Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this report, we describe the use of two human colon carcinoma cell lines, HCT-8 and HT-29, as potential models to study DNA- and RNA-directed cytotoxicity due to 5-fluorouracil (FUra) exposure by flow microfluorimetric analysis of DNA cell content. The sensitivity of the HT-29 line (EC50 = 0.9 microM) to FUra was somewhat greater than that of the HCT-8 line (EC50 = 4 microM), but each presented a dramatically different DNA histogram after exposure to FUra. In HCT-8, an unexpected and nearly complete disappearance of cells in S-phase occurred, whereas in HT-29 the expected accumulation of cells at the G1-S border was observed. The absence of HCT-8 cells in S-phase also occurred as a result of two RNA polymerase inhibitors: actinomycin D and dichloro-D-ribofuranosylbenzimidazole. However, an accumulation of cells in S-phase was observed in the presence of 5-fluorodeoxyuridine. These results suggest that in the HCT-8 cell line, FUra predominantly causes an RNA-related toxicity. By comparison, the rate of formation of 5-fluorodeoxyuridine monophosphate, the increased dUMP pool size, and low thymidylate synthase activity in the HT-29 line are consistent with its greater susceptibility to DNA-directed toxicity. Further evidence was seen in the prevention of FUra cytotoxicity by thymidine in HT-29, but not in HCT-8 cells. Similarly, Leucovorin synergized the action of FUra in HT-29 but not in HCT-8. Enzymatic correlates supporting these observations are seen in the greater activity of uridine kinase than thymidine kinase (20:1) in HCT-8 cells compared with that in HT-29 cells (4:1).
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PMID:Aberrant cell cycle inhibition pattern in human colon carcinoma cell lines after exposure to 5-fluorouracil. 787 61

We demonstrated in this study that inhibition of intra-hepatic growth of colon cancer by TAC-101 is mediated by inhibition of angiogenesis. In vitro experiments showed that TAC-101 inhibited the proliferation of murine hepatic sinusoidal endothelial (HSE) cells induced by coculture with murine colon 26-L5 (L5) cells. HSE cell proliferation was also enhanced by conditioned medium of L5 cells (CM-L5), and this enhancement of proliferation was abrogated by anti-vascular endothelial growth factor antibody. CM-L5 also induced in vitro tube formation of HSE cells on Matri-gel, and this activity of CM-L5 was abrogated by TAC-101 in a concentration-dependent manner. On the other hand, p.o. administration of TAC-101 inhibited tumor-induced angiogenesis in vivo and decreased the weights of L5 tumors in the mouse liver. Reverse transcriptase-PCR analysis using in vivo tumor tissue suggested that repression of vascular endothelial growth factor expression by TAC-101 was associated with the antiangiogenic activity. TAC-101 alone and 5-fluorouracil (5-FU)/D,L-leucovorin (LV) significantly inhibited the intrahepatic growth of L5 tumors (P = 0.002 and 0.001, respectively), whereas 5-FU alone did not (P = 0.088). When TAC-101 was administered with 5-FU/LV, marked enhancement of antitumor activity was observed (95% inhibition; P<0.001). This enhanced antitumor effect was also observed in experiments using Co-3 human colon adenocarcinoma. Concurrent treatment with TAC-101 and 5-FU/LV and sequential treatment with 5-FU/LV followed by TAC-101 resulted in significant augmentation of antitumor activity against Co-3 (overall P = 0.007 and 0.015, respectively). These findings indicate that TAC-101 inhibits tumor angiogenesis and suggest that it may be effective against hepatic metastasis of colon cancer.
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PMID:Inhibition of angiogenesis and intrahepatic growth of colon cancer by TAC-101. 1049 97