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)

An in vivo model is described for assessing the antitumor activity of chemotherapeutic agents. Tumors derived from human colon carcinoma cell lines injected into antithymocyte serum (ATS) immunosuppressed mice were used. In this system, both antitumor effects and host toxicity can be quantitated, permitting calculation of a Therapeutic Index. Compared with other xenograft models, the present system is simple, experiments are completed in less than 2 weeks, and the use of cultured cell lines allows in vitro studies to be performed. The in vitro sensitivities of one colon cell line to 22 chemotherapeutic agents and of four cell lines to three agents is reported. Four drugs used in treating colon cancer (Mitomycin C, 5-FU, BCNU, and methyl-CCNU) show antitumor activity in vivo in this system. Each has a low therapeutic index. Further work with this model is indicated, with the goal of finding new drugs with high Therapeutic Indices.
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PMID:Chemotherapy of cell-line-derived human colon carcinomas in mice immunosuppressed with antithymocyte serum. 30 40

Human colon cancer is resistant to a variety of alkylating agents including the nitrosoureas. To specifically evaluate nitrosourea resistance, we studied the role of O6-alkylguanine-DNA alkyltransferase (alkyltransferase) which is known to repair nitrosourea-induced cytotoxic DNA damage. Alkyltransferase activity varied over a similar wide range in 25 colon cancer biopsies and 14 colon cancer cell lines but the activity was not correlated with differentiation status, Dukes' classification or in vitro growth characteristics. 1,3-Bis-(2-chloroethyl)-1-nitrosourea (BCNU) resistance and alkyltransferase activity were highly correlated (R2 = 0.929, P less than 0.001) in 7 different colon cancer cell lines, suggesting that the alkyltransferase is an important component of nitrosourea resistance in colon cancer cells. In the BCNU-resistant, high alkyltransferase VACO 6 cell line, inactivation of the alkyltransferase by O6-methylguanine caused a proportional decrease in the BCNU IC50, consistent with that predicted by the regression line. Enzyme inactivation was also associated with a marked increase in DNA cross-link formation. Because alkyltransferase correlates with BCNU resistance in colon cancer, and resistance can be reversed by inactivating the protein, the alkyltransferase may have an important role in nitrosourea resistance in human colon cancer cells. These data provide the rationale for clinical trials in colon cancer with biochemical modulators of the alkyltransferase to increase the therapeutic response to nitrosoureas.
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PMID:Modulation of nitrosourea resistance in human colon cancer by O6-methylguanine. 155 83

In previous studies, we have found that combined treatment with BCNU and sodium cyanate could have a greater effect on the survival of mice bearing B16 melanoma than treatment with either agent alone. With rat hepatoma and human colon cancer cells in culture, we have obtained evidence that the inhibition of cell proliferation by sodium cyanate is greater at pH 6.6 than at pH 7.4. In the present work, the effects of combination treatments on the proliferation of cancer cells were studied with cyanate, pH, BCNU, and hyperthermia. With HT29 human colon cancer cells, the inhibitory effect of BCNU (50-100 micrograms/ml) was greater when the cells were treated at pH 6.6 than at pH 7.4. The influence of pH appeared to be absent or minimal at lower or higher concentrations of BCNU. We confirmed our previous observation that the inhibition of proliferation of LS174T human colon cancer cells is greater at pH 6.6 than at pH 7.4, and we observed an inhibitory effect of BCNU (50 or 200 micrograms/ml). However, no more than additive effects were seen with combination treatment. An inhibitory effect of hyperthermia was seen for the incorporation of [3H]-leucine into protein of rat hepatoma cells (HTC) and for that of [3H]-thymidine into DNA of human colon cancer (HT29) cells. In neither case was the effect of hyperthermia significantly enhanced by treatment with sodium cyanate beyond that seen with one of the treatments alone. The data confirmed that the inhibitory effect of sodium cyanate on cell proliferation can be enhanced by a low pH but did not provide evidence for synergistic effects in combination with BCNU or hyperthermia.
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PMID:Combined effect of pH and sodium cyanate on the inhibition of tumor cell proliferation and metabolism by BCNU and hyperthermia. 236 91

Several different strategies to improve the in vitro cytocidal effect of 5-fluorouracil/leucovorin (5FU/LV), including modulation of dosage and schedule and combination with other cytotoxic agents or biochemical modulators, were examined in the COLO 320DM and Ht-29 cell lines by means of the Bactec system. Modest enhancement of 5FU activity by coadministration of LV was observed in both human colon cancer cell lines. Neither increased concentrations of LV nor prolonged drug exposure or preincubation with LV were found to enhance significantly the growth inhibitory activity of combined 5FU/LV. The only parameter that was found to affect the killing potential of the combination was the concentration of 5-FU, suggesting that lower doses of the antimetabolite would be more effective (COLO 320DM: P less than 0.003; Ht-29 P less than 0.02). The addition of either cisplatin, hyaluronidase or dipyridamole to 5-FU/LV yielded synergistic growth inhibition in 3/6, 2/6 and 2/6 human colon cancer cell lines, respectively. Strictly additive effects were noted for the combination with BCNU as well as concurrent exposure of the cells to 42 degrees C hyperthermia. Whether or not certain combined 5FU/LV drug regimens will result in an improved therapeutic index, however, remains to be determined in properly designed clinical trials.
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PMID:A study of various strategies to enhance the cytotoxic activity of 5-fluorouracil/leucovorin in human colorectal cancer cell lines. 262 28

Chlorozotocin is a glucose-substituted chloroethyl nitrosourea with pharmacologic properties suggesting it is a relatively nonmyelosuppressive cancer chemotherapy drug. Preclinical studies have shown that this drug possesses approximately twice the in vitro alkylating activity of the chloroethyl nitrosoureas BCNU and CCNU. In the L1210 leukemia system, chlorozotocin has curative activity at doses that result in minimal bone marrow toxicity. In vitro studies of human bond marrow stem cells have shown that chlorozotocin is relatively sparing of these cells compared to BCNU. Phase I and phase II trials in man have been performed that show that chlorozotocin's dose-limiting toxicity is thrombocytopenia at doses greater than 120 mg/m2. In the phase II trial, 16% of patients with colon cancer and 20% of patients with malignant melanoma evidenced objective regression of disease. Chlorozotocin is now undergoing phase II evaluation in combination chemotherapy trials in colon and stomach cancer.
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PMID:Preclinical and clinical studies on chlorozotocin, a new nitrosourea with decreased bone marrow toxicity. 644 66

The effects of combination chemotherapy with 5FU and BCNU on rats with dimethylhydrazine (DMH)-induced colon cancer were investigated in a long term survival study. Eighty Wistar rats received a colon cancer producing regimen on DMH (40 mg/kg body weight/week, subcutaneously for 10 weeks). After presenting with signs of colonic disease, all rats underwent diagnostic laparotomy and colonoscopy when colon tumours were located, measured and the extent of the disease staged. Only animals with tumours (n = 63) were included and allocated to one of three tumour stages. Stage A (n = 17), had colonic tumours without serosal involvement; stage B (n = 28) had serosal involvement without metastases; stage C (n = 18) had serosal involvement with lymphadenopathy and/or metastases. Each group was randomly allocated into two subgroups, one serving as untreated controls while the other received 5FU (300 mg/m2 weekly intragastrically for life) together with BCNU (40 mg/m2 intraperitoneally on days 0, 42 and 84). The effect of chemotherapy on tumour growth was measured sequentially by colonoscopy. Animals were observed until death and necropsied, when colon carcinoma was histologically confirmed and survival analysed. The results indicate that chemotherapy significantly prolongs the survival of rats with the least advanced disease (stage A) but was of no benefit to rats with locally advanced or metastatic disease (stages B and C). Furthermore, chemotherapy was associated with a significant reduction in tumour size. Survival analyses in untreated animals show that the laparotomy staging system adopted provides accurate prognostic information. This study shows that DMH-induced colon tumours are chemosensitive, and suggests that this animal model may be a valuable testing ground for new chemotherapeutic agents.
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PMID:Combination chemotherapy with 5-fluorouracil (5FU) and 1,3-bis(2-chloro-ethyl)-1-nitrosourea (BCNU) prolongs survival of rats with dimethylhydrazine-induced colon cancer. 662 14

The ability of lonidamine (LND), an energolytic derivative of indazole carboxylic acid, to modulate the cytotoxic activity of mitomycin C (MMC) and 1,3,bis(2-chloroethyl)-1-nitrosourea (BCNU) was investigated in two human adenocarcinoma cell lines (LoVo and HT29) expressing different sensitivity profiles to the drugs. After a 1-h treatment with MMC or BCNU, cells were postincubated for 24 h with 150-225 microM LND. In the LoVo cells, a synergistic interaction between LND and MMC or BCNU was observed at both LND concentrations. In HT29 cells, only additive effects of the drugs given in sequence were seen. Flow cytometric analysis indicated that LND was generally able to stabilise the cell cycle perturbations induced by MMC and BCNU in the two cell lines. The ability of LND to potentiate anticancer drug activity, and the consideration that LND causes side-effects different from those of conventional antitumour drugs, make this compound an attractive candidate for multidrug combination therapy in colon cancer.
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PMID:In vitro effect of lonidamine on the cytotoxicity of mitomycin C and BCNU in human colon adenocarcinoma cells. 783 93

The DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase) repairs cytotoxic DNA damage formed by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). High levels of this repair protein cause tumor drug resistance to nitrosoureas. To investigate the ability of a direct alkyltransferase inhibitor, O6-benzylguanine, to reverse the nitrosourea resistance of human colon cancer cells, we studied the VACO 6 cell line which has high alkyltransferase and is completely resistant to BCNU at maximal tolerated doses in the xenograft model. O6-Benzylguanine at 0.5 microgram/mL for 1 hr inactivated VACO 6 alkyltransferase by > 98% and reduced the IC50 of BCNU by 3- to 4-fold. Further analysis indicated that these two agents act in a highly synergistic fashion. In xenograft bearing athymic mice, dose-dependent depletion of hepatic and tumor alkyltransferase was noted. To maintain alkyltransferase depletion in the xenograft for at least 24 hr, two doses of 60 mg/kg O6-benzylguanine were given 1 hr prior and 7 hr after BCNU. Under these conditions, VACO 6 xenografts became responsive to BCNU with significant reductions (P < 0.001) in the tumor growth rate. The combination increased toxicity to the host, reducing the maximum tolerated dose of BCNU by approximately 50%. This study provides definitive evidence that high alkyltransferase activity is responsible for BCNU resistance in human colon cancer xenografts and that with careful drug scheduling, O6-benzylguanine can sensitize a tumor which is completely unresponsive to BCNU alone. Further studies which optimize the therapeutic index of BCNU and O6-benzylguanine in vivo will define the schedule to be used in broader preclinical studies.
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PMID:Synergistic efficacy of O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in a human colon cancer xenograft completely resistant to BCNU alone. 843 98

We investigated the ability of 5-(dimethyltriazeno)imidazole-4-carboxamide (DTIC, decarbazine) and an analogue, temozolomide, to deplete cells or tumors of O6-alkylguanine-DNA alkyltransferase (AGT) and to enhance the antitumor effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Human colon cancer (HT29) cell survival was decreased by almost 1 log when treated with 500 microM temozolomide prior to 150 microM BCNU. Administration of the maximal tolerated dose of DTIC (300 mg/kg) to nude mice carrying HT29 xenografts resulted in complete depletion of AGT activity in tumors at 4 h and 16 h. Administration of 150 mg/kg DTIC caused a 76% reduction in AGT activity at 4 h, but only a 28% reduction at 16 h. The maximally tolerated doses of DTIC and BCNU, alone and in combination, were used to treat nude mice bearing HT29 xenografts. No difference in tumor growth occurred when animals were treated with either BCNU alone (50 mg/kg), DTIC alone (300 mg/kg), DTIC (150 mg/kg) followed by BCNU (12.5 mg/kg), or BCNU (25 mg/kg) followed by DTIC (150 mg/kg). These data suggest that methylating agents such as DTIC may be too toxic to be used in combination with BCNU to deplete tumor alkyltransferase levels effectively and increase the therapeutic index of BCNU.
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PMID:Effect of temozolomide and dacarbazine on O6-alkylguanine-DNA alkyltransferase activity and sensitivity of human tumor cells and xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea. 846 25

We have shown earlier that pre-treatment of V79 Chinese hamster cells with 6-aminonicotinamide (6-AN) or 2-deoxyglucose (2-dG) results in over-expression of the Mr 78,000 glucose-regulated stress protein (GRP78) and the subsequent development of resistance to inhibitors of topoisomerase II. These phenomena also occur in V79-derived cell lines that are deficient in poly(ADP-ribose) (p(ADPR)) metabolism. In contrast, over-expression of GRP78 under the conditions outlined above is found to be associated with hypersensitivity to several clinically-relevant DNA cross-linking agents, namely, 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, and melphalan. We have also previously shown that pre-treatment with 6-AN, an inhibitor of p(ADPR) metabolism, causes an increase in the life span in BCNU-treated mice bearing L1210 tumors. These observations prompted us to examine whether 6-AN pre-treatment can result in the over-expression of GRP78 in human colon cancer cell lines and, if so, whether this increase is associated with sensitization to DNA cross-linking agents outlined above. Following treatment of three colon cancer cell lines, HCT116, SW480, and VACO-8, for 48 h with 0.1 mM 6-AN, cytosolic GRP78 levels were elevated approximately 4.2 times, 8 times, and 2.5 times for each cell line respectively, as measured by Western immunoblotting. To determine sensitivity after GRP78 up-regulation, the cells were washed and grown for 412 h in growth medium devoid of 6-AN, before being treated with DNA cross-linking agents. The 412 h time period allowed p(ADPR) metabolism to return to normal while GRP78 levels remained elevated, thus allowing us to associate GRP78 over-expression with sensitivity to those agents. After treating cells for 1 h with BCNU, cisplatin, or melphalan, cell sensitivity was determined by clonogenic survival assay or a fluorescence-based cytotoxicity assay. Based on changes in IC50 values, 6-AN caused an increase in sensitivity for HCT116, SW480, and VACO-8 cells of 1.5, 2.3, and 1.0 times, respectively, for BCNU, 4.8, 3.8, and 2.6 for cisplatin, and 6.4, 3.7, and 2.2 times for melphalan. Thus, our results show that over-expression of GRP78 in human tumor cell lines is associated with increased sensitivity to clinically useful chemotherapy agents. This sensitization occurred in three different tumor cell lines, each bearing a separate genetic defect associated with altered sensitivity.
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PMID:Increased sensitivity of human colon cancer cells to DNA cross-linking agents after GRP78 up-regulation. 1019 18


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