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Showing papers in "Cancer and Metastasis Reviews in 1989"



Journal ArticleDOI
TL;DR: Altered expression of PKC in human colon and breast tumors indicates that PKC isozymes may be useful markers for these diseases.
Abstract: Protein kinase C (PKC) is composed of a family of isozymes that transduce signals of certain hormones, growth factors, lectins, and neurotransmitters. This review addresses the role of PKC in the regulation of cellular proliferation and its disorders. PKC is directly activated in vivo by the second messenger diacylglycecrol, a lipid produced by phospholipase C-catalyzed hydrolysis of phosphatidylinositol and polyphosphoinositides. Diacylglycerol activates PKC by reducing the enzyme's requirement for Ca2+. Phorbol ester tumor promoters and related agents potently activate PKC by a mechanism analogous to that of diacylglycerol, providing evidence that PKC activation is a critical event in tumor promotion. However, the role of PKC activation in tumor promotion is not entirely clear. For example, bryostatin is a potent PKC activator that antagonizes phorbol ester-mediated tumor promotion, and mezerein is a second-stage tumor promoter that potently activates PKC. In addition to studies concerned with tumor promotion, studies of oncogene action also indicate a role for PKC in carcinogenesis. A number of plasma membrane-associated oncogene products and related proteins are PKC substrates, and PKC activation leads to induction of the expression of oncogenes that code for nuclear proteins. PKC is implicated in human breast and colon carcinogenesis. tumor-promoting bile acids activate PKC, and PKC expression studies in rat colonic epithelial cells and human breast cancer cells indicate a positive role for PKC in the proliferation of the cells. Altered expression of PKC in human colon and breast tumors indicates that PKC isozymes may be useful markers for these diseases.

117 citations


Journal ArticleDOI
TL;DR: The role that CEA plays in the development of mestastases by colorectal carcinoma is examined and it is suggested that it may be involved in intercellular recognition and binding.
Abstract: Carcinoembryonic antigen (CEA) is a glycoprotein that has been useful as a tumor marker to predict recurrence in gastrointestinal malignancies, but whose biological function has not been elucidated. With the recent evidence that CEA is a member of the immunoglobulin supergene family, CEA may be involved in intercellular recognition and binding. This review examines the role that CEA plays in the development of mestastases by colorectal carcinoma.

83 citations


Journal ArticleDOI
TL;DR: In this paper, the frequency of chemically increased incidences of neoplastic responses in one or more of the 524 species-gender experiments was evaluated, usually involving male and female rats and mice, and only 5 of the 143 chemicals studied (3.5%) induced benign neoplasia alone, and those observed benign lesions are known to progress to malignancy.
Abstract: Recent carcinogenicity studies conducted and evaluated by the National Toxicology Program/National Institute of Environmental Health Sciences were examined to determine the frequency of chemically increased incidences of neoplasia. Many of the chemicals originally selected for study were chosen because of an a priori suggestion that they might be carcinogens. Of the 143 chemical studies evaluated, usually involving male and female rats and mice, 42 (29%) did not induce any neoplasms, 20 (14%) gave marginal or equivocal neoplastic responses, and 81 (57%) showed positive neoplastic responses in one or more of the 524 species-gender experiments. Of these 81 positive studies, 60 (74%) were considered positive based on malignant neoplasia, 16 (20%) were positive due primarily to benign neoplasia, but hd supporting evidence of malignant neoplasia in the same organ/tissue, and 5 (6%) were positive based only on benign neoplasia. These five chemicals are a) allyl isothiocyanate (transitional cell papillomas of the urinary bladder in male rats), b) 2-amino-4-nitrophenol (tubular cell adenomas of the kidney in male rats), c) asbestos intermediate range chrysotile (adenomatous polyps of the large intestine in male rats), d) decabromodiphenyl oxide (neoplastic nodules of the liver in male and female rats), and e) nitrofurazone (fibroadenomas of the mammary gland in female rats and benign mixed tumors and granulosa cell tumors of the ovary in female mice). For all but one of these lesions (mammary gland), the occurrence in historic controls is low. Thus, only 5 of the 143 chemicals studied (3.5%) induced benign neoplasia alone, and those observed benign neoplasms are known to progress to malignancy. Accordingly, we consider chemically induced benign neoplasia to be an important indicator of a chemical's carcinogenic potential in rodents, and believe it should continue to be made an integral part of the overall weight-of-the evidence evaluation process for identifying potential human health hazards.

57 citations


Journal ArticleDOI
TL;DR: The Secretariat, UKCCCR, The Medical Research Council, 20 Park Crescent, London W1N 4AL, United Kingdom as mentioned in this paper, has published a survey on the role of cancer in cancer research.
Abstract: The Secretariat, UKCCCR, The Medical Research Council, 20 Park Crescent, London W1N 4AL, United Kingdom

57 citations


Journal ArticleDOI
TL;DR: Kupffer cells, tissue-fixed macrophages located in the sinusoids of the liver, represent the highest concentration of mononuclear phagocytes in the body as mentioned in this paper.
Abstract: Kupffer cells, tissue-fixed macrophages located in the sinusoids of the liver, represent the highest concentration of mononuclear phagocytes in the body. Their ability to act as scavengers of particulate material in the blood has given rise to speculation that they play a role in controlling hepatic metastases derived from blood-borne tumor cells. Circumstantial evidence for such a role has been obtained from animal studies where Kupffer cell function has been compromised or inhibited, and from anecdotal clinical observations. Current evidence suggests that Kupffer cells are capable of nonspecifically climinating some circulating tumor cells from the circulation via phagocytosis. This surveillance mechanism would appear to be limited in capacity, and subject to a number of external factors. Recent studies have demonstrated that Kupffer cells can be activated to a tumoricidal state via the administration of biological response modifiers such as gamma interferon or muramyl peptides. The localization of liposomes within Kupffer cell after systemic administration has provided a considerable stimulus for the efficient targeting of macrophage-activating compounds to these cells. Such therapeutic intervention, while capable of inducing Kupffer cell tumoricidal activity in situ and inhibiting tumor growth, is limited with respect to the location of the tumor cells (sinusoidal versus parenchymal) and to the size of the metastatic nodule. Therapeutic intervention using liposomes containing macrophage-activating agents may only be of benefit in patients with minimal tumor load who are at risk for hepatic metastases, rather than those patients who already have clinically detectable liver tumors.

55 citations


Journal ArticleDOI
TL;DR: An overview of the current status of hyperthermia in the febrile or tumor therapeutic ranges and the factors that have shaped it is given, and recent experimental work with macrophages and their monokines is described, which the author feels offers new scientific and clinical opportunities for future studies.
Abstract: Hyperthermia in the febrile (≤41° C) or tumor therapeutic (≥42° C) ranges is known to alter tumor-host interactions: there are reports of either inhibitory or enhancing effects on tumor metastasis and various host defense mechanisms. Historically, this has been an area of conflicting and often anecdotal reports, and there are still significant gaps in our knowledge of the effects of temperature on tumor-host interactions. However, we believe that the tools are now available to further our understanding of the complex relationships between febrile episodes or therapeutically applied heat and various tumor-host cytotoxic mechanisms, and that potentially important and exploitable relationships can be defined. In this review we give an overview of the current status of this field and the factors that have shaped it. We also describe our recent experimental work with macrophages and their monokines, primarily tumor necrosis factor (TNF), which we feel offers new scientific and clinical opportunities for future studies.

22 citations



Journal ArticleDOI
TL;DR: The clinical data from Institut Gustave Roussy, Villejuit, shows that alternating chemotherapy and radiotherapy produced an excellent complete response rate of 79% and a 4 year relapse-free survival rate of 22% in 109 patients with limited small cell lung cancer.
Abstract: Clinical and experimental results with radiotherapy and chemotherapy for the treatment of cancer emphasize the necessity of giving treatment with both modalities with the greatest intensity possible in the initial phase of induction therapy. This ben best be accomplished by utilizing new approaches, such as alternating the chemotherapy with newer methods of delivery of radiotherapy, which has the potential for greater destruction of tumor within acceptable limits of host toxicity. The clinical data from Institut Gustave Roussy, Villejuit, shows that alternating chemotherapy and radiotherapy produced an excellent complete response rate of 79% and a 4 year relapse-free survival rate of 22% in 109 patients with limited small cell lung cancer. Based on 5 year survival criteria, approximately one-fourth of the patients can be considered cured in 1 more year if no further change occurs. The results of the University of Virginia experimental studies have also lemonstrated the superiority of alternating cyclophosphamide and radiotherapy in three courses of induction therapy over conventional methods of delivery of the two modalities. Using the experimental solid fumor 3924A, a cure rate of 50% or greater was obtained with this protocol with acceptable toxicity to the host, as opposed to no cures from three or more courses of either modality alone. One of the major deterrents to tumor cure with concomitant chemotherapy and radiotherapy has been excessive toxicity, which can be avoided by temporal separation (±7 days) of the delivery of the two modalities without a significant loss of therapeutic effectiveness. Well-defined clinical protocols to determine how to more effectively interact chemotherapy with radiotherapy offer some of the greatest potential for a more rapid improvement in treatment.

9 citations


Journal ArticleDOI
TL;DR: In this paper, the authors found that growth factors acting in synergy can recruit more primitive cells than had previously been appreciated, and that these factors can also determine the lineage that the progeny of multipotential progenitors will adopt.
Abstract: Nlature blood cells of all lineages are derived from a single class of cell, the haemopoietic stem cell. Stem cells are pluripotent and capable of almost limitless self-renewal. In the bone marrow they form part of a hierarchy that includes progenitor cells, which are more restricted in the lineages their progeny can adopt, and precursor cells, which are committed to differentiation. The mechanisms that regulate progression through is hierarchy are not fully understood, but evidence suggests that both bone marrow stromal cells and bluble growth factors have a role in controlling haemopoiesis. Four growth factors act on progenitor cells to promote their survival, proliferation, differentiation, and naturation: interleukin-3 (IL-3), granulocyte/macrophage-colony stimulating factor (GM-CSF), granulovte-CSF (G-CSF), and macrophage-CSF (M-CSF). They can also activate the function of mature cells. Considerable overlap is found in the target cells for these four growth factors. We have found that growth factors acting in synergy can recruit more primitive cells than had previously been appreciated. These factors an also determine the lineage that the progeny of multipotential progenitors will adopt. Thus, colony-stimulating factors (CSFs) have the potential to regulate the development of primitive haemopoietic cells in vivo. The properties of CSFs have made them useful in treating malignant disease: G-CSF, in particular, has been used to reduce the period of neutropaenia that follows cytotoxic therapy for various malignancies. The success of these early trials gives ground for cautious optimism about the clinical use of these compounds.

6 citations


Journal ArticleDOI
TL;DR: This review will examine the animal models and human syndromes of malignant hypercalcaemia and show now animal models, although helpful, fail to delineate the relative importance of the various potential humoral factors.
Abstract: Hypercalcaemia in malignancy is a major clinical problem. It contributes significantly to morbidity and mortality and can present difficult diagnostic and management dilemmas. Direct bony invasion by tumour cells rather than humorally mediated hypercalcaemia is probably the most common cause of malignant hypercalcaemia. Yet even in this situation the mechanism of bone resorption or the reason that the normal homeostatic mechanisms cannot cope with the calcium load are poorly understood. It is likely that the tumoral and paracrine factors produced by tumours which result in hypercalcaemia or in osteosclerotic bone metastases, are interposing themselves into the normal regulatory processes and deranging them. Humoral hypercalcaemia of malignancy is an important model for studying these questions, and it also provides some insight into the normal regulation of bone turnover. This review will examine the animal models and human syndromes of malignant hypercalcaemia and show now animal models, although helpful, fail to delineate the relative importance of the various potential humoral factors. A most interesting recent development in this area is the description of a new hormone, the parathyroid hormone-related peptide, which may explain many of the cases of humoral hypercalcaemia of malignancy. It is also a useful model with multiple sites of action within the bone and calcium homeostatic process. The active hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3, may also be involved in a small proportion of cases, but again it is a useful model of some of the factors that may operate. Of considerable interest are the tumour derived factors, such as the transforming growth factors, and the cytokines, such as tumour necrosis factors, interleukins, and haemopoietic colony stimulating factors. Prostanoids are seldom of major importance, but may be important in certain tumour types. Osteosclerotic metastases, although seldom associated with hypercalcaemia, may provide insight into osteoblast regulating factors. Treatment of hypercalcaemia is discussed to show ways in which response to treatment may shed light on underlying pathophysiological mechanisms. Most effective treatments have many potential modes of action, and further study of the interactions of these agents and tumour types may help to unravel some of the enigmas in this human syndrome. The major advances in this complex problem involve the realisation of the necessity of multiple sites of action, including renal calcium handling as well as relative increases in bone resorption and/or intestinal calcium absorption. Various animal models and human examples indicate that rather than single factors operating alone, many humoral factors may act in concert to cause hypercalcaemia. Study of this problem has recently led to the discovery of a new calcium regulating hormone as well as to new roles for existing hormones and factors, aided by such powerful tools as molecular biology. Developments in assay systems for bone formation and bone resorption, renal calcium handling, and intestinal calcium absorption are essential if further advances are to be made.