Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, it was shown that lipoprotein lipase (LPL) was produced in neonatal but not in adult rat liver. In an attempt to further define the mechanism involved in liver LPL expression, we identified a neonatal mouse hepatoma cell line, BWTG3, capable of producing LPL. The regulation of LPL expression by various extracellular stimuli was investigated in this cell line. Progesterone caused a rise in LPL production by BWTG3 cells. Other hormones tested, such as insulin, glucagon, adrenalin, testosterone, and thyroid hormone, had no effect on LPL production. The effects of progesterone on LPL production showed slow kinetics reaching a maximum 24 h after addition. Cotransfection of a progesterone receptor expression vector with a 5'-LPL-CAT reporter construct resulted in an induction of CAT activity, suggesting that the increase in LPL accumulation after progesterone was linked to transcriptional induction of the LPL gene. Stimuli causing an elevation of protein kinase A activity in the cells also increased LPL production. Three agents capable of elevating intracellular cAMP levels, i.e., forskolin, dBcAMP, and choleratoxin, caused an elevation of LPL production. The increase in LPL activity caused by forskolin and choleratoxin was paralleled by an elevation of LPL mRNA levels, while dBcAMP only induced a small elevation of LPL mRNA levels. The increase in LPL production was shown to be linked to the stimulation of the PKA signal transduction pathway and was apparently transmitted via the transcription factor CREB. No effect of the stimulation of protein kinase C or calcium/calmodulin-dependent kinase on LPL production was detected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipoprotein lipase expression in undifferentiated hepatoma cells is regulated by progesterone and protein kinase A. 132 33

Well over 100,000,000 women have used the combined oral contraceptive (OC) pill. As a result of the population explosion in the 1970s and 1980s, there will be almost one third more women in fertile age in the year 2000 than in 1991. In the developing world outside China, the total number of contraceptive users could double in roughly 10 years. China, the total number of contraceptive users could double in roughly 10 years. The pill has a low failure rate, but one study in Egypt found that 90% of women made errors in moving from one packet to the next. Similarly, a 60% error rate was found among users in Colombia. The vaginal ring delivers combined progestogen and estrogen through a silastic wall. The device can be left in place for 21 days out of 28, and such delivery would virtually eliminate the low risk of hepatocellular carcinoma among OC users. A vaginal progestogen ring is being tested. Over 700,000 women have used Norplant, the subdermal implant method with an effectiveness rate of 99%. Depo-provera and norethindrone enanthate injections last 2 to 3 months. The Progestasert IUD, containing 38 mg progesterone released at a rate of 65 mcg per day, is effective. Progesterone-releasing IUDs lasting from 3 to 5 years could complement subdermal implants. Ethinyl estradiol (205 mg) and diethylstilbestrol (25-50 mg) have both been used as postcoital agents taken within 36 hours for 5 consecutive days after unprotected intercourse. In more than 3000 cases there were 17 pregnancies (.05%). These regimens are replaced by giving combined oral contraceptive tables (e.g., .25 mg d-norgestrel and 50 mg ethinyl estradiol), taken 2 at a time and repeated 12 hours later, within 72 hours of unprotected intercourse. Epidemiological studies have confirmed that the use of the combined oral contraceptive for 3 to 5 years halves a woman's risk of ovarian or endometrial cancer, and the protection persists for 10 to 18 years after cessation of use.
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PMID:The future of hormonal contraception. 168 5

Progesterone receptors (PgR), estrogen receptors (ER), and androgen receptors (AR) were assayed consecutively for hepatocellular carcinoma (HCC) that was surgically removed from 19 men and three women. The methods of receptor assay were the enzyme immunoassay (EIA) for PgR and the dextran-coated charcoal (DCC) technique for ER and AR. The patients ranged in age from 32 to 77 years (average, 60.3 years). No patients had received any specific anti-cancer therapy before tissue collection. All patients but one had underlying liver disease: cirrhosis in 13 and chronic hepatitis in eight. The positive rate of each receptor was 18% for PgR, 48% for ER, and 82% for AR. The titer was highest for AR, intermediate for ER, and lowest for PgR. The titers of PgR in four PgR-positive patients ranged from only 1.1 to 3.0 fmol/mg of protein. There was no relationship between PgR, ER, and AR in terms of positivity and titer. Also, other clinical and histopathologic data did not influence the positivity or concentration of these three sex hormone receptors. It can be concluded that no or little PgR exists in the cytosol of untreated HCC.
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PMID:Progesterone receptor in hepatocellular carcinoma. Correlation with androgen and estrogen receptors. 184 88

Cytochromes P-450IIA1 and IIA2 are steroid hydroxylases that are expressed in rat liver. The cDNAs for these enzymes were recently sequenced and compared. To study and compare the catalytic activities of IIA1 and IIA2, their cDNAs were inserted into a vaccinia virus expression vector and expressed in human hepatoma Hep G2 cells. IIA2 was able to efficiently catalyze ethoxycoumarin O-deethylation and propoxycoumarin O-depropylation, while IIA1 was inactive toward these substrates. Neither enzyme could catalyze ethoxy- and pentoxyresorufin dealkylation reactions. Both cDNA-expressed IIA1 and IIA2 metabolize testosterone and these activities were quantitatively and qualitatively similar to those obtained with the purified enzymes. IIA1 produced 7 alpha-hydroxy, 6 alpha-hydroxy, and delta 6-testosterone at ratios of 9:0.5:0.5 while IIA2 formed 15 alpha-hydroxytestosterone, an unknown metabolite and four minor metabolites. Progesterone metabolism was also studied. IIA1 yielded a 9.5:0.5 ratio of 7 alpha-hydroxy and 6 alpha-hydroxyprogesterone, while IIA2 produced at least six metabolites. These studies establish the conditions and verify the reliability and accuracy of the vaccinia virus expression system for studies on the enzymology of IIA1 and IIA2.
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PMID:cDNA-directed expression of rat P450s IIA1 and IIA2. Catalytic activities toward steroids and xenobiotics and comparison with the enzymes purified from liver. 197 3

Morris hepatoma 44, whose growth is sensitive to thyroid hormones and prolactin, contains specific receptors for these hormones. In the present experiments, male Buffalo rats bearing Morris hepatoma 7787 were studied to determine the effects of several sex steroid hormones. Castration 1 week postimplantation inhibited tumor growth relative to controls (-53%). Replacement with testosterone propionate (1 mg per day s.c. injection) restored tumor growth to control levels, whereas administration of testosterone (2 mg per day s.c. injection) to castrated controls resulted in significant stimulation. Testosterone administered to control animals at a dose of 1 mg per day stimulated tumor growth (62%), whereas 2 mg per day failed to do so. Progesterone (4-pregnon-3,20-dione) at doses of 125 or 250 micrograms per day (Silastic implants) had no effect on tumor growth, whereas 500 micrograms per day stimulated tumor growth relative to controls. Estrogen (17 beta-estradiol) at doses of 6, 12, or 24 micrograms per day (Silastic implants) did not influence tumor growth. Cytoplasmic testosterone receptors have been demonstrated in tumors (2.2 +/- 0.8 fmoles per mg cytoplasm), although specific cytoplasmic estrogen and progesterone receptors could not be identified in this model. In female rats bearing either Morris hepatoma 44, 7787 or 5123-D, testosterone markedly stimulated tumor growth (226, 328 and 58%, respectively, relative to controls). In conclusion, although Morris hepatoma 7787 appears to be androgen (testosterone) dependent and contains cytoplastic androgen receptors, it lacks specific cytoplasmic receptors for estrogen and progesterone and is not influenced by these hormones except at very high doses of progesterone.
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PMID:The effect of several sex steroid hormones on the growth rate of three Morris hepatoma tumor lines. 292 66

Investigations with the fluorinated spermidine analogues show clearly that these compounds have significant potential for studying the metabolism and functions of the polyamines. However, the biochemical and biological properties of these analogues are dissimilar. This is due to the influence of the fluorine substituent(s) on the basicity of the amine function proximal to the fluoromethylene group, this effect being amplified by geminal disubstitution. The monofluorinated spermidine analogues compare well with the natural amine in their ability to regulate the expression of the decarboxylase enzymes, to be substrates of spermine synthase and to support growth of polyamine-deficient cells. It is also likely that 6-monofluorospermine, formed biochemically in situ, shares with spermine similar functions. These findings raise the possibility of using these spermidine analogues to study the metabolism and pharmacology of polyamines in vivo but also to provide more insight into the regulatory role of spermidine in ODC and SAM-DC expression. Another potential application may be the use of these analogues as probes in tumor imaging and therapy control. This indication has been inferred by studies in tumor-bearing animals, using 19F-NMR spectroscopy determination of tissue fluorospermidine and fluorospermine, formed biochemically from the precursors 2-fluoro or 2,2-difluoroputrescine, and which demonstrate preferential accumulation in tumor versus normal tissue. Finally, these monofluorinated spermidine analogues may exert beneficial effects in pathological states associated with polyamine deficiency. These diseases remain however to be identified. Among the difluorinated spermidine analogues, 7,7-difluorospermidine possesses the most interesting properties. This spermidine analogue still possesses ODC and SAM-DC repressing activities although at much higher concentration than spermidine. More importantly it is a potent inhibitor of spermine synthesis both in cultured cells and in vivo due to its efficient competition with spermidine in the spermine synthase reaction. This compound not only depletes tumor cell of its spermine content but, in addition, appears to exert by itself and/or via 6,6-difluorospermine, the product of its metabolism, polyamine antagonist effects. Combined with MAP but also with DFMO, two potent irreversible inhibitors of ODC which block the synthesis of the natural endogenous polyamines, 7,7-difluorospermidine causes an immediate decrease of viability in cultured HTC cells and promotes tumor regression and stabilization in hepatoma-bearing rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fluorine-containing polyamines: biochemistry and potential applications. 307 45

The restoration of the polyamine content in polyamine-deficient rat hepatoma tissue-culture (HTC) cells, after short duration of incubation in the presence of DL-alpha-difluoromethylornithine (F2MeOrn) or of (2R,5R)-6-heptyne-2,5-diamine [(2R,5R)MAP], two potent irreversible inhibitors of L-ornithine decarboxylase, has been studied in relation to cell proliferation. Both L-ornithine decarboxylase inhibitors deplete the cells of their putrescine and spermidine contents within one day after their addition to the culture medium. Thereafter, intracellular putrescine and spermidine concentrations are restored to near control values within one day when (2R,5R)MAP is removed from the medium, but remain at low levels at least for one day or longer after removal of F2MeOrn. In both conditions, spermine concentration stays at normal or above normal values and cell growth rates are unaffected. Thus, the total intracellular spermine content per culture parallels, in fact, the increase in cell number. The continuous presence of the drugs maintains the depletion of putrescine and spermidine and decreases the total intracellular spermine content of the culture to the same order of magnitude as it reduces the increase in cell numbers. These findings suggest that the antiproliferative effects of these L-ornithine decarboxylase inhibitors in HTC cells is primarily associated with the limitation of spermine biosynthesis rather than to the almost complete reduction of the putrescine and spermidine pools.
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PMID:Restoration of the polyamine contents in rat hepatoma tissue-culture cells after inhibition of polyamine biosynthesis. Relationship with cell proliferation. 308 34

The effect of carcinogenesis on various hepatic microsomal parameters and related cell functions was studied in two tumor models. Hepatocarcinoma was produced by diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF) (Solt-Farber model) and mammary adenocarcinoma using R3230 AC cancer cell line. In these models the effect of the tumor on metabolic functions of hepatocytes was studied. In the DEN/2AAF tumor model in nodules phase I components (cytochrome P-450, aminopyrine N-demethylase, arylhydrocarbon hydroxylase) were reduced, together with microsomal progesterone content and total and specific progesterone binding. Phase II components (glutathione, glutathione S-acyltransferase, UDP-glucuronyl transferase, epoxide hydrolase) were increased. In hepatoma the effects were more enhanced. Nodules grown in the speen retained the dedifferentiated enzyme characteristics. In the R3230 AC mammary adenocarcinoma phase I components of the hepatic endoplasmic reticulum were reduced, and phase II components increased. Progesterone content and receptor binding were also increased. These results indicate that enzymatic abnormalities in the liver cell are connected with cancer production and the hepatic dedifferentiation seems to be indistinguishable in tumor-bearing liver from those seen with extrahepatic neoplasms.
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PMID:Hepatic metabolism and carcinogenesis. Its role in hepatoma and adenocarcinoma. 338 80

Hepatocyte nodules that persist throughout chemical carcinogenesis are linked to carcinomas both as one site at which hepatomas are seen to arise and as a tissue which shows more than a dozen significant protein changes also found in liver cancers. In view of the differential stimulus to growth of these persistent nodules by progesterone, progesterone metabolism and binding to the microsomes of nodules and hepatomas were studied. Progesterone metabolizing enzyme activities in nodule microsomes showed striking shifts with a 42% decrease in 16 alpha-hydroxylase activity and a 2- to 3-fold increase in 6 beta-hydroxylase activity compared to control levels. Hepatomas had a dramatic 20-fold increase relative to nodules or controls in the reductive pathway for progesterone metabolism as measured by delta 4-5 alpha-hydrogenase activity. The rate and saturation of the specific binding of progesterone to microsomes of nodules and liver cancers were significantly decreased when compared either to the tissue surrounding the nodules or to their respective control microsomes. This change in progesterone binding of nodular microsomes may relate to an altered balance of progesterone content and its metabolites in the nodular cells or to alterations in the microsomal membrane binding site. The functional significance of reduced binding of progesterone for liver carcinogenesis is thus open to further inquiry.
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PMID:Changes in progesterone binding and metabolism in liver microsomes from persistent hepatocyte nodules and hepatomas in male rats. 394 Feb 12

MCF-7 cells contain progesterone, estradiol and glucocorticoid receptors. Following addition of these hormones to the growth medium of the cells, hormone-receptor complexes were found to sediment with chromatin fragments produced by trace digestion with micrococcal nuclease. The binding in all cases could be competed by excess unlabeled hormone. In each case the fragments with which the hormone-receptor complexes were associated tended to be smaller than the bulk chromatin fragments, indicating a greater sensitivity of those chromatin regions to the nuclease. The mononucleosomes released by more extensive digestion with micrococcal nuclease contained different amounts of each of the three hormone-receptor complexes. Progesterone could usually be detected on mononucleosomes only after very brief sedimentation analyses, whereas glucocorticoid- and estradiol-labeled mononucleosomes were stable during long centrifugations. Comparison of glucocorticoid- and estradiol-labeled mononucleosomes indicated that their sedimentation rates differed from one another and from bulk nucleosomes. Estradiol nucleosomes from MCF-7 cells and rat uterus (Senior and Frankel, 1978) sediment significantly faster than bulk nucleosomes, while glucocorticoid nucleosomes from MCF-7 cells and rat hepatoma cells sediment with, or even fractionally slower than, bulk nucleosomes.
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PMID:Progesterone, glucocorticoid and estradiol receptors in MCF-7 cells bind to chromatin. 686 95


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