Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the action of recombinant human gamma-interferon (rHuIFN-gamma) against human ovarian cancer xenografts growing as ascites or as bulky solid i.p. tumors in nude mice. Both forms of the disease responded to i.p. rHuIFN-gamma with significant increases in mouse survival time, and in 2 of 3 ascitic models the mice were cured of peritoneal disease. The activity of rHuIFN-gamma was dose and schedule dependent, and xenografts derived from 3 different patients showed a heterogeneity of response. Peak i.p. levels of rHuIFN-gamma in nude mice bearing multiple i.p. solid tumors were similar to those found in ovarian cancer patients receiving i.p. rHuIFN-gamma, but clearance was more rapid in the mice. Rat gamma-interferon had no antitumor activity at the same doses and schedules although it had some biological activity in the nude mice. Histological examination of treated tumors revealed increased necrosis and loss of cellular organization with large areas of hypocellular epithelial mucin. These changes were preceded by a fall in tumor tryptophan and a rise in tumor kynurenine. We conclude that rHuIFN-gamma has a direct dose related antitumor effect on ovarian cancer xenografts that is preceded by increased metabolism of tryptophan.
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PMID:Antitumor activity of gamma-interferon in ascitic and solid tumor models of human ovarian cancer. 174 38

We have studied the relationship between L-tryptophan metabolism and the response to human IFN-gamma in 3 human ovarian cancer xenografts growing in nude mice. During IFN-gamma therapy all 3 tumours showed a profound depletion in L-tryptophan and a corresponding rise in L-kynurenine. The microenvironment surrounding the tumours was also depleted of L-tryptophan. The IFN-gamma-inducible enzyme indoleamine dioxygenase, IDO, was induced in treated tumours. While there was a variability in IDO mRNA expression in the different xenografts tested, in situ hybridization showed that the gene was induced at all levels of the tumour, and not just the periphery. These results show that induction of IDO by IFN-gamma in vivo can metabolize L-tryptophan rapidly enough for it to become depleted, despite a continued supply of L-tryptophan from the host. The IDO mRNA and protein remained induced after the L-tryptophan levels had returned to normal, suggesting that the gene may be post-transcriptionally regulated and/or the IDO co-factor supply may be limited. Another IFN-gamma-inducible gene, tryptophanyl tRNA synthetase, was also induced in the tumour. It is possible that this enzyme, which is responsible for synthesizing tryptophanyl tRNA, acts in a compensatory manner by allowing protein synthesis to continue despite low free L-tryptophan concentrations. There was no correlation of the above parameters with the anti-tumour response to IFN-gamma, suggesting that other mechanisms must play a role. L-tryptophan depletion may be a contributor to a multifactorial growth inhibition of tumour cells following IFN-gamma treatment, but cannot on its own explain their growth inhibition.
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PMID:The role of indoleamine 2,3-dioxygenase in the anti-tumour activity of human interferon-gamma in vivo. 781 43

Terbium (Tb3+) has been shown to increase the cellular accumulation and cytotoxicity of cisplatin in cisplatin-resistant human breast and ovarian cancer cells. Time-resolved Tb3+ luminescence was used to describe the binding of cisplatin to cisplatin-resistant C13* cells. A high-affinity Tb3+ binding site was identified in the plasma membrane of the C13* cells (n=105+/-2 fmol/cell and Kd=36. 3+/-5.2 microM). The binding of Tb3+ is suggested to occur through a cation-pi interaction with tryptophan residues in the plasma membrane, resulting in an enhancement of the intensity and lifetime of Tb3+. Stern-Volmer quenching analysis revealed that the Tb3+ binding site is not readily accessible to the aqueous environment. The quenching of the Tb3+-C13* intensity by cisplatin occurred by static quenching processes, involving both a direct electron-exchange interaction as well as an indirect dipole-dipole resonant energy transfer mechanism. Formation of the Tb3+-C13*-cisplatin complex does not interfere with the high-affinity binding of Tb3+; cisplatin and Tb3+ bind within 5 to 10 A of each other. A specific terbium/cisplatin binding protein is suggested to play a role in the cellular accumulation and cytotoxicity of cisplatin. Therefore, the transport of cisplatin across the plasma membrane must also involve a facilitated diffusion process. Our results indicate that the binding of Tb3+ to the plasma membrane may be potentially useful in the reversal of cisplatin resistance.
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PMID:Binding of terbium and cisplatin to C13* human ovarian cancer cells using time-resolved terbium luminescence. 982 75

A review of findings is given which relate to the levels of circulating melatonin as well as the urinary excretion of its main peripheral metabolite 6-sulphatoxymelatonin (aMT6s) in patients with different types of cancer as well as in tumor-bearing animals. Clinical results show that circulating melatonin tends to be depressed in patients with primary tumors of different histological types including both endocrine-dependent (mammary, endometrial, prostate cancer) and endocrine-independent tumors (lung, gastric, colorectal cancer). Reduction of melatonin is most pronounced in patients with advanced localized primary tumors, such as mammary and prostate cancer where a clear negative correlation with tumor-size exists. The phenomenon of a reduction of circulating melatonin appears to be a transient one since patients with recidives show a normalization of melatonin. Surgical removal of the primary tumor does, however, not lead to normalization indicating that complex systemic changes appear to be involved in the down-regulation of melatonin. It is unclear at present, whether circulating melatonin is depleted in cancer patients due to a reduced production by the pineal gland or due to certain peripheral metabolic processes, although no evidence for an enhanced hepatic degradation to aMT6s, the main peripheral metabolite of melatonin, was found. The reduction of circulating melatonin is accompanied by neuroendocrine changes affecting the circadian secretion of the adenohypophyseal hormones prolactin, somatotropin and thyroid-stimulating hormone. In contrast to the above-described types of tumors many patients with ovarian cancer show highly elevated levels of melatonin perhaps due to the production of tissue-specific growth factors that could affect pineal melatonin secretion. Experiments with tumor-bearing animals clearly demonstrate that nocturnal circulating melatonin is modulated due to malignant growth. Detailed investigations with chemically induced mammary tumors in rats and serial transplants derived thereof show that slow-growing and well-differentiated tumors containing epithelial cell elements (adenocarcinomas and carcinosarcomas) lead to an enhanced production of melatonin involving activation of the rate-limiting enzyme of pineal melatonin biosynthesis (serotonin N-acetyltransferase) probably due to elevation of the sympathetic tone in response to a stimulation of the cellular immune system by malignant growth. As opposed to that nocturnal melatonin is depleted in animals with fast-growing mammary tumor transplants when myoepithelial-mesenchymal conversion leads to pure sarcomas. The reduction of melatonin appears to be due to either a reduced availability of the precursor amino acid tryptophan because of a glucocorticoid-induced activation of the hepatic enzyme tryptophan 2,3-dioxygenase or a direct peripheral degradation of melatonin via indoleamine 2,3-dioxygenase expressed in tumor and/or other tissues. The significance of these clinical and experimental findings relating to melatonin is discussed both in terms of their practical application as a possible tumor marker and from a theoretical point of view to understand better the mechanisms involved in complex host-tumor interactions involving the neuroimmunoendocrine network.
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PMID:Melatonin in cancer patients and in tumor-bearing animals. 1072 Oct 63

The synthesis and biological evaluation of novel L-tryptophan pyrrole, imidazole polyamide conjugates (16-21), L-tryptophan-glycosylated pyrrole polyamide conjugates (28-30), L-tryptophan dimers (37-42) with straight carbon links of varying length, and L-tryptophan dimers (68-73) linked with pyrrole and imidazole polyamide from both sides by a flexible methylene chain of variable length are described. The compounds were prepared with varying numbers of pyrrole- and/or imidazole-containing polyamides and glycosylated pyrrole polyamides to determine the structural requirements for optimal in vitro antitumor activity. The compounds listed in Table 1 have been evaluated in a three cell line, one dose primary anticancer assay. The compounds listed in Table 2 have been evaluated against nine panels of 60 human cancer cell lines including leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer. It is observed from the initial cytotoxic data (Table 1) that compounds 16-19, 28-30, 68-69, and 71-73 have varying cytotoxic potencies against the three cancer cell lines. It is also observed, from the biological data from Table 2 for compounds 20-21, 37-42, and 70 against the 60 different tumor cells, that the L-tryptophan dimers 37-42 linked by a different number of carbon chains are more active than the L-tryptophan dimers linked by pyrrole or imidazole polyamides. The cytotoxic potency in tryptophan dimers, linked by a different number of carbon atoms increased the number of carbons between the two L-tryptophan rings.
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PMID:Synthesis and in vitro cytotoxicity studies of novel L-tryptophan-polyamide conjugates and L-tryptophan dimers linked with aliphatic chains and polyamides. 1497 56

Despite evidence that gonadotropins may facilitate peritoneal metastasis of ovarian cancer by increasing cell adhesion, the action and molecular mechanism of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in ovarian cancer invasion is not well characterized. In the present study, we investigated the effects of FSH and LH on the invasive activity and the expression of metastasis-related proteinases in human epithelial ovarian cancer by Western blot, zymography, reverse transcription-PCR (RT-PCR), ELISA, and Boyden chamber assay. Treatment with FSH or LH (10, 100, or 1,000 ng/mL) significantly increased the invasion of ovarian cancer cell lines, including BG-1, CaOV-3, and SKOV-3 cells but not OVCAR-3 cells. In addition, treatment of SKOV-3 cells with FSH or LH (100 or 1,000 ng/mL) enhanced the expression and activation of matrix metalloproteinases (MMP-2 and MMP-9) as shown by RT-PCR, gelatin zymography, and ELISA. Pretreatment with [(2R)-2-(hydroxamido-carbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (10 micromol/L), a total MMP inhibitor, and 3-(4-phenoxyphenylsulfonyl)-propylthiirane (20 micromol/L), a specific gelatinase inhibitor, neutralized the proinvasive effect of gonadotropins in SKOV-3 cells. In addition, the secretion of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and plasminogen activator inhibitor-1 was significantly decreased by FSH and LH (100 or 1,000 ng/mL). We further showed that gonadotropins induced an increase in SKOV-3 invasiveness via the activation of protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. Taken together, these results suggest that gonadotropins may contribute to ovarian cancer metastasis via activation of proteolysis and increase in invasion through the PKA and PI3K pathways.
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PMID:Gonadotropins activate proteolysis and increase invasion through protein kinase A and phosphatidylinositol 3-kinase pathways in human epithelial ovarian cancer cells. 1658 20

FBXW7 (F-box and WD40 domain protein 7) is an F-box protein with 7 tandem WDs (tryptophan-aspartic acid) that functions as a phosphoepitope-specific substrate recognition component of SCF (Skp1-Cul1-F-box protein) ubiquitin ligases and catalyzes the ubiquitination of proteins promoting cell proliferation, such as CCNE1, MYC, AURKA, NOTCH1, and JUN, which are frequently activated in a wide range of human cancers. FBXW7 is a candidate tumor suppressor, and mutations have been reported in some human tumors. In this study, we analyzed 84 human tumor cell lines in search for genetic alterations of FBXW7, as well as mRNA and protein expressional changes, and compared them with expression levels of the CCNE1, MYC, and AURKA proteins. We found a novel nonsense mutation in a colon cancer cell line SCC and confirmed the missense mutations in SKOV3, an ovarian cancer cell line, and LoVo, a colon cancer cell line. Moreover, suppressed expression of FBXW7 accompanied by activation of the target proteins were observed in ovarian, colon, endometrial, gastric, and prostate cancers. It is notable that highly suppressed mRNA expression of the FBXW7 beta-form was found in all the human glioma cell lines analyzed; enhanced expressions of CCNE1, MYC, and AURKA were observed in these cells. Our present results imply that FBXW7 plays a pivotal role in many tissues by controlling the amount of cell cycle promoter proteins and that dysfunction of this protein is one of the essential steps in carcinogenesis in multiple organs.
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PMID:The FBXW7 beta-form is suppressed in human glioma cells. 1727 47

Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. Here, we used truncated mutagenesis and alanine replacement techniques to identify a binding site on mesothelin for CA125. We examined the molecular interaction by Western blot overlay assays and further quantitatively analyzed by enzyme-linked immunosorbent assay. We also evaluated the binding on cancer cells by flow cytometry. We identified the region (296-359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin as the minimum fragment for complete binding activity to CA125. We found that substitution of tyrosine 318 with an alanine abolished CA125 binding. Replacement of tryptophan 321 and glutamic acid 324 with alanine could partially decrease binding to CA125, whereas mutation of histidine 354 had no effect. These results indicate that a conformation-sensitive structure of the region (296-359) is required and sufficient for the binding of mesothelin to CA125. In addition, we have shown that a single chain monoclonal antibody (SS1) recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.
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PMID:A binding domain on mesothelin for CA125/MUC16. 1907 18

It has been reported that levo-1-methyl tryptophan (L-1MT) can block indoleamine-2,3-dioxygenase (IDO) expressed by human dendritic cells (DC), whereas dextro-1-methyl tryptophan (D-1MT) is inefficient. However, whether L-1MT or D-1MT can efficiently reverse IDO-induced arrest of human T-cell proliferation has not been clarified. Here, we show a marked immunosuppressive effect of IDO derived from INDO-transfected 293 cell, IDO+ ovarian cancer cells, and monocyte-derived DCs on CD4+ Th1 cells, CD8+ T cells, and natural killer cells derived from peripheral blood, ascites, and tumors of ovarian cancer patients. We found that, whereas L-1MT and D/L-1MT can restore proliferation of tumor-derived and peripheral blood T-cell subsets, D-1MT does not effectively restore IDO-induced arrest of T-cell proliferation. Although D-1MT inhibited kynurenine production at high concentrations, L-1MT was more effective in abrogating kynurenine generation and tryptophan depletion, whereas tryptophan was completely depleted by IDO even in the presence of high amounts of D-1MT. Together, the results indicate that, whereas the generation of tryptophan metabolites (kynurenines) by IDO is important in mediating suppression of T-cell proliferation, the degree to which tryptophan depletion is restored by 1MT is also critical in overcoming IDO-induced arrest of T-cell proliferation.
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PMID:Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T-cell proliferation in human epithelial ovarian cancer. 1949 Dec 79

With metastatic disease at diagnosis for 70% of patients, ovarian cancer represents the most lethal gynecological malignancy. Ovarian carcinomas are aggressive malignancies that can evade immune surveillance and frequently develop into metastases. The tumor microenvironment is decisive for preventing immune attack but, in the case of ovarian carcinoma, the mechanisms are unclear. We recently isolated a novel type of stromal cell from the ascitis of patients with ovarian carcinoma that interacts with epithelial ovarian cancers conferring them chemoresistance. These cells, called Hospicells, have the cell surface markers CD9, CD10, CD29, CD146 and CD166. Here, we investigated whether Hospicells also have immunomodulatory functions that might interfere with immunity to cancer. We report that Hospicells inhibit the proliferation of human CD4(+), CD8(+) and Vgamma9Vdelta2 T cells in vitro and the production of cytokines by these immune cells. The immunosuppression of CD4(+) T cells is independent of direct contact with the Hospicells and is mainly due to nitric oxide produced by the inducible nitric oxide synthase and to products of the tryptophan degradation by indoleamine 2,3-dioxygenase. We proposed that Hospicells in the microenvironment of the tumor mediate immunosuppression of T cells and thus allow ovarian cancers to evade immune surveillance. Targeting of Hospicells could be an alternative to strong chemotherapy through the recovery of immune responses against tumor cells.
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PMID:Hospicells derived from ovarian cancer stroma inhibit T-cell immune responses. 1973 80


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