Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Currently the only treatment available for inoperable pheochromocytoma is symptomatic and palliative with alpha- and beta- adrenergic blockade. Pheochromocytoma is a tumor of chromaffin tissue derived from the neural crest and closely related to other APUD (amine precursor uptake and decarboxylation) cell tumors, including those of the pancreatic islets. Streptozocin has been used with varying success in some of these tumors and therefore merited a trial in pheochromocytoma. We used streptozocin to treat two patients with inoperable pheochromocytoma; the drug failed to have any effect, either on catecholamine excretion or tumor growth.
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PMID:Attempted treatment of inoperable pheochromocytoma with streptozocin. 14 Dec 42

Three members of a kindred exhibiting bilateral adrenal pheochromocytomas are presented together with previously reported 15 familial cases in Japan. The rate of tumor growth, the stage of asymptomatic or chemical pheochromocytoma and the importance of urinary catecholamine assay for detection and diagnosis in this type of tumor are particularly emphasized.
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PMID:Pheochromocytomas occurring in 3 members in a family. 112 74

Laminin is a basement membrane glycoprotein that has diverse biological activities. A sequence on the A chain containing IKVAV (Ile-Lys-Val-Ala-Val) has been shown to promote neurite outgrowth, cell adhesion, and tumor growth and metastasis. Here we have determined the structural requirements of this synthetic peptide for biological activity. Twelve-amino acid-long all-L- (LAM-L) and all-D-peptide (LAM-D) segments as well as an alternating D- and L-amino acid-containing peptide (LAM-DL), which included the IKVAV sequence (residues 2097-2108), were synthesized. Circular dichroism spectral analysis revealed a mirror image conformation of LAM-D and LAM-L with mainly beta-sheet and to a minor extent alpha-helical structure. LAM-DL did not exhibit any significant ordered conformational features. LAM-D and LAM-L showed similar cell attachment activities for rat pheochromocytoma cells (PC12), whereas LAM-DL was inactive. A peptide analog with randomized IKVAV sequence (LAM-RM) was also inactive. A similar trend was observed in competition experiments of the four peptides with laminin in analogous cell attachment assays. In in vivo experiments, both LAM-D and LAM-L were capable of increasing tumor growth when subcutaneously injected into mice with murine melanoma cells B16F10. Results indicate that the conformational status of the IKVAV domain is a contributing factor in determining the biological activity but that there is no strict requirement for a specific chirality. There is a likely sequence specificity to the IKVAV region.
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PMID:The all-D-configuration segment containing the IKVAV sequence of laminin A chain has similar activities to the all-L-peptide in vitro and in vivo. 162 12

The investigation and management of pheochromocytoma have been of special interest at the Mayo Clinic since 1926, when Dr. C. H. Mayo successfully removed an adrenal tumor. Recent clinical developments include the detection of asymptomatic paroxysms of hypertension by 24-hour ambulatory monitoring, detailed characterization of catecholamine cardiomyopathy by echocardiography, and further experience with Carney's triad and other polyglandular and multiple neoplasia syndromes associated with pheochromocytoma. Refinement in interpretation of catecholamine measurements and the development of radionuclide scanning with m-[131I]iodobenzylguanidine, computed tomography, and magnetic resonance imaging have greatly enhanced our diagnostic acumen. Developments in antihypertensive drug therapy and chemotherapy have improved our management of cathecholamine hypersecretion and tumor growth, respectively, in inoperable patients and in the preparation of patients for anesthesia and surgical treatment. Flow cytometry to detect abnormal DNA histograms may prove particularly useful in predicting the malignant nature of the tumors.
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PMID:Recent developments in the diagnosis and treatment of pheochromocytoma. 196 25

Pheochromocytomas, neural crest tumors, express an abundance of insulin-like growth factor-II (IGF-II). To assess further the potential for IGF-II to play an autocrine role for these tumors, we measured 1) IGF-II content by RRA in 7 pheochromocytomas and peripheral blood in these patients, 2) IGF-II receptors by Western analysis, and 3) characterized the tumor binding proteins by ligand blot studies. IGF-II levels in the tumors varied from 2.8-41 micrograms/g. Chromatography revealed that 60% of the peptide eluted as a large mol wt form of IGF-II (8.7-10 kDa); the remainder coeluted with mature peptide (7.5 kDa). This was in contrast to IGF-II levels in normal adrenal tissue (0.225 +/- 0.005 micrograms/g) or another neural crest-derived tumor, medullary carcinoma of the thyroid (0.63 +/- 0.02 micrograms/g). Serum IGF-II levels in the 7 patients with pheochromocytoma (720 +/- 71 ng/mL) were similar to those in 35 normal controls (762 +/- 69 ng/mL). Radiolabeled IGF-II (9 +/- 1%) and IGF-I (20 +/- 2%) bound specifically to pheochromocytoma membranes. Western analysis of these membranes using a specific antiserum directed against the type II receptor demonstrated a band at 210 kDa. Affinity cross-linking studies with [125I]IGF-I demonstrated a specific band at 140 kDa. Ligand blot analysis was performed on the void volume pools from the Sephadex G-75 column and demonstrated bands at about 30 and 25 kDa. In conclusion, these data 1) confirm that pheochromocytomas have increased levels of IGF-II; 2) demonstrate that despite high IGF-II concentrations in the tumors, peripheral levels are not elevated, suggesting that very little tumoral IGF-II is released into the circulation, unlike catecholamines; 3) demonstrate the presence of IGF-II and IGF-I receptors; 4) describe binding protein species similar to those present in other tissues. Thus, the presence of high levels of IGF-II and both type I and type II receptors suggests that IGF II may act through both receptors to alter tumor growth.
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PMID:Insulin-like growth factor-II: possible local growth factor in pheochromocytoma. 217 73

The possibility of employing PC12 pheochromocytoma cells for transplantation into the rat brain as a substitute for adrenal chromaffin cells was examined. Cultured PC12 cells were implanted into the striatum of rats and examined after one day to 20 weeks by fluorescence histochemistry and immunocytochemical staining for tyrosine hydroxylase and a surface antigen of PC12 cells. Between 800 and 3000 cells survived the implantation procedure and persisted relatively unchanged for about one week. Long-term survival of small numbers of PC12 cells was observed in nine of 14 animals, although the number of surviving cells was reduced after 7.5-20 weeks as compared to earlier time periods. By 14-20 weeks after implantation, most of the remaining cells had developed processes. In other animals, there appeared to have been an initial large increase in the number of cells, followed by complete death of the graft. In many of these animals with no surviving cells, large deposits of hemosiderin were found at the implantation site, an apparent residue of earlier tumor growth. Thus in some animals, the number of PC12 cells apparently increased initially, but in these animals the graft was ultimately rejected. In other animals, small numbers of PC12 cells survived for up to 20 weeks, and many of these cells eventually developed neurite-like processes. Continued uncontrolled tumor growth was not observed.
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PMID:Properties of PC12 pheochromocytoma cells transplanted to the adult rat brain. 287 97

A 29-year-old female who had undergone resection of an abdominal paraaortic pheochromocytoma weighing 33 g at the age of 20 had had severe headaches, hypertension and hyperhidrosis 3 years prior to the surgery. Postoperatively, her symptoms completely disappeared and urinary catecholamines were normalized. She was well and had married and had had 2 children. She was admitted to our hospital on August 22, 1982, for further evaluation of hypertension (154/100), which had been diagnosed 2 months previously. Endocrinological studies confirming the presence of a pheochromocytoma were as follows: 1) Plasma noradrenaline level was significantly elevated to 1750 pg/ml. 2) Urinary catecholamine and their metabolites (Metanephrines and VMA) were markedly elevated. Her blood pressure was borderline hypertension and its diurnal rhythm was lost. Her blood pressure decreased to normal values after the oral administration of labetalol (100 mg). Plasma noradrenaline level was still high at 180 minutes after the oral administration of clonidine (150 micrograms). Hypertensive response to insulin-induced hypoglycemia (regular insulin 0.1 u/kg i.v.) was observed, but blood pressure returned to normal after the infusion of glucose alone. Hypertensive response to both metoclopramide (5 mg i.v.) and sulpiride (50 mg per os) was observed accompanying the significant elevation of plasma noradrenaline. Computed tomography and ultrasonography revealed a tumor localized between the aorta and the vena cava inferior. Selective venous sampling also revealed an intrathoracic pheochromocytoma. On October 8, 1982, a 28 g mass was removed from the mediastinum just above the diaphragma. Histologically, it was typical of a pheochromocytoma. Electron microscopy showed large polygonal cells with numerous large secretory granules characteristic of noradrenaline-granules. Postoperative blood pressure was normal, but repeated measurements of plasma and urinary catecholamines were still slightly high. We, therefore, followed her case carefully at our out-patient clinic. In order to clarify the mechanism of catecholamine release by metoclopramide and sulpiride, tissue cultures of removed pheochromocytoma with and without these drugs were carried out. The in vitro studies revealed that metoclopramide released noradrenaline eight-fold and sulpiride 13-fold as compared with noradrenaline in a control medium. We concluded that both drugs stimulated catecholamine secretion directly from the tumor and thus, careless administration of these drugs should be avoided when pheochromocytoma was suspected, large or small. Finally, the rate of tumor growth seemed to be very slow because it took 9 years to ach
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PMID:[Case of intrathoracic pheochromocytoma occurring 9 years after resection of intraabdominal paraaortic pheochromocytoma: effect of metoclopramide and sulpiride on catecholamine secretion in vitro]. 666 41

To elucidate the role gap junctions play in the bystander effect, we examined the cytotoxic effect of herpes simplex virus thymidine kinase (HSVtk) modified tumor cells on gap junction communication-deficient tumor cells and their connexin transfectants. Communication competent Walker 256 tumor cells engineered to express the HSVtk gene (Walker-tk+) when cocultured with N2A mouse neuroblastoma and PC12 rat pheochromocytoma cells with absent endogenous junctional conductance showed no bystander cytotoxicity. Transfection of N2A cells with the rat connexin37 gene (5Q) and PC12 cells with the human connexin43 gene rendered them susceptible to bystander cell death. Additionally, communication-deficient N2A cells transfected with the HSVtk gene failed to exert a bystander effect, whereas N2A transfectants coexpressing the connexin37 and HSVtk genes (5Qtk+ cells) exerted bystander cytotoxicity on gap junction communication-competent 5Q but not on communication-deficient N2A cells in vitro. In vivo experiments also showed tumor growth inhibition of communication-competent 5Q but not communication-incompetent N2A cells by 5Qtk+ cells. In conclusion, these results indicate that in several cellular environments the bystander effect is dependent on connexin expression and gap junctional communication between HSVtk-positive and HSVtk-negative cells.
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PMID:The bystander effect exerted by tumor cells expressing the herpes simplex virus thymidine kinase (HSVtk) gene is dependent on connexin expression and cell communication via gap junctions. 923 Oct 74

Local invasion and metastatic spread to distant sites are major causes of death in patients with malignant pheochromocytoma. Since appropriate in vivo models do not exist, little is known about the underlying mechanisms of tumor growth and invasion. We, therefore, developed an animal model of malignant pheochromocytoma and established organotropic metastatic variants of PC12 rat pheochromocytoma cells. PC12 cells were established as xenografts to BALB/c NCR-NU mice. Subsequent to development of tumors or metastases, primary cultures from local tumors, metastases to lymph nodes, lungs and liver were established. These were subcultured in vitro and reinjected for up to five successive in vivo/in vitro cycles. Xenografted PC12 cells grew tumors with a doubling time of 6.78 +/- 0.58 days during log phase of tumor growth, killing hosts within 5-12 weeks depending on the experimental conditions. Tumors reproducibly metastasized to lymph nodes and the lung. Spontaneous metastases to the liver were not observed, but were achieved by intrasplenic injection of parent PC12 cells. In vitro, the metastatic cell lines displayed striking differences in morphology, overall growth patterns and nutritional requirements as well as binding to purified extracellular matrix proteins compared to the parent cell line. In vivo, the metastatic variants showed marked enhancement of metastatic ability. This is the first report of PC12 rat pheochromocytoma cells to exhibit the malignant phenotype in vivo. We also established variant PC12 cell lines that preferentially metastasized to specific sites and that had acquired different in vitro behavior and ability to metastasize. This unique model system should be useful for further studies relating to the invasion and metastases of pheochromocytoma and may prove valuable for investigations of novel antineoplastic therapies in vitro and in vivo.
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PMID:A unique allogenic model of metastatic pheochromocytoma: PC12 rat pheochromocytoma xenografts to nude mice and establishment of metastases-derived PC12 variants. 962 13

[(131)I]Metaiodobenzylguanidine ([(131)I]MIBG) targeted radiotherapy is effective in debulking childhood neuroblastoma. The high-energy beta-emitter [(131)I]MIBG is, however, not very well suited to treat submillimeter tumors. The [(125)I]MIBG emission is more fully absorbed in small target volumes and therefore advocated for treatment of microscopic neuroblastoma. We investigated whether i.v. [(125)I]MIBG can have a therapeutic advantage over i.v. [(131)I]MIBG in realistic animal models. We used BALB/c nu/nu mice, bearing neuroadrenergic xenografts which differ in MIBG handling, i.e., extragranular vs. granular MIBG storage in the SK-N-SH human neuroblastoma and PC12 rat pheochromocytoma, respectively. Groups of 4-9 animals were treated with 10-100 MBq radioiodinated MIBG. Responses were calibrated against the effect of 4-5 Gy of external beam X-rays. SUBCUTANEOUS XENOGRAFTS: Due to the more extensive MIBG accumulation, the estimated MIBG exposure of the PC12 tumor was nearly 20-fold higher compared with the SK-N-SH xenograft which corresponded with a marked, i.e., nine-fold increased tumor growth delay after radioiodinated MIBG therapy. Both xenografts were equally sensitive to high-dose rate local irradiation. In neuroblastoma as well as pheochromocytoma, the therapeutic efficacy of [(131)I]MIBG was 6 times higher compared to the [(125)I]MIBG which is in reasonable agreement with the reported "131-I over 125-I" ratio of approximately 9 for the calculated absorbed radiation doses per unit of radioactivity. Apparently, the neuroblastoma was not relatively more sensitive to the (ultra)short range emitter [(125)I]MIBG than the pheochromocytoma, indicating that its therapeutic efficacy is independent of the intracellular MIBG storage mode. MICROSCOPIC TUMORS: The pheochromocytoma model consisted of widespread disease after i.v. cell injection with survival as endpoint. For the neuroblastoma, we induced focal intrahepatic microscopic tumors by intrasplenic injection and evaluated total liver weights 26 days after therapy. Theoretically, the therapeutic potential of [(125)I]MIBG at the cellular level should be at least as high as [(131)I]MIBG, but we failed to show any effect of [(125)I]MIBG therapy in both models. In contrast, measurable responses were obtained with [(131)I]MIBG, but these were lower than in the s.c. tumors when related to the responses induced by external X-rays. In conclusion, [(131)I]MIBG is decreasingly effective in microscopic disease and can therefore not be curative as a single agent. Our results strongly argue against the clinical use of [(125)I]MIBG and indicate that conventional total body irradiation was superior to [(131)I]MIBG for microscopic neuroblastoma. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 312-325 (2000).
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PMID:[(131)I] and [(125)I] metaiodobenzylguanidine therapy in macroscopic and microscopic tumors: a comparative study in SK-N-SH human neuroblastoma and PC12 rat pheochromocytoma xenografts. 1118 Jan 34


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