Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A relationship between blood plasma levels of polypeptide growth factors and those of peptide and sex steroid hormones, as assayed radioimmunologically, was studied in 91 patients with bone tumors of various histology and 45 healthy donors. The levels of insulin-like growth factor (IGF-1) and somatotropic hormone were significantly higher in cases of chondrosarcoma and patients suffering osteogenic sarcoma in the late puberal period as compared to controls and cases of fibrous histiocytoma, giant-cell tumor, benign tumors and tumor-like lesions of the bone. The peak levels of IGF-1, somatotropic hormone and insulin were registered in osteogenic sarcoma patients who developed pulmonary metastases either in the course or after the completion of combined treatment. Somatostatin level was significantly lower in patients with osteogenic sarcoma aged 11-20 years as compared to healthy adolescents, the lowest level being observed in adolescents suffering osteogenic sarcoma with metastases to the lungs. No relationship was established between total testosterone level, on the one hand, and those of IGF-1 and epidermal growth factor, on the other. A reverse correlation was established between concentrations of IGF-1 and total estradiol. The role of polypeptide growth factor antagonists in combined treatment of bone sarcomas is discussed.
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PMID:[Polypeptide growth factors and their interrelation with hormones in the blood plasma of patients with primary bone tumors]. 184 44

Because of its widespread distribution within the nervous system and the gastro-enteropancreatic (GEP) system and its diverse physiological inhibitory actions on various gastrointestinal functions, including endocrine and exocrine secretion, motility, liver and splanchnic blood flow and absorption, native somatostatin has been viewed as a possible therapy for many diseases. However, its short duration of action and consequent limited clinical usefulness have been overcome with the availability of Sandostatin, a long-acting, synthetic octapeptide analogue of the naturally occurring hormone. Sandostatin represents a significant advance in the treatment of GH and TSH secreting pituitary tumours and GEP endocrine tumours (carcinoid tumour, VIPoma, glucagonoma, insulinoma, and gastrinoma). Preclinical in vitro and animal studies have shown the antineoplastic activity of the compound. Moreover, because of a possible direct effect on somatostatin receptor-positive endocrine tumour cells and indirect effect whereby Sandostatin lowers GH, IGF-1 and numerous gastrointestinal peptides, Sandostatin may prove useful as an adjunctive therapy in cancer patients. In vivo labelling of somatostatin receptor-positive tumours with radiolabelled somatostatin analogues now allows localisation of such tumours and their metastases. Moreover, targeted irradiation of these tumours by beta particle emitting isotopes attached to such somatostatin analogues may become possible. The use of Sandostatin in acute oesophageal variceal bleeding, pancreatic pseudocysts, gastrointestinal and pancreatic external fistulae, short bowel syndrome, dumping syndrome and AIDS-related refractory hypersecretory diarrhea has provided encouraging results. Preliminary reports indicate efficacy of Sandostatin in psoriasis, autonomic neuropathy (postprandial and orthostatic hypotension) and its ability to reduce height velocity in tall adolescents. The ultimate role of Sandostatin as a therapeutic agent in these disorders is being explored in prospective clinical trials.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Future medical prospects for Sandostatin. 198 Jul 78

There are 36 reported cases of metastatic pituitary carcinoma and almost half (44%) of these were associated with syndromes of hormonal hypersecretion. The case of a 56-year-old acromegalic man with cervical lymphatic and spinal metastases from a primary pituitary carcinoma is described. Elevated basal levels of plasma growth hormone (GH) and insulin growth factor-1/Somatomedin C (IGF-1/SmC) were found. GH levels did not increase after TRH or LHRH administration but decreased after L-Dopa and glucose. Immunostaining of the metastatic tumor for GH and electron microscopy findings confirmed the diagnosis of pituitary GH-secreting carcinoma. Striking clinical improvement and a 46% decrease in plasma GH levels were observed with bromocriptine treatment, although IGF-1/SmC levels increased during therapy. The clinical course of most reported cases of pituitary adenocarcinoma has been one of progressive intracranial expansion of a pituitary neoplasm. In only 25% were metastatic lesions discovered antemortem, and disabling symptomatology caused by metastases was rare. Only four previously reported patients of 36 with pituitary carcinoma had acromegaly.
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PMID:Pituitary adenocarcinoma in an acromegalic patient: response to bromocriptine and pituitary testing: a review of the literature on 36 cases of pituitary carcinoma. 266 75

The ability of malignant cells to form metastases in secondary sites remains a major obstacle to the curative treatment of cancer. Previously, we identified type 1 insulin-like growth factor (IGF-1) as a paracrine mitogen for highly metastatic murine carcinoma, H-59 cells. Here the role of IGF-1 and its receptor (IGF-1R) in metastasis was further investigated using H-59 cells transfected with a plasmid vector expressing IGF-1R cDNA in the antisense orientation. The transfectants had a markedly reduced expression of IGF-1R and lost the ability to respond to IGF-1 in vitro. When injected in vivo, either directly into the microvasculature of the liver or lung (experimental metastasis) or s.c. to allow the growth of primary local tumors (spontaneous metastasis), these cells did not give rise to any metastases under conditions which allowed wild-type or control transfectants to form multiple hepatic and pulmonary metastases. The results demonstrate that the IGF-1R can play a critical role in the regulation of carcinoma metastasis.
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PMID:Loss of the metastatic phenotype in murine carcinoma cells expressing an antisense RNA to the insulin-like growth factor receptor. 786 82

The authors report their experience with octreotide in 20 patients (median age 57 years, 10 M, 10 F) from 1984 to 1991; 16 had metastatic APUDoma: 1 PPoma with VIPoma, 1 glucagonoma, 5 gastrinoma including 1 associated to PP-oma, 9 mid-gut carcinoid; 3 patients had multiple-endocrine neoplasia type I (MEN-I) with Zollinger-Ellison syndrome (ZES) and 1 patient a non-metastatic VIPoma. Octreotide (200-750 micrograms/day) was administered bid or tid with regular laboratory controls and morphological assessment. There was a striking improvement of symptoms, particularly in the carcinoid group (reduction of flushing in all patients and of diarrhoea in 3/5), in the patient with gastrinoma + acromegaly (regression of congestive heart failure) and in the patient with non-metastatic VIPoma. The hormonal markers were markedly reduced, particularly gastrin, PP (except in the patient with PPoma + VIPoma), VIP, GH and Somatomedin-C and urinary 5HIAA in 4/9 patients with carcinoid. There was only one partial regression of metastases (gastrinoma) and 4 apparent stabilizations of tumour growth, in the 16 metastatic cases. Among them, 4 patients died: 1 glucagonoma, 1 PPoma + VIPoma, 2 mid-gut carcinoids after a treatment of 5, 16, 30, 36 months, respectively. The patient with acromegaly + ZES died after 6 years of treatment at age 81. A patient with prolactinoma, resected insulinoma, hyperparathyroidism and ZES was not improved by a short course of octreotide (hypoglycemia); he died later of recurrent insulinoma. In conclusion, octreotide is a useful drug to control most of the symptoms related to gut endocrine tumours; it may inhibit tumour growth.
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PMID:Use of octreotide in the treatment of digestive neuroendocrine tumours. Seven year experience in 20 cases including 9 cases of metastatic midgut carcinoid and 5 cases of metastatic gastrinoma. 826 71

The invasion-suppressor molecule E-cadherin (E-CAD) can be regulated at multiple levels: synthesis, processing and stability of mRNA; synthesis, processing and stability of protein; localization and posttranslational modification of protein; binding to catenins (E-CAD-associated proteins); and size and charge of cell surface glycosaminoglycans. Loss of E-CAD antigen and of E-CAD function in vivo has been observed with cell lines that homogeneously expressed functional E-CAD in vitro. These observations led to the idea that factors in the host may downmodulate E-CAD on the cancer cells, thereby promoting cell invasion. Nude mouse cancers that were homogeneously E-CAD-positive and noninvasive in vitro, formed by epithelioid MDCK or NMuMG cells, stained heterogeneously for E-CAD; such cancers were invasive and metastatic. The in vivo downmodulation appeared to be transient. Ex vivo cultures from primary cancers, as well as from metastases, produced homogeneously E-CAD-positive and noninvasive cells. Downmodulation did not occur when cells were micro-encapsulated and then implanted in the mouse, suggesting a role for immediate cancer cell-host cell contact. Similar in vitro/in vivo/ex vivo experiments with mouse MO4 fibrosarcoma cells, transfected with E-CAD cDNA under the control of a b-actin promotor, showed downregulation at the transcriptional or mRNA stability level. This downregulation was rapidly reversible upon ex vivo culture of the tumor cells. TGF-bl and IGF-I were found, respectively, to downregulate and upregulate the expression or the function of E-CAD. We speculate that IGF-1 restores the function of E-CAD through interaction of the IGF-I tyrosine kinase receptor with the catenin-actin cytoskeletal complex. In human cancers, immunohistochemistry has revealed changes in E-cadherin that agree with the experimental data on transient downmodulation of the invasion-suppressor function of E-cadherin by host factors.
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PMID:Downregulation in vivo of the invasion-suppressor molecule E-cadherin in experimental and clinical cancer. 898 64

In the preceding sections we have emphasized the current status of our knowledge concerning the involvement of apoptosis in normal and abnormal renal developmental processes, in control of the adult kidney size and capacity, in the development of renal disease states and in renal oncogenesis. At several points, we noted that studies of apoptosis in the kidney and in renal cells lag behind those in other organ systems. Even with the rudimentary knowledge now available, however, it is apparent that apoptosis is an extremely important process in the kidney. Recent observations lend credence to the view that continued study of this unique cell death process might enable the generation of novel and more effective therapies to treat renal diseases and renal malignancies. We wish to highlight several areas that require particular attention. First, the relationship between blood supply and apoptosis in the kidney requires further investigation. Benign human renal diseases are common in our population; and we now know that most of these diseases are associated with abnormal rates of apoptosis. Although the initiating agents for the various renal diseases vary, there is good reason to believe that much of the apoptosis that occurs in these adult diseases is the end result of reduced renal blood flow initiated by the causative agent. Cytokines or other extrinsic agents that can reduce the apoptotic loss of renal cells under these conditions hold theoretical promise in treating these diseases. Second, there is an urgent need to define the endocrine, paracrine, or autocrine roles of cytokines in normal renal physiology and in the pathogenesis of various renal syndromes. As indicated above, elaboration of fibrous extracellular material by fibroblasts in the tubulointerstitial regions of the kidney appears to be part of the final common pathway leading to end-stage renal disease. It is important to understand how the function of these fibroblasts is controlled. Conversely, apoptosis of glomerular or renal tubular cells also appears to play a role in the development of many of these syndromes. There is already experimental and clinical evidence showing that IGF-1 and hepatocyte growth factor therapies can be useful in renal diseases [57, 58]. It remains to be determined how much of the usefulness of these cytokines is related to their ability to suppress apoptosis as opposed to their ability to promote true growth. Finally, the analysis of apoptotic regulation during renal oncogenesis is critical. Maligant renal cell cancers are difficult to detect in adults before their metastases cause symptoms; and by this late stage renal tumors are almost invariably fatal. The ability of these tumors to regress spontaneously indicates that most apoptotic pathways are retained in these cells, yet their disappointing response to chemotherapy indicates that we have much to learn about how to trigger these pathways. Hopefully a better understanding of the control of these pathways will lead to improved therapy for this devastating group of neoplasms.
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PMID:Apoptosis in the mammalian kidney: incidence, effectors, and molecular control in normal development and disease states. 920 52

A 50-year-old male presented with diabetes mellitus and Cushing's syndrome associated with a large mediastinal mass. The levels of serum cortisol were high (1500-1800 nmol/l) without diurnal variation. Plasma ACTH levels (200-250 ng/l) and urinary excretion of cortisol were also increased. The levels of these hormones did not change in response to stimulation with corticotrophin releasing hormone (CRH) or suppression with high doses of dexamethasone. The patient had an elevated baseline GH level (7.3 mU/l), and the levels of immunoreactive GH-releasing hormone (GHRH) in eight plasma samples were markedly increased (600-1500 ng/l). Circulating levels of IGF-1, chromogranin A and neuropeptide Y (NPY) were also increased. Computer-assisted tomography and octreotide scintigraphy revealed a large mediastinal tumour and metastases in the left supraclavicular fossa. During treatment with octreotide, the baseline GH level was decreased (to 4.4 mU/l), while the GH pulse height was unchanged. Surgical removal of most of the tumour tissue resulted in a further decrease in the baseline serum GH level to a value (1.6 mU/l) about 20% of that before treatment, while the pulse height and mean GH were affected to a lesser extent. Postoperatively, circulating levels of cortisol and IGF-1 decreased, and the patient exhibited clinical improvement. Histological examination showed a neuroendocrine tumour with characteristics consistent with a foregut carcinoid of thymic origin. Immunoreactive GHRH, ACTH and NPY, but not immunoreactive GH, were detected in 80-90% of the tumour cells and the three peptides appeared to be co-localized. In primary culture, cells from this tumour displayed calcium influx in response to GHRH or GH releasing peptide-6 (GHRP-6), while there were not such responses by cells from another carcinoid not producing GHRH, ACTH or NPY. These results demonstrate a rare case of ectopic production of GHRH, ACTH and NPY, and indicate that the tumour cells were responsive to GHRH and GHRP-6 as well as octreotide.
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PMID:Acromegaly and Cushing's syndrome due to ectopic production of GHRH and ACTH by a thymic carcinoid tumour: in vitro responses to GHRH and GHRP-6. 957 39

The activation of the insulinlike growth factor 1/IGF-1 receptor system (IGF1/IGF1-R) has recently emerged as critical event in transformation and tumorigenicity of several murine and human tumors. Expression of IGF1 and of IGF1-R has been demonstrated in normal and neoplastic intestinal cell lines of rats and humans. However, the modulation of IGF1-R expression during the progression from normal colonic mucosa to adenoma, to carcinoma, and to metastasis, has not been evaluated. In this retrospective study, we investigated the expression of IGF1-R in 12 colonic adenomas (AD), 36 primary colorectal adenocarcinomas (CA), and in 27 corresponding metastases (MT). Normal colonic mucosa (N) was adjacent to the CA in 34 cases. Formalin-fixed, paraffin-embedded tissues of each case were immunostained using the avidin-biotin-peroxidase method. We used an anti-IGF1-R rabbit polyclonal antibody (Santa Cruz Biotechnology, CA; dilution 1:100). Positive staining was quantitated by CAS-200. Moderate to strong cytoplasmic immunostaining was observed in 34 of 36 CA (96%), and in 25 of 27 MT (93%). In all of the positive MTs, the intensity of the staining was always strong. In 10 of 12 ADs (83%), only a faint cytoplasmic stain was identified. Normal mucosa when present was negative. Strong IGF1-R positivity correlated with higher grade and higher-stage tumors (P < .01). These data suggest a role of IGF1-R expression during the progression of colorectal adenoma to carcinoma. An increased number of IGF1-R receptors may favor the metastasis of colorectal cancer.
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PMID:Expression of insulin-like growth factor-1 receptor in human colorectal cancer. 1053 57

MECHANISMS OF BONE LOSS: In patients with bone metastases, bone loss is the consequence of a dissociated process combining excessive bone resorption and inhibited bone formation. This destructive process occurs in response to soluble factors secreted by metastatic cells (PTH-rP, cytokines) which activate osteoclasts. These cells also secrete proteases (cathepsin K, metalloprotease MMP-9) which degrade the bone's collagen network. Excessive bone resorption is also favored by direct interaction between the metastatic cells and stromal cells in the bone marrow in response to the activation of membrane receptors (integrins a4 beta 1 and a4 beta 7). Finally, metastatic cells secrete non-identified soluble factors capable of inhibiting osteoblast proliferation in vitro. EFFECT OF BONE LOSS ON THE METASTASIS: Bone is a major reservoir of growth factors (mainly TGF beta and IGF-1). Positive feedback mechanism operates at the site of osteolysis where TGF beta released by bone tissue induces a paracrine stimulation of PTH-rP production by metastatic cells. IGF-1 released by the bone favors grow of metastatic cells present in the marrow. In addition, IGF-1 as well as collagen proteolytic fragments may stimulate recruitment of new metastatic cells at the site of the bone metastasis. This creates a vicious circle of mutual stimulation between bone destruction and tumor proliferation.
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PMID:[Bone hyperresorption in bone metastases]. 1074 42


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