Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Medroxyprogesterone acetate (MPA) (1,000 mg daily per os) yielded (mainly subjective) remissions in 8 of 21 patients with hormone-resistant cancer of the prostate. In 24 comparable patients, treated with prednisolone (20 mg daily per os) 3 remissions were observed, indicating a slight superiority of high-dose MPA considering the response rate. The response duration for both drugs was relatively short (2-7 months). No survival benefit for either drug was observed. In patients with hormone-resistant cancer of the prostate, a significant improvement of the performance status should be registrated as subjective response. This is a major aim of any treatment in these patients. Normalization of serum acid phosphatase may also be considered as remission. The type of remission (greater than 50% reduction of measurable tumor lesions, reduction of serum acid phosphatase, subjective remission) should always be indicated in the individual report dealing with phase II/phase III studies in patients with hormone-resistant prostatic cancer.
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PMID:High-dose medroxyprogesterone acetate versus prednisolone in hormone-resistant prostatic cancer. A pilot study. 315 71

Studies using [3H]androstenedione (A) demonstrated that this substrate can be aromatized to estrone (E1) in homogenates of breast carcinoma tissue and breast adipose tissue, in breast carcinoma and breast adipose stromal cells in culture, and in cultured adipose stromal cells from sites remote from the tumor. Using cultured breast carcinoma cells, it was shown that estrogen formation was stimulated by cortisol (10(-6) M) and inhibited by endogenous 5 alpha-reduced androgens: 5 alpha-androstene-dione greater than androsterone greater than dihydrotestosterone greater than epiandrosterone greater than 3 alpha- and 3 beta- androstanediol. It was also shown that 19-nortestosterone and 19-norandrostenedione (10(-6) M) inhibited E1 formation by 80%. Progesterone (10(-6) M) had no effect on aromatase activity, while the progestational agent R5020 (10(-6) M) caused a 70% inhibition. These studies emphasize that a variety of compounds can influence aromatase activity and that drugs which are used as aromatase inhibitors in patients with breast carcinoma may have multiple sites of action.
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PMID:Aromatase activity in the breast and other peripheral tissues and its therapeutic regulation. 333 39

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

Zinc is essential for the proliferation of tumor cells. It is suggested that tumor cell growth is inhibited by zinc deficiency in Yoshida sarcoma-bearing rats fed on a zinc-deficient diet. Clinically applicable methods for inducing a zinc-deficient condition in tumor cells were investigated for the therapeutic application of the above phenomenon. As one of these methods, the administration of progesterone to tumor-bearing rats was tried experimentally, and the changes in the zinc content of the tumor tissue and tumor growth were studied and compared with those of tumors in a control group. Progesterone is a competitive inhibitor of glucocorticoid which stimulates zinc uptake by tumor cells. In Yoshida sarcoma-or AH 109A-bearing rats, a tendency of reduction in zinc content in the tumor tissue and inhibition of the tumor growth in the progesterone-administered group was observed in comparison with the control group, although this was not very significant.
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PMID:[Hormonal control of zinc uptake in tumor cells]. 356 93

Ninety-five patients diagnosed as having stage I endometrial carcinoma (EC) were divided into two groups, one with associated adenomatous hyperplasia (AH; group 1) and the other without (group 2). Adenomatous hyperplasia results from estrogenic stimulation of the endometrium. Therefore, patients in group 1 are considered to have an estrogen-related EC. Group 1 included 49 patients with an average age of 59; group 2 included 46 patients with an average age of 65. Review of the histologic characteristics of EC showed that group 1 tumors are better differentiated and less invasive and that their morphology is closer to the normal glandular structure of the endometrium. Group 2 tumors are less well differentiated, more often invade the myometrium, and include histologic variants such as papillary, clear cell, and anaplastic carcinoma that are dissimilar from the glandular structure of the normal endometrium. Mucinous adenocarcinomas and the presence of stromal foam cells were found to be associated with group 1 EC. Progesterone receptors (PR) were measured in a sample of 30 patients. They were present in all cases of group 1 ranging from 50 to 2,400 fmol/mg protein and absent or very low (30-190 fmol/mg protein) in group 2. All EC with stromal foam cells had high PR (380-2,400 fmol/mg protein). This study confirms that estrogen-related EC is generally a better differentiated and less aggressive tumor and suggests that there are two types of EC. The tumors not related to estrogens, which are histologically more malignant, were seen in an older age group of patients. In addition to the currently accepted methods of clinical evaluation of EC patients, defining the morphologic and biochemical characteristics of two types of EC may contribute to the management of EC, now the most prevalent cancer of the female pelvis. The patients known to be at risk for endometrial carcinoma, identifiable by abnormal hormonal manifestations (obesity, infertility, and other conditions related to hyperestrogenism) as well as those receiving exogenous estrogens are likely to develop a better differentiated and less aggressive form of neoplasia. It would be important to elaborate a system of early detection of EC in the group of elderly patients with no signs of hyperestrogenism prone to develop the less differentiated and biologically more aggressive tumors.
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PMID:Endometrial carcinoma: two diseases? 356 22

The prolactin (PRL) release-inhibitory effects of progesterone, dexamethasone, megestrol acetate, and mifepristone (RU 38486) were studied in cultured pituitary tumor cells prepared from the 7315a and 7315b tumor. Both tumors contain similar numbers of estrogen and progesterone receptors, while only the 7315a tumor also has glucocorticoid receptors. PRL release by the 7315a tumor was stimulated by low concentrations of dexamethasone (10(-10)-10(-9) M) and was inhibited in a dose-dependent manner by higher concentrations (-86% by 10(-7) M). In contrast only 10(-6) and 10(-5) M dexamethasone inhibited PRL release by the 7315b cells by 14 and 24%, respectively. Progesterone caused a dose-dependent inhibition of PRL release, which was similar in the 7315a and b tumor cells. Progesterone (10(-9) M) inhibited PRL release by 62% and this inhibition was completely prevented by 100 nM estradiol, which was stimulatory by itself (+48%). Mifepristone inhibited PRL release by both tumors in a dose-dependent manner, but more powerfully in the 7315a tumor; 10(-6) M concentrations of the compound inhibited PRL release by 52% in the 7315a and by 26% in the 7315b tumor cells. Megestrol acetate inhibited PRL release in both tumors in a dose-dependent manner, but more powerfully in the 7315b tumor; a 10(-8) M concentration of the compound inhibited PRL release by 54% in the 7315b tumor and by 14% in the 7315a tumor. In the 7315a tumor 10(-9) M megestrol acetate even stimulated PRL release, suggesting a dexamethasone-like glucocorticoid effect of the drug on this tumor. Thereafter the interaction of mifepristone and megestrol acetate on PRL release was investigated. In the 7315a tumor cells different combinations of both drugs neutralized each other's inhibitory effects on PRL release, while both drugs had additional inhibitory effects on PRL release by 7315b tumor cells. Changes in PRL release by the cultured pituitary tumor cells were in all instances closely correlated with changes in the PRL content, the protein content, and the DNA content of the tumor cells. This suggests that the inhibitory effect of the compounds studied on PRL release is paralleled by an inhibitory effect on the number of pituitary tumor cells. These studies show the importance of the presence of glucocorticoid receptors in the effectiveness and mechanism of action of the antitumor effects of megestrol acetate and mifepristone.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prolactin release-inhibitory effects of progesterone, megestrol acetate, and mifepristone (RU 38486) by cultured rat pituitary tumor cells. 359 32

The growth fraction (GF) of human breast adenocarcinomas was studied in order to determine whether it was influenced by certain biologic characteristics of the host and whether it was modulated by the tumor's steroid hormone receptor status. It was also examined whether steroid treatment in vitro stimulated tumor's GF. Thirty-five primary breast adenocarcinomas from patients ranging in age from 26 to 85 years were analyzed for size and estrogen receptor (E2R) and progesterone receptor (PR) status. One portion of each tumor was cultured in medium 199 under four different conditions: addition of insulin alone or with 17 beta-estradiol (E), progesterone (P), or a combination of both hormones (E + P). In six cases, a dose-response curve was established for E (10(-14) to 10(-12) mol/L) and P (10(-11) to 10(-9) mol/L). Tissues were exposed to a continuous pulse of 2.5 microCi/mL (3H)-thymidine for five days before fixation and processing for autoradiography. GF ranged from 0.0074 to 0.3852, median 0.0550, and it was arbitrarily classified as low GF, less than 0.0550; or high GF, equal or greater than 0.0550. GF was significantly higher in patients with lymph nodes free of metastatic tumor than in those with positive lymph nodes. Estradiol treatment at low doses increased GF in 40% of tumors, whereas high doses increased GF in 14%. Progesterone treatment increased GF in 30% of tumors treated with low doses and in 14% of those treated with high doses. Treatment with E + P markedly depressed the GF of 85% of the tumors. It was concluded that the GF of breast carcinomas showed a great variability, which seemed to be independent of host factors such as age, menopausal status, parity history, or smoking habits; a second conclusion was that breast tumors' GF was not stimulated by steroid hormone treatment in vitro, and its response did not correlate with their hormone receptor status.
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PMID:Influence of steroid hormones on the growth fraction of human breast carcinomas. 361 47

The human fibrosarcoma cell line HT-1080 exhibits rapid growth following s.c. inoculation in 4-6-week-old male athymic mice. Cytosols from tumors carried in athymic mice bind glucocorticoid (Kd, 1.8 +/- 0.48 X 10(-8) M; Bmax, 240.5 +/- 35.3 fmol/mg cytosol protein, mean +/- SEM). Receptor sediments primarily in the 8-9S region on 5-20% sucrose gradients and is specific for the glucocorticoids. HT-1080 growth in vitro (as measured by cell count) was inhibited over a range of 10(-6)-10(-8) M after 7 days of incubation with dexamethasone and triamcinolone acetonide. Progesterone, estradiol, and dihydrotestosterone had no effect on HT-1080 growth in vitro. Preincubation with a 100-fold excess of progesterone reversed the growth inhibition observed with triamcinolone acetonide but not dexamethasone acetate. HT-1080 tumor cell growth responded biphasically to dexamethasone in vivo. Athymic mice given s.c. injections every other day with 5 or 25 micrograms dexamethasone showed an increase in tumor size inversely proportional to dose. In contrast, 200 micrograms of dexamethasone significantly inhibited tumor growth. Adrenalectomy did not significantly alter HT-1080 growth or glucocorticoid binding to tumor cytosols (Kd, 3.4 X 10(-8) +/- 1.1, Bmax, 236.9 +/- 9.9 fmol/mg cytosol protein, mean +/- SEM) although tumor incidence was decreased in sham adrenalectomized mice. Glucocorticoid binding in tumors grown in vivo was decreased by increasing amounts of dexamethasone. High pharmacological doses of glucocorticoids inhibit the growth of human fibrosarcomas in vivo and in vitro.
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PMID:Effects of glucocorticoids on the growth of human fibrosarcoma cell line HT-1080. 375 54

The nuclear area and nucleus to cytoplasmic (N/C) ratio were measured in visually normal intermediate cells of cervical smears from 151 women with cervical intraepithelial neoplasia (CIN III) or invasive carcinoma, and from 360 normal controls, and the effect of timing of the menstrual cycle, or pill cycle or Depo-Provera contraception was determined. Morphometry was done on visually normal, polygonal intermediate cells without signs of human papilloma virus infection, with a graphic tablet and cursor under 40x oil immersion, and data were handled by microcomputer. The N/C ratio from abnormal smears taken together differed significantly from normals (p.001), but this difference was not apparent taking individual diagnoses separately. The percentages of cells correctly classified as positive or negative were significantly better in cycling women than in those using hormonal contraception (p.025), especially so in ovulatory cycle week II. The mean percentage of correct classification of intermediate cells as coming from positive or negative smears was low in women using any type of hormonal contraception. When hormonal contraception and neoplasia were both present, the increase in N/C ratio was less than expected in some cases. Thus hormonal contraceptives can mask the quantitative features of visually normal intermediate cells from patients with cervical intraepithelial neoplasia, and their contraceptive status needs to be taken into account.
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PMID:Masking effect of hormonal contraceptives on discriminating quantitative features of visually normal intermediate cells in positive and negative cervical smears. 377 14


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