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

The goal of this study was to demonstrate that glutathione S-transferase (GST)-pi is directly involved in the intrinsic and acquired resistance of cancer cells to anticancer drugs. To this end, GST-pi antisense cDNA was transfected into the cultured human colon cancer cell line M7609, which expresses an innately high level of GST-pi and shows intrinsic drug resistance, and into an M7609 strain with acquired resistance to Adriamycin (ADR;i.e., M7609/ADR cells). The changes in the sensitivity of these transfectants to various anticancer drugs were investigated. The intracellular concentrations of GST-pi in M7609/anti-1 cells and M7609/anti-2 cells, two clones that were established by transfection of GST-pi antisense cDNA into M7609 cells, were decreased to approximately half of those detected in the parent cells (M7609) and in the control cells transfected with vector alone (M7609/pLJ). The sensitivities of the antisense transfectants in relation to ADR, cisplatin, melphalan, and etoposide were increased -3.3-fold, 2.3-fold, 2.2-fold, and 2.1-fold, respectively, compared with those of M7609 and M7609/pLJ. On the other hand, the sensitivities of the antisense transfectants to Taxol, vincristine, 5-fluorouracil, and mitomycin C were not significantly changed. Similarly, the transfection of antisense cDNA into M7609/ADR cells resulted in the reduction of intracellular GST-pi concentration (by about half) and an increased sensitivity to ADR (4.4-fold), but no increase in 5-fluorouracil sensitivity. Thus, GST-pi is considered to be a multidrug resistance factor that is responsible for both the intrinsic and acquired resistance of cancer cells to anticancer drugs such as ADR, cisplatin, melphalan, and etoposide.
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PMID:Transfection of glutathione S-transferase (GST)-pi antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan, and etoposide. 875 29

Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the cytostatics capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) and its intermediate metabolite [5'-deoxy-5-fluorouridine (5'-dFUrd)] to 5-fluorouracil in tumors. We have tried to identify the best partners of capecitabine in combination therapy, such as dThdPase up-regulators, which may enhance the efficacy of this compound. Among various cytostatics studied with the WiDr human colon cancer xenograft model, Taxol, Taxotere, and mitomycin C greatly increased levels of human dThdPase in tumors, and cyclophosphamide slightly increased the enzyme level. These cytostatics simultaneously increased the levels of human tumor necrosis factor alpha (TNFalpha), which is an up-regulator of dThdPase. In cultures of the WiDr cells, however, Taxol did not up-regulate TNFalpha to a detectable level and only slightly enhanced levels of dThdPase. These results suggest that Taxol might indirectly elevate TNFalpha in tumor cells, which in turn up-regulated dThdPase in the tumor cells in the WiDr cancer xenograft. In the combination therapy, the efficacy of Taxol and Taxotere with either capecitabine or 5'-dFUrd was more than just additive. In contrast, Taxol and either 5-fluorouracil or UFT (a mixture of tegafur and uracil) in combination showed only additive activity. Taxol and Taxotere might enhance the efficacy of capecitabine and 5'-dFUrd, probably by modulating dThdPase activity in tumor tissues.
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PMID:Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. 956 97

Herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) gene therapy can induce apoptosis in tumor cells that are normally resistant to this type of cell death, although the cellular mechanisms by which this occurs remain to be elucidated. Human colon tumor cell lines expressing HSV-TK were treated with GCV or four other inducers of apoptosis: butyrate, camptothecin (CPT), Taxol (paclitaxel), or 7-hydroxystaurosporine (UCN-01). Over a 2-4 day treatment period with GCV or the other four drugs, protein levels of the apoptosis agonist Bak increased 1.5- to 3-fold, whereas a corresponding decrease in the levels of the apoptosis antagonist, Bcl-X(L), was observed in butyrate-, CPT-, and 7-hydroxystaurosporine (UCN-01)-treated cells. GCV and paclitaxel treatments resulted in increased levels of Bcl-X(L). In two-drug combinations with GCV plus one of the four other drugs, increased tumor cell killing was found with GCV plus UCN-01 or with some GCV/butyrate combinations; the other two tested combinations were largely antagonistic. The GCV/UCN-01 and GCV/butyrate combinations resulted in increased Bak and decreased Bcl-X(L) protein levels, while the GCV/CPT and GCV/paclitaxel combinations resulted in increased levels of both proteins. The results highlight the potential for new combination therapies of HSV-TK/GCV and chemotherapeutic drugs that result in increased tumor cell apoptosis for future treatments of colon cancer.
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PMID:Two-drug combinations that increase apoptosis and modulate bak and bcl-X(L) expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase. 1081 74

Protein kinase A type I (PKAI) transduces mitogenic signals from different growth factors and oncogenes and is overexpressed in the majority of human cancers. We and other investigators previously have reported that different PKAI inhibitors, including antisense oligonucleotides, have antitumor activity. In this study, we used a novel hybrid DNA/RNA mixed-backbone oligonucleotide (MBO) targeting the PKAI subunit RIalpha. We demonstrated that after oral administration, the MBO antisense RIalpha inhibited the growth of human colon cancer xenografts in nude mice and showed a cooperative antitumor effect with Taxol, which outlasted treatment withdrawal and significantly prolonged survival of mice compared with untreated controls or to single-agent-treated mice. Immunohistochemical analysis of tumor specimens showed inhibition of target protein RIalpha and of growth factor expression along with a marked inhibition of angiogenesis and an increase in p27 expression. In conclusion, a novel MBO that targets PKAI, administered p.o., is effective and cooperates with the anticancer drug Taxol on both tumor growth and expression of factors involved in the control of cell proliferation, cell cycle, and angiogenesis. Because the MBO described has completed a phase I trial involving i.v. injection in cancer patients, these results provide the biological rationale of its activity after oral administration and may be translated into a therapeutic strategy in a clinical setting.
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PMID:Oral antisense that targets protein kinase A cooperates with taxol and inhibits tumor growth, angiogenesis, and growth factor production. 1087 6

Vinorelbine (VNR) is a new vinca alkaloid derivative semi-synthesized by Potier et al. The antitumor activity of VNR was superior to other vinca alkaloid antitumor agents, and the neuro-toxicity of VNR was weaker than those of other vinca alkaloids. In nude mice xenografted human tumor models, VNR showed antitumor activity against eight of eleven tumor models (non-small cell lung cancer: 4/4, breast cancer: 2/3, colon cancer: 0/2, stomach cancer: 2/2). Especially, VNR showed tumor-regressive activity against LC-6 non-small cell lung cancer and MX-1 breast cancer. The antitumor activity of VNR against non-small cell lung cancer was superior to that of vindesine (VDS), which had been one of the key drugs of non-small cell lung cancer in the clinic. In combination chemotherapy, VNR plus cisplatin (CDDP) was better than VDS plus CDDP, which had been one of the standard regimens of non-small cell lung cancer chemotherapy. The potent antitumor effect of VNR with minor neurotoxicity was explained by VNR having stronger activity on mitotic microtubules than axonal microtubules. It was supposed that less activity of VNR against mitotic microtubules would be related to different composition of microtubule-associated TAU isoforms in the two types of microtubules. In non-small cell lung cancer, VNR resulted in a significantly higher response rate than VDS. In combination with CDDP, VNR resulted in longer survival than VDS with a significant log-rank test. In advanced breast cancer, VNR resulted in a high response rate in 1st line and 2nd line treatment. VNR is effective in combination with chemotherapeutic agents such as anthracycline, fluorouracil and Taxol. In Japan, the clinical trial in breast cancer is now ongoing.
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PMID:[Properties of antitumor activity of vinorelbine tartrate, a new vinca alkaloid antitumor agent]. 1108 18

Modulation of the immune response against tumour cells is emerging as a valuable approach for cancer treatment. Some experimental studies have shown that secretion of colony stimulating factors by cancer cells reduces their tumorigenicity and increases their immunogenicity probably by promoting the cytolitic and antigen presenting activities of leukocytes. We have observed that human colon cancer cells (HT-29) are able to secrete granulocyte-macrophage-colony stimulating factor, granulocyte-colony stimulating factor and macrophage-colony stimulating factor when stimulated with cytokines (IL-1beta and TNF-alpha). In this study we assessed, for the first time, the effects of several anticancer drugs on colony stimulating factor release or apoptosis in HT-29 cells. Cytokine-induced release of granulocyte-macrophage-colony stimulating factor, granulocyte-colony stimulating factor and macrophage-colony stimulating factor was significantly increased by cisplatin and 6-mercaptopurine. Taxol only increased macrophage-colony stimulating factor release while reduced that of granulocyte-colony stimulating factor. No changes in colony stimulating factor secretion were observed after treatment with methotrexate. Only cisplatin and taxol induced apoptosis in these cells. Secretion of colony stimulating factors by colon cancer cells may contribute to the immune host response against them. Anticancer drugs such as cisplatin and 6-mercaptopurine increase colony stimulating factor secretion by cytokine stimulated cancer cells probably through mechanisms different to those leading to cell apoptosis, an effect that may contribute to their anti-neoplasic action.
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PMID:Modulation of colony stimulating factor release and apoptosis in human colon cancer cells by anticancer drugs. 1195 91

A series of Taxol derivatives tethered at C2' and C-7 to glutamate and folate have been synthesized for evaluation as prodrugs which release Taxol via hydrolytic lability of their alpha-alkoxy and alpha-amino esters. The half-time for hydrolysis of these materials was determined in pH 7 and pH 5 buffer. The in vitro cytotoxicity has been assessed in cell culture against A-549 lung cancer, MCF-7 breast cancer, and HT-29 colon cancer. Selected agents were further screened for folate binding and competitive binding with free folic acid. One agent (54), further evaluated in animal studies was found to increase the lifespan in mice, but was less effective than Taxol itself.
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PMID:Synthesis and evaluation of taxol-folic acid conjugates as targeted antineoplastics. 1198 37

Sangre de grado is an ethnomedicinal red tree sap obtained from Croton spp. that is used to treat gastrointestinal ulcers, cancer and to promote wound healing. To evaluate the potential role of sangre de grado (SdG) in cancer we examined its effects on human cancer cells, AGS (stomach), HT29 and T84 (colon). Viability of cells treated with SdG (10-200 microg/ml) decreased (P<0.01) in a dose dependent manner measured over a 24-h period. Cell proliferation at 48 h decreased (P<0.01) in all cells treated with SdG (>100 microg/ml). When cells in suspension were treated with SdG (100 microg/ml) cell adherence was severely compromised (>85%). Cells treated with SdG (100 microg/ml) underwent apoptosis as detected by nucleus condensation and DNA fragmentation determined by ELISA, and flow cytometry. Morphological changes as assessed by acridine orange. These effects were similar to that observed with Taxol (30 microM). A significant alteration of microtubular architecture was equally observed in both stomach and colon cancer cells exposed to SdG (100 microg/ml). The induction of apoptosis and microtubule damage in AGS, HT29 and T84 cells suggest that sangre de grado should be evaluated further as a potential source of anti-cancer agents.
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PMID:Sangre de grado Croton palanostigma induces apoptosis in human gastrointestinal cancer cells. 1200 1

Anticancer compound screening of natural products using tumor cell lines has been commonly used to identify anticancer drugs. Two highly significant anticancer drugs, paclitaxel (Taxol) and camptothecin, were discovered using tumor cell lines by the U.S. National Cancer Institute (NCI) screening program of plants. It has been recently reported that the inhibition of cancer cell proliferation by fruit extracts was indirectly caused by phenolic-induced H(2)O(2) production in the cell culture media, suggesting that many previously reported effects of flavonoids and phenolic compounds on cultured cells might be from an artifact of H(2)O(2)-induced oxidative stress. The objective of the present study was to determine if apple extracts induced H(2)O(2) formation in common cell culture media and to investigate if the antiproliferative activity of apple extracts was due to phenolic-induced H(2)O(2) formation. It is reported here that apple extracts did not induce H(2)O(2) formation in WME, DMEM, or DMEM/Ham F12 media with the cell culture conditions tested. These same extracts inhibited proliferation of HepG(2) and Caco-2 cells. Therefore, antiproliferative activity of apple extracts was not due to the phenolic-induced H(2)O(2) production in cell culture media. In addition, H(2)O(2) added to the culture medium at 100 microM did not cause inhibition of cell proliferation in either HepG(2) liver cancer cells or Caco-2 colon cancer cells in vitro.
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PMID:Antiproliferative activity of apples is not due to phenolic-induced hydrogen peroxide formation. 1261 11

When SW620 colon cancer-derived metastatic cells were exposed to nanomolar concentrations of Taxol, colchicine or (Z)-3,5,4'-trimethoxystilbene (R3), huge aneuploid, polynuclear cells survived the treatment. These cells released considerable amounts of the matrix metalloproteinase matrilysin (MMP-7), and tissue-type plasminogen activator (tPA) into the surrounding culture medium. MMP-7, and other proteolytic enzymes were highly expressed by these cells. In spite of their enormous size, the polyploid cells exhibited a considerable migratory capacity, as was demonstrated by their migration through an artificial basement membrane. While colchicine and R3-treated cells showed an inverse relationship between drug concentration and invasiveness, treatment with Taxol increased the capacity of the SW620 cells to penetrate through the membrane. The invasive capacity was not correlated with the induction and release of proteolytic enzymes. The idea that expression and release of proteolytic enzymes is a fundamental prerequisite of tumour cell invasiveness is generally accepted. The ability of the cells to respond to chemotactic signalling, and the filamentous structures of the cells, together with several cell adhesion factors, which are the basis of cell migration, are prerequisites of invasiveness. These factors are presumably different in the aneuploid cells produced by Taxol, colchicine and R3, and await scrutiny.
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PMID:Polyploidisation of metastatic colon carcinoma cells by microtubule and tubulin interacting drugs: effect on proteolytic activity and invasiveness. 1537 54


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