Biomedical subjects
Publications and source records attributed to H Yoshimi.
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It is generally accepted that ectopic ACTH-producing tumors produce not only ACTH but beta-MSH or beta-LPH as well. Using a sensitive radioimmunoassay for beta h-endorphin, we have demonstrated the presence of beta-endorphin immunoreactivity with size heterogeneity according to Sephadex gel chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis in 6 ectopic ACTH/beta-LPH-producing tumors, providing further evidence for the role of a common precursor to ACTH and beta-LPH/beta-endorphin in the peptide biosynthesis in these tumors, in a manner similar to the biosynthetic events in the pituitary gland of several species.
High molecular weight forms of immunoreactive ACTH (IR-ACTH) were studied in a human pituitary gland and 4 ectopic ACTH-producing tumors in man. Both the pituitary and tumor extracts contained "big" IR-ACTH, which eluted near the void volume, and a small amount of "intermediate" IR-ACTH components, which eluted between the void volume and 125I-alpha h1-39 ACTH, in addition to "little" ACTH which coeluted with 125I-alpha h1-39ACTH by Sephadex G-100 gel filtration. A significant amount of the "big" IR-ACTH applied bound to the concanavalin A-agarose column and was eluted with 0.2 M alpha-methyl-D-mannopyranoside, indicating the glycoprotein content of "big" IR-ACTH fractions. When the "big" and "intermediate" fractions were further analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, they were resolved into 4 molecular forms of IR-ACTH with apparent molecular weight of 37,000, 24,000 , 18,000 and 4,500, respectively. These results indicate that 3 high molecular forms of IR-ACTH are present in the human pituitary and the ectopic ACTH-producing tumors.
Adenylate cyclase responses to pituitary hormones including adrenocorticotropic hormone (ACTH), biogenetic amines, prostaglandin E1 (PGE1), angiotensin II, and glucagon were evaluated in adrenocortical tumors and hyperplastic adrenal tissues, obtained from patients with Cushing's syndrome at surgery, and in normal adrenals. The adenylate cyclase of two normal adrenals was activated only by ACTH and PGE1 among the hormones tested, while that of two hyperplastic adrenal tissues due to excessive pituitary ACTH secretion was stimulated only by ACTH. Of five ACTH-responsive adrenocortical adenomas, in contrast, three were stimulated by norepinephrine, two by epinephrine, one by thyroid-stimulating hormone, and one by luteinizing hormone in addition to ACTH, indicating the presence of multiple receptors for hormones other than ACTH and PGE1 in these four tumors. The cyclase of an ACTH-unresponsive adrenocortical carcinoma ws activated only by PGE1 and not by other hormones including ACTH, whereas that of an ACTH-responsive adrenocortical nodular hyperplasia was stimulated by ACTH and glucagon but not by other hormones including PGE1. These results indicate the presence of multiple receptors for hormones other than ACTH and PGE1, the normal adrenocortical stimulants, in human adrenocortical tumors, particularly in adrenal adenomas, but not in normal and hyperplastic (of whichever an etiology) adrenocortical tissues, suggesting a functional alteration of the cellular membrane receptors in human adrenocortical tumors.
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Tumor tissues obtained from two patients with the ectopic ACTH syndrome caused by medullary carcinoma of the thyroid and malignant epithelial thymoma were dispersed by tryptic digestion and mechanical agitation. Using the isolated cells, the effects of various agents on ACTH secretion and intracellular cAMP concentrations were studied. Addition of rat median eminence extract significantly stimulated ACTH secretion and increased levels of intracellular cAMP in both cell preparations, and a dose-response relationship appeared to exist between the dose of rat median eminence extract added and either ACTH secretion or intracellular cAMP formation in the thymic tumor cells. High concentrations of calcium also produced a marked ACTH secretion in both cases. In the thymic tumor cells, norepinephrine, serotonin, and TRH were found to be effective in increasing ACTH secretion and intracellular cAMP levels, whereas biogenic amines, hypothalamic hormones, and gastrointestinal hormones did not affect hormone secretion in the thyroid tumor cells. These results suggest that a corticortropin-releasing factor-like substance(s), as yet unspecified, may play some role in stimulating ectopic ACTH secretion by certain tumors, that both intracellular cAMP and Ca++ may be involved in ectopic hormone secretion, and that the inappropriate hormonal secretory responses of some tumors to a variety of stimuli might be mediated by altered membrane receptors of the neoplastic cells.
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The prevalence of human chorionic gonadotropin (hCG) was estimated by measuring immunoreactive hCG in plasmas and tumor tissues from patients with various neoplasms. To detect small amount of plasma hCG in the presence of luteinizing hormone (LH), plasma hCG level was measured by heterologous radioimmunoassay using anti-hCG-beta antiserum and compared with plasma LH level measured by heterologous radioimmunoassay using anti-LH-beta antiserum. All 56 samples obtained from control subjects were found to be negative for hCG, while 10 of 100 plasma samples from patients with malignancies were positive for hCG. The prevalence of hCG in 64 tumor tissues was 42% (27/64); it was 32% (8/25) in so-called amine precursor uptake and decarboxylation (APUD) tumors and 49% (19/39) in non-APUD tumors. The difference in the prevalence of hCG in APUD vs. non-APUD tumors was not statistically significant. However, the amounts of hCG in APUD tumors were found to be less than 50 ng/g wet tissue, whereas those of non-APUD tumors ranged from several ng to thousands of ng/g wet tissue. These results suggest the APUD tumors produce less amounts of hCG than do non-APUD tumors.
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The adenylate cyclase responses of the human GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors to TRH, LH-RH, biogenic amines, peptides hormones, PGE1 and rat median eminence extract (MEE) have been examined. Out of 4 GH producing pituitary adenomas obtained from patients with active acromegaly at hypophysectomy two were stimulated by TRH, two by LH-RH, three by norepinephrine, one by dopamine, four by PGE1 and none by serotonin. Glucagon stimulated the adenylate cyclase in one of three and MEE in both of two tested. The positive responses of paradoxical GH release after TRH and/or LH-RH before surgery in these patients coincidentally related to the response of adenylate cyclase of each pituitary adenoma. There seems, however, to be no consistent correlation between the adenylate cyclase responses to biogenic amines and the GH release after L-Dopa or 5-hydroxytroptophan tested. The adenylate cyclase of a pituitary adenoma from case of Cushing's disease was stimulated by LH-RH, norepinephrine glucagon and MEE but not by TRH. Plasma levels of ACTH, beta-MSH and cortisol increased after LH-RH but not after TRH in this patient before hypophysectomy. The adenylate cyclase of two ectopic ACTH producing tumors (gastric carcinoid and malignant thymoma) was activated by TRH, LH-RH, norepinephrine, epinephrine, serotonin, PGE1 and MEE. These results indicate the presence of multiple hormone receptors in GH or ACTH producing pituitary adenomas and ectopic ACTH producing tumors, and suggest that the paradoxical GH or ACTH release after TRH and/or LH-RH injection in acromegaly and Cushing's syndrome might be caused by an alteration of the cellular membrane receptors of the pituitary adenomas.
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