificity, and the route of immunization.
Abstract: Immunization with anti-idiotypic antibodies is a strategy which, with variable success, can be used to elicit or amplify antigen-specific immune response. This article discusses the manipulation of specific idiotypes in anti-tumor immunity, emphasizing the appropriate consideration of genetic restriction, the choice of idiotype specificity, and the route of immunization. Two independent pathways are outlined: One uses anti-idiotypic antibodies to select and amplify tumor-specific T and B cells via their preexisting antigen-specific receptors, and the other uses anti-idiotypes as primary internal image immunogens to elicit immune recognition of determinants shared by the anti-idiotype and by tumor-associated antigens. Both pathways can be manipulated in attempts to favor the generation of anti-tumor effector cells and minimize the elicitation of suppression.
TL;DR: The effect of interferons on cell proliferation, function, and growth is examined, focusing primarlily on in vitro cell systems.
Abstract: Interferons can regulate growth and differentiation in a wide range of cell types. These mechanisms are currently being examined. Interferons inhibit the growth of tumour cells and are thus potential anti-cancer agents. They can also inhibit normal cell growth in vitro, and stimulate tumour cell growth in vitro. They may also be involved in some autoimmune diseases. This review examines the effect of interferons on cell proliferation, function, and growth, focusing primarily on in vitro cell systems.
TL;DR: This article reviews the current information on hypersensitivity reactions to antincoplastic drugs and provides a logical approach for their assessment.
Abstract: Antitumor drugs, like any other therapeutic agent, have the ability to incite hypersensitivity reactions. Certain of such drugs (e.g., L-asparaginase and taxol) cause reactions with great enough frequency to be a major impediment to repetitive use of the drug. Very few antitumor drugs have not had at least one reported instance of causing a hypersensitivity reaction. Most reactions are of the type I category in the Gell and Coombs classification, but there also are instances of types II, III, and IV reactions caused by many of the antineoplastic agents. The mechanisms of such reactions have been poorly evaluated in many reports. In analyzing a hypersensitivity reaction in a patient being treated for cancer, one should document that the antitumor drug is indeed the offender, and not an ancillary drug or a formulation product that is being used. There are many tests that evaluate the source and mechanism of hypersensitivity reactions. This article reviews the current information on hypersensitivity reactions to antineoplastic drugs and provides a logical approach for their assessment.
TL;DR: Investigation of this phenomenon shows that drug induced modifications of the host, including immunosuppression and vascular damage, can indeed facilitate metastasis and it is suggested that this possibility should be considered in the design of treatment protocols.
Abstract: Cancer chemotherapy is currently undergoing an intensive reappraisal because of its unimpressive performance against the major common cancers. There are a number of possible reasons for this lack of success; one considered here is that under some circumstances anti-neoplastic drug treatment actually increases the malignant behaviour of tumours. Support for this idea comes mainly from experimental studies in which drug treatments increased metastatic spread. Investigation of this phenomenon shows that drug induced modifications of the host, including immunosuppression and vascular damage, can indeed facilitate metastasis. In addition, new data are presented demonstrating that the direct action of drugs on the tumour cells themselves can have similar enhancing effects. The possible mechanisms underlying such direct effects are discussed and the ability of anti-cancer drugs to cause genetic mutations, amplify genes, and alter gene expression are considered. While the nature and extent of this facilitation of tumour malignancy is not fully understood, it is suggested that this possibility should be considered in the design of treatment protocols.
TL;DR: Future challenges include the definition of new cytomorphogenetic entities and subgroups of the currently defined forms of embryonal CNS tumors based on the presence of specific growth factors and neuroregulatory neurotransmitters, or their receptors, and the characterization of neoplastic receptor responses mediating any modulatory role in central neuroepithelial tumors.
Abstract: While the embryonal central neuroepithelial tumors present complex conceptual and clinical problems, advances in cell type identification by special neurohistological, immunohisto- and immunocytochemical techniques have permitted discrimination of distinct cytomorphogenetic entities. These are based in part on their resemblance to the normal phases of neurocytogenesis. Four of these tumors, medulloepithelioma, desmoplastic infantile ganglioglioma, pineoblastoma and medulloblastoma, are designated as multipotential in light of their capacity to undergo divergent differentiation. Cytomorphogenetic, clinical and experimental data implicate fetal neural cell targets for transformation and raise the possibility that aberrant developmental regulatory mechanisms may contribute to the biologic behavior of these tumors. Growth factors and some neuroregulatory neurotransmitters (such as serotonin) are known to act as modulators of normal neuromorphogenesis. They could play a regulatory role in central neuroepithelial tumors on the hypothesis that the aberrant behavior of the embryonal neoplasms could either be modified by fuctional receptor responses or result from abnormal receptor responses to these substances. Future challenges include 1) the definition of new cytomorphogenetic entities and subgroups of the currently defined forms of embryonal CNS tumors based on the presence of specific growth factors and neuroregulatory neurotransmitters, or their receptors, 2) the characterization of neoplastic receptor responses mediating any modulatory role of the presently known growth factors or neuroregulatory neurotransmitters on the growth and maturation potential of the embryonal central neuroepithelial tumors and 3) the further definition of developmental, stage-specific modulators that might be operative in these tumors.
TL;DR: The majority of the agents that activate NK activity fall into two basic categories; the interferons and interleukin-2 and this review will concentrate on studies regarding these two agents.
Abstract: Cells mediating natural killer (NK) activity mediate lysis against a variety of tumor cells and may serve as important effector cells in host resistance to infection. NK active cells are present in virtually all individuals and can be rapidly activated by a wide range of stimuli. Their activities are non-MHC restricted and do not depend on sensitization by antigens, a prerequisite for specific immunity. Several important components of the immunoregulation of NK active cells are: 1) positive or negative signals that regulate the expression of NK activity, and 2) the ability of these cells to function as immunoregulatory cells. The majority of the agents that activate NK activity fall into two basic categories; the interferons and interleukin-2. This review will concentrate on studies regarding these two agents, and will primarily discuss the results obtained with recombinant molecules.
TL;DR: Protein-energy malnutrition (PEM) is common in cancer patients and may develop into the syndrome known as ‘cancer cachexia’, characterised by complex disturbances in carbohydrate, lipid, protein, and electrolyte metabolism.
Abstract: Protein-energy malnutrition (PEM) is common in cancer patients and may develop into the syndrome known as ‘cancer cachexia’. This is characterised by complex disturbances in carbohydrate, lipid, protein, and electrolyte metabolism. The actiology is equally complex, with host and therapeutic factors contributing to the reduced food intake and effects on host tissues. Anorexia is of prime importance, differing in its cause from one patient to another and often presenting a barrier to successful nutritional support. Further research is necessary to elucidate the interaction of central and peripheral factors that may be involved in the aetiology of anorexia. Because of the interplay of biochemical, physiological, and psychological consequences of cancer, the nutritional support of the patient presents a considerable challenge to the caring professions.
TL;DR: On balance, the problems of occult blood testing currently appear to outweight the merits, however, this could change, with the newer testing techniques and with awaited mortality data from controlled clinical trials now underway.
Abstract: Testing feces for occult blood is widely recommended as a means of detecting subclinical colorectal tumors. Guaiac tests such as Hemoccult® are the most widely used, but chemical sensitivity is relatively low and the tests are affected by dietary peroxidases, the state of fecal hydration, and certain drugs. The newly devised HemoQuant® and immunologic techniques appear more sensitive and specific, but they require further evaluation before widespread clinical usage can be recommended.
TL;DR: Recent advances in molecular biology have permitted the molecular cloning and amplification of HPV viral DNA, thereby facilitating its use as a probe for the detection of miniscule amounts of HPV DNA and HPV RNA in tumor biopsies, and DNA transfections of cells in culture have been extremely useful in the study of viral DNA replication and transformation properties.
Abstract: Numerous studies over the past several years have demonstrated that human papillomaviruses (HPV) may play a significant role in the development of several types of human neoplasia. Although it has been accepted for some time that HPVs are responsible for benign epithelial tumors, data accumulated in more recent years have implicated this group of animal viruses in a number of premalignant lesions, as well as a variety of epithelially derived malignancies. Genital, oral, and some rare types of cutaneous cancers have all been found to contain varying degrees of HPV DNA. In several instances secondary tumors resulting from metastases to lymph nodes and lungs have also been demonstrated to contain HPV DNA. Although there is a strong correlation between the presence of the virus and the malignant phenotype in several of these cancers, the precise role of the virus in the development of malignant tumors has not yet been elucidated. A major difficulty in elucidating the role of papillomaviruses in oncogenesis has been the lack of an appropriate in vitro culture system that would permit the growth of the virus and allow an analysis of its transforming properties. Nevertheless, recent advances in molecular biology have permitted the molecular cloning and amplification of HPV viral DNA, thereby facilitating its use as a probe for the detection of miniscule amounts of HPV DNA and HPV RNA in tumor biopsies. Moreover, DNA transfections of cells in culture have been extremely useful in the study of viral DNA replication and transformation properties, providing information on the maintenance and oncogenicity of HPV DNA. These advances have implications for the improved detection of HPV infections, which will aid in patient diagnosis and prognosis. In addition, future treatment and prevention programs may come as a direct result of these basic studies on the mechanism of HPV-induced oncogenesis.
TL;DR: The hypoferremic response appears to be a consistent and predictable biochemical response to pathogenesis, and has been shown to be of great protective value to the host against infection and neoplasia.
Abstract: Invasion of the vertebrate host by microorganisms or neoplastic cells triggers a variety of metabolic responses. One of them, the hypoferremic response, is the decrease in serum iron levels. This hypoferremia is observed not only during infections of various etiologies and neoplasia but also during trauma, myocardial infarction, surgery, and inflammation. The hypoferremic response thus appears to be a consistent and predictable biochemical response to pathogenesis. Hypoferremia has been shown to be of great protective value to the host against infection and neoplasia. Suppression of the iron-withholding ability of the host by excess iron is associated with a greater incidence and severity of infection and neoplasia. The potential therapeutic applications of the hypoferremic response are discussed.
TL;DR: Blood group-related oligosaccharides have been isolated from a limited number of carcinomas and show chain elongation, for example due to repeating Gal 1,4 GlcNAc 1,3 sequences, or a higher degree of branching, which permit increased sialylation and fucosylation.
Abstract: Blood group-related oligosaccharides have been isolated from a limited number of carcinomas. The carcinoma-associated oligosaccharides show chain elongation, for example due to repeating Gal 1,4 GlcNAc 1,3 sequences, or a higher degree of branching, which permit increased sialylation and fucosylation. Abnormal carbohydrate structures have been demonstrated on tumor cell membranes by immunological techniques, which suggests deletion of ABH, accumulation of ‘crypt’ antigens such as I and T antigens, andabnormal expression of Lewis antigens. Changes in carcinoma-associated oligosaccharides can result from altered biosynthetic processing in the Golgi apparatus or the occurrence of abnormal tumor glycosyltransferase isoenzymes. Structural alterations of oligosaccharides on the tumor cell membrane are related to the regulation of tumor growth, cell-cell interaction, cell differentiation, and metastasis. Glycoproteins secreted by tumor cells into the circulation evoke cellular and humoral immunity and cause immune suppression by binding to cytotoxic T lymphocytes and lymphocyte subsets. The relationship of oligosaccharide structures to biologic function awaits elucidation.
TL;DR: Evidence at the present time supports the view that rather than being immunologically invisible, tumour cell antigens are recognised by at least three lymphocyte subsets, and the finding of these auto-tumour reactivities has important implications for the search for immunomodulating drugs for cancer treatment.
Abstract: Data continues to accumulate on the immunological reaction against solid human cancers. The evidence at the present time supports the view that rather than being immunologically invisible, tumour cell antigens are recognised by at least three lymphocyte subsets. Helper T cells can be induced to proliferate upon exposure to cells of the autologous tumour and to secrete detectable levels of interleukin 2 (IL-2). Cultured T cell lines and clones can be shown to respond in primed lymphocyte tests not only to autologous tumour cells but also to allogeneic tumour cells of the same histology and anatomic location. Cytotoxic T cells manifest specific reactivity against cells of the autologous tumour which is distinguishable from natural killing (NK) on the basis of specificity and organ distribution. Natural killer cells can lyse freshly isolated autologous tumour cells after purification on Percoll gradients or when activated by IL-2. There is thus a demonstrable heterogeneity of response to human cancer in unseparated lymphocyte populations and at the clonal level. In limiting dilution assays lymphocytes at the tumour site respond more frequently to autologous tumour relative to NK targets. For at least some tumours there is evidence that the expression of auto-tumour reactivity but not NK correlates with the clinical course of the disease and is a favourable prognostic indicator. The finding of these auto-tumour reactivities has important implications for the search for immunomodulating drugs for cancer treatment. However, it must be recognised that the response is heterogenous and that the immune system comprises multiple interactive elements that exhibit both positive and negative control. Any treatment modality must take this into account and seek to focus on specific activation of the tumour lytic populations or the inhibition of negative regulatory elements as opposed to seeking a more general augmentation of immune reactivity which may, by stimulating suppressor cells, have a counterproductive effect.
TL;DR: The results of studies from the authors' laboratory pertaining to the therapeutic activity of the purine nucleoside, FAraA, in murine tumor models provide evidence for a determining role of both membrane transport and intracellular phosphorylation in the selective antitumor action of this agent against murine leukemia.
Abstract: This article summarizes recent studies characterizing nucleoside transport in mammalian cells and discusses evidence for a role of membrane transport in the pharmacologic action of nucleoside analogues. Some of these studies have also addressed the controversy concerning the multiplicity in transport routes. It seems clear that erythrocytes and, perhaps, some other mammalian cells possess a single, broadly specific system for transporting nucleosides. However, substantial evidence from valid studies discriminating between transport and intracellular metabolism suggests that at least some mammalian cells, including some tumor cells, possess more than a single system. Evidence now exists for a determining role of membrane transport of nucleoside analogues in their cytotoxicity and, in the case of one pyrimidine nucleoside (AraC), in therapeutic responsiveness in leukemic patients. There are also numerous examples of transport-related resistance to nucleoside analogues. Included in this article are the results of studies from the authors' laboratory pertaining to the therapeutic activity of the purine nucleoside, FAraA, in murine tumor models. These studies provide evidence for a determining role of both membrane transport and intracellular phosphorylation in the selective antitumor action of this agent against murine leukemia. Substantially increased transport inward of FAraA occurs at pharmacologically achievable concentrations of this agent in tumor cells as compared to drug-limiting, normal proliferative epithelium of the small intestine. The basis for this differential appears to be the kinetic duality of FAraA and adenosine transport inward found in tumor cells, but not in proliferative intestinal epithelial cells. Tumor cells have highly saturable (low influx Km) and poorly saturable (high influx Km) systems for adenosine transport, both of which are shared by FAraA. In contrast, proliferative epithelial cells have only a poorly saturable system for these substrates. If a similar kinetic duality of nucleoside transport is found in other tumor cells certain implications arise concerning the significance of the duality to neoplastic transformation.
TL;DR: Lectins are currently used not only to identify cells with specified carbohydrate groups, but also to quantitate the carbohydrate groups or to isolate the carbohydrate-bearing cells or structures.
Abstract: Mammalian cells invariably contain a vast array of glycosylated moieties, both inside the cell and on the cell surface. There is an increasing awareness of the utility of these carbohydrates in delineating the phenotype or function of many populations of cells. To this end lectins are extremely useful reagents. Lectins are carbohydrate-binding proteins and glycoproteins of non-immune origin derived from numerous plants and animals. A wide variety of lectins with many distinct carbohydrate specificities have been isolated. Historically the most common laboratory techniques utilizing lectins have been agglutination, mitogen stimulation, and fluorescence techniques. Recent advances in the development and conjugation procedures for labels and matrices have led to the creation of numerous novel lectin-based assays. Lectins are currently used not only to identify cells with specified carbohydrate groups, but also to quantitate the carbohydrate groups or to isolate the carbohydrate-bearing cells or structures