Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The angiogenesis inhibitor O-(chloroacetyl-carbamoyl)fumagillol (TNP-470) showed antitumor activity in three human cancer xenograft systems. TNP-470 potently inhibited the tumor growth of hormone-independent prostate cancer PC-3 cells and breast cancer MDA-MB-231 cells dose dependently at weekly s.c. doses of 50-200 mg/kg with maximum inhibition of 96 and 88% (tumor growth, 4 and 12% of that in the respective control). In experiments of combination therapy with chemotherapeutic agents, the combination of TNP-470 (100 mg/kg) and cisplatin (5 mg/kg) showed an additive antitumor effect (from treated versus control, 38 and 22% to 5%) against PC-3 carcinoma. 5-Fluorouracil and Adriamycin alone did not significantly inhibit MDA-MB-231 tumor growth (treated versus control, 131 and 64%, respectively). TNP-470 also inhibited tumor growth of WiDr colon cancer; although the inhibition was less marked (treated versus control, 39%) than that observed with the hormone-independent cancers used in this study. In an in vitro study, all the cell lines tested were considerably insensitive to TNP-470 in monolayer cultures (50% inhibitory concentration, approximately 5 micrograms/ml), whereas TNP-470 inhibited the anchorage-independent growth of PC-3 and MDA-MB-231 cells (50% inhibitory concentration, 0.05 and 470 ng/ml, respectively). The inhibitory activity of TNP-470 against anchorage-independent growth correlated well with the in vivo antitumor activity among the cell lines tested. Thus, this inhibitory action may partly contribute to the potent antitumor activity of the angiogenesis inhibitor TNP-470, at least in the case of PC-3 and MDA-MB-231. These results suggest that hormone-independent prostate and breast cancers may be appropriate target diseases for TNP-470 clinical trials.
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PMID:Angiogenesis inhibitor TNP-470 (AGM-1470) potently inhibits the tumor growth of hormone-independent human breast and prostate carcinoma cell lines. 769 35

Attainment of cell type-specific cytotoxicity with minimal side effects is the ultimate goal of cancer therapy. By employing the prostate-specific antigen promoter (PSAP), we investigated (1) whether PSAP-driven antisense genetic constructs targeting DNA polymerase-alpha and topoisomerase II alpha (Top II alpha), designated PSAP-antipol and PSAP-antitop respectively, could induce death of prostate cancer cells, and (2) whether the cytotoxicity is restricted to cells of prostate origin. A PSAP-driven beta-galactosidase gene, PSAP-LacZ, was also used to estimate the expression of the PSAP-driven transcripts. Lipofection-mediated gene transfers were performed with these 3 constructs and a control plasmid, pCDNA3, in 3 human prostate cancer cell lines (LNCaP, DU-145, PC-3) and 5 other cell lines (Cos-1 [monkey kidney], HL-60 [human myeloid leukemia], Hep G2 [human hepatoma], NCI H460 [human lung cancer] and SW 480 [human colon cancer]). On transfection with PSAP-LacZ, LNCaP, DU-145, and PC-3 showed a 10.8, 1.8, and 1.6 fold increase in beta-galactosidase activity, respectively. The remaining 5 cell lines showed no changes after transfection. Corresponding to the levels of the induced beta-galactosidase activity, LNCaP showed the strongest growth inhibition by the antisense constructs: 36% by PSAP-antipol, 39% by PSAP-antitop and 80% by PSAP-antipol+PSAP-antitop. DU-145 and PC-3 had minimal growth inhibition with PSAP-antipol alone or PSAP-antitop alone. However, when cotransfected with PSAP-antipol and PSAP-antitop, DU-145 and PC-3 displayed 42% and 55% growth inhibition, respectively. In contrast, no cytotoxicity was observed in the remaining 5 cell lines when transfected with PSAP-antipol, PSAP-antitop or both. Therefore, PSAP-driven antisense gene therapy targeting DNA polymerase-alpha and Top II alpha inhibits the growth of human prostate cancer cells and the cytotoxic effect is restricted in cells of prostate origin.
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PMID:Prostate-specific antigen promoter driven gene therapy targeting DNA polymerase-alpha and topoisomerase II alpha in prostate cancer. 871 4

The combined effect of hormone and cytotoxic therapy on the growth of prostate cancer PC-3 in nude mice was investigated. PC-3 cell was derived from the bone metastasis of a hormone-refractory prostate cancer. Each group consisted of seven animals. After the inoculation of cancer cells, diethylstilbestrol (DES: 20 mg/kg) and futraful with uracil (UFT: 20 mg/kg) were administered for 25 days. DES and UFT synergically inhibited the growth. DES had no effect as a single agent on the growth of a hormone-independent cell line (KM20C) derived from human colon cancer. It also had no additive effect when given with UFT.
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PMID:[Inhibition of prostate cancer growth in nude mice by hormone and chemotherapy]. 883 49

Okadaic acid (OA), a toxin from the black sponge Halicondria okadai, is a specific inhibitor of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A). OA is a tumor promoter but also induces apoptosis in some tumor cell lines. In this study, we determined whether ras mutation and/or p53 status are characteristics associated with the cell's sensitivity to the induction of apoptosis by OA. Several cell lines that differed in ras and p53 mutations were treated with OA (10-100 nM). At 24 to 48 h after treatment, the percentage of cells undergoing apoptosis was quantitated. The cell lines with mutations in either H-ras (human bladder carcinoma cell line T24 and mouse keratinocyte cell line 308), or K-ras (human colon carcinoma cell lines DLD-1 and HCT116; human prostate cancer cell lines LNCaP and PC-3; human lung cancer cell lines Calu-6 and SKLU-1; and human pancreatic cancer cell line MIAPaCa2) were more sensitive to OA-induced apoptosis (3- to 10-fold) than the cell lines that lacked the ras mutation (mouse epidermal cell lines C50 and JB6; murine fibroblast cell line NIH3T3; human colon cancer cell line HT29; human kidney epithelial cell line Hs715.K; and human pancreatic cancer cell line Bx-PC3). Similarly, using isogenic cell lines we found that overexpression of mutated H-ras in NIH3T3 and in SV40 immortalized human uroepithelial cells (SVHUC) enhanced their sensitivity to undergo apoptosis in response to OA treatment. The T24, DLD-1, SKLU-1, Calu-6, and MIAPaCa2 cell lines express mutated p53. The SVHUC as well as their ras-transfected counterparts have inactive p53 due to complex formation between large "T" antigen and p53. Taken together, these results imply that OA-induced apoptosis may involve a p53-independent pathway. The transfectants (NIH3T3-ras and SVHUC-ras), which express mutated H-ras, have up-regulated PP2A activity. OA treatment inhibited in vivo the levels of PP1 and PP2A activity, and induced apoptosis in SVHUC-ras and other cell lines. We conclude that OA-induced cell death pathway in ras-activated cell lines may involve a cross talk between PP1 and PP2A and ras signaling pathways. In light of the present results, the current theory that OA promotes mouse skin tumor formation by selective expansion of initiated cells that harbor ras mutations needs reevaluation.
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PMID:Ras mutation, irrespective of cell type and p53 status, determines a cell's destiny to undergo apoptosis by okadaic acid, an inhibitor of protein phosphatase 1 and 2A. 1046 39

The 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. In humans there are two 3beta-HSD isoenzymes, the type 1 gene being predominantly expressed in the placenta and peripheral tissues, whereas the type 2 gene is the predominant 3beta-HSD expressed in the adrenal glands and gonads. We have recently showed that interleukin (IL)-4 and IL-13 induce 3beta-HSD type 1 gene expression in human breast cancer cell lines as well as in normal human mammary epithelial cells. The present study was designed to investigate whether such a cytokine-induced 3beta-HSD type 1 expression would also be observed in cell types derived from other peripheral sex steroid target tissues. To gain further knowledge about the molecular mechanism of IL-4 action, we have studied whether the induction of 3beta-HSD type 1 expression in IL-4-responsive cell types would always be associated with the activation of Stat6, a member of the Signal Transducers and Activators of Transcription (STAT) gene family. Stat6 is recognized as the principal transcription factor mediating the effects of IL-4. In normal human prostate epithelial cells (PrEC), no 3beta-HSD activity was detectable under basal culture conditions, while exposure to IL-4 or IL-13 caused a potent induction of this activity. This effect results from a rapid induction of 3beta-HSD type 1 messenger RNA levels as determined by Northern blot and RT-PCR analyses. Furthermore, IL-4 and IL-13 also increased 3beta-HSD type 1 gene expression in human HaCaT immortalized keratinocytes, ME-180 cervix cancer cells, HT-29 colon cancer cells as well as in BT-20 and ZR-75-1 breast cancer cells. However, IL-4 and IL-13 failed to modulate the 3beta-HSD type 1 expression in human LnCAP and PC-3 prostate cancer cells, Caco-2 colon cancer cells as well as in JAR and JEG-3 choriocarcinoma cell lines. The DNA-binding activity of Stat6 was activated after a 30-min exposure to IL-4 in PrEC and in all the cell types where IL-4 induced 3beta-HSD expression, but not in those that failed to respond to IL-4. Our data therefore suggest that IL-4 and IL-13 may play a role in the biosynthesis of active sex steroids from the inactive adrenal steroid dehydroepiandrosterone, not only in breast cells but also in various cell types derived from peripheral target tissues, such as normal human prostate epithelial cells, immortalized keratinocytes, as well as colon and cervix cancer cell lines. Our data also demonstrates that the stimulatory effect of IL-4 was always associated with the activation of Stat6, thus supporting the essential role of Stat6 in this induction of 3beta-HSD type 1 gene expression.
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PMID:Induction of 3beta-hydroxysteroid dehydrogenase/isomerase type 1 expression by interleukin-4 in human normal prostate epithelial cells, immortalized keratinocytes, colon, and cervix cancer cell lines. 1049 13

We previously reported that a novel promoter enhancer element "human tissue inhibitors of metalloproteinases 1 (TIMP-1) enhancer" (HTE) and a novel transacting protein "cysteine rich transcription factor" (CRTF) induced TIMP-1 synthesis in prostate cancer cells 2xN.I.PC-3. In the present study, to clarify the significance of CRTF in gastrointestinal cancers we measured the binding activity of CRTF to HTE using an electrophoretic mobility shift assay (EMSA), and the TIMP-1 concentration by ELISA after various stimulation of six cancer cell lines (KE-3, TE-9, MKN-28, MKN-45, KM12SM, SW620). In three cell lines (KE-3, MKN-45, SW620), both the binding activity of CRTF and TIMP-1 concentration significantly increased after IL-10 stimulation. Fetal bovine serum (FBS) did not affect the binding activity of CRTF, whereas FBS induced TIMP-1 synthesis in all cell lines. In KE-3 esophageal cancer cells and SW620 colon cancer cells, both the binding activity of CRTF and TIMP-1 concentration increased in the presence of a conditioned medium (CM) of fibroblasts which was isolated from human colon cancer tissues, but did not increase in MKN-45 cells. Moreover, in the fibroblasts, both the binding activity of CRTF and the TIMP-1 concentration increased in the presence of CM from KM12SM, SW620, and TE-9 cancer cell lines. These results suggested that IL-I0, and unknown factors in addition to IL-10, induced TIMP-1 synthesis via an increase in the binding activity of CRTF in gastrointestinal cancers, and that interaction between cancer cells and fibroblasts may play an important role in TIMP-1 synthesis through a signal transduction pathway consisting of CRTF phosphorylation and HTE activation.
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PMID:Significance of cysteine rich transcription factor (CRTF) in the synthesis of tissue inhibitor of metalloproteinases 1 (TIMP-1) in gastrointestinal cancers. 1137 Aug 21

From the supernatant of rabbit bone marrow, we isolated an organ-specific factor, which was related with the metastasis of prostate cancer to the bone and examined its adhesion to prostate cancer cells (PC-3). Molecular weight and amino acid sequence analyses of the active component obtained by high performance liquid chromatography revealed that a component identical to the alpha chain of hemoglobin accounted for 80% of the biological activity. Hemoglobin showed over 50% adhesion to PC-3 cells but only 10% adhesion to human colon cancer cell lines, representative of organ non-specific metastasis, and leukemia cells line, representative of a non-solid tumor. Some substance in the bone marrow may promote the first step of adhesion of cancer cells to bone marrow in the metastasis of prostate cancer to the bone, possibly an amino acid sequence or some tertiary structure similar to hemoglobin.
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PMID:Human prostate cancer cells adhere specifically to hemoglobin: a possible role in bone-specific metastasis. 1152 Jun 4

Cancer-induced angiogenesis is the result of increased expression of angiogenic factors, or decreased expression of anti-angiogenic factors, or a combination of both events. For instance, in colon cancer, the malignant cells, the stromal fibroblasts, and the endothelial cells all exhibit strong staining for cyclooxygenase-2 (COX-2), the rate-controlling enzyme in prostaglandin (PG) synthesis. In various cancer tissues, vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta) co-localize with COX-2. Strong COX-2 and VEGF expression is highly correlated with increased tumor microvascular density (MCD); new vessels proliferate in areas of the tumor that express COX-2. Moreover, high MVD is a predictor of poor prognosis in breast and cervical cancers. COX-2 and VEGF expression are elevated in breast and prostate cancer tissues and their cell-lines. In vitro, PGE2 induces VEGE Supernatants of cultured cells from breast, prostate, and squamous cell cancers contain angiogenic proteins such as COX-2 and VEGF that induce in vitro angiogenesis. A selective COX-2 inhibitor, NS-398, restores tumor cell apoptosis, reduces microvascular density, and reduces tumor growth of PC-3 prostate carcinoma cells xenografted into nude mice. The COX-2 produced by a malignant tumor and COX-2 produced by the surrounding host tissue both contribute to new vessel formation, which explains how selective COX-2 inhibition reduces tumor growth where the tumor COX-2 gene has been silenced by methylation.
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PMID:Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis. 1168 44

Juvenile Batten disease is a neurodegenerative disease caused by accelerated apoptotic death of photoreceptors and neurons attributable to defects in the CLN3 gene. CLN3 is antiapoptotic when overexpressed in NT2 neuronal precursor cells. CLN3 negatively modulates endogenous ceramide levels in NT2 cells and acts upstream of ceramide generation. Because defects in regulation of apoptosis are involved in the development of cancer, we evaluated the expression of CLN3 on both mRNA and protein levels in a variety of cancer cell lines and solid colon cancer tissue. We also observed the effect of the blocking of CLN3 protein expression on cancer cell growth, survival, ceramide production, and apoptosis by using an adenovirus-bearing antisense CLN3 construct. We show that CLN3 mRNA and protein are overexpressed in glioblastoma (U-373G and T98g), neuroblastoma (IMR-32 and SK-N-MC), prostate (Du145, PC-3, and LNCaP), ovarian (SK-OV-3, SW626, and PA-1), breast (BT-20, BT-549, and BT-474), and colon (SW1116, SW480, and HCT 116) cancer cell lines but not in pancreatic (CAPAN and As-PC-1) or lung (A-549 and NCI-H520) cancer cell lines. CLN3 is also up-regulated in mouse melanoma and breast carcinoma cancer cell lines. We found CLN3 expression is 22-330% higher than in corresponding normal colon control tissue in 8 of 10 solid colon tumors. An adenovirus-expressing antisense CLN3 (Ad-AS-CLN3) blocks CLN3 protein expression in DU-145, BT-20, SW1116, and T98g cancer cell lines as seen by Western blot. Blocking of CLN3 expression using Ad-AS-CLN3 inhibits growth and viability of cancer cells. It also causes elevation in endogenous ceramide production through de novo ceramide synthesis and results in increased apoptosis as shown by propidium iodide and JC-1 staining. This suggests that Ad-AS-CLN3 may be an option for therapy in some cancers. More importantly these results suggest that CLN3 is a novel molecular target for cancer drug discovery.
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PMID:The CLN3 gene is a novel molecular target for cancer drug discovery. 1183 May 36

We identified a novel mouse gene, mRTVP-1, as a p53 target gene using differential display PCR and extensive promoter analysis. The mRTVP-1 protein has 255 amino acids and differs from the human RTVP-1 (hRTVP-1) protein by two short in-frame deletions of two and nine amino acids. RTVP-1 mRNA was induced in multiple cancer cell lines by adenovirus-mediated delivery of p53 and by gamma irradiation or doxorubicin both in the presence and in the absence of endogenous p53. Analysis of RTVP-1 expression in nontransformed and transformed cells further supported p53-independent gene regulation. Using luciferase reporter and electrophoretic mobility shift assays we identified a p53 binding site within intron 1 of the mRTVP-1 gene. Overexpression of mRTVP-1 or hRTVP-1 induced apoptosis in multiple cancer cell lines including prostate cancer cell lines 148-1PA, 178-2BMA, PC-3, TSU-Pr1, and LNCaP, a human lung cancer cell line, H1299, and two isogenic human colon cancer cell lines, HCT116 p53(+/+) and HCT116 p53(-/-), as demonstrated by annexin V positivity, phase-contrast microscopy, and in selected cases 4',6'-diamidino-2-phenylindole staining and DNA fragmentation. Deletion of the signal peptide from the N terminus of RTVP-1 reduced its apoptotic activities, suggesting that a secreted and soluble form of RTVP-1 may mediate, in part, its proapoptotic activities.
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PMID:mRTVP-1, a novel p53 target gene with proapoptotic activities. 1197 68


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