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)

Limited studies have indicated that some chemotherapy agents activate the transcription factor nuclear factor-kappaB (NF-kappaB), and that this leads to suppression of the apoptotic potential of the chemotherapy. In contrast, it was reported recently that stable inhibition of NF-kappaB in four different cancer cell lines did not lead to augmentation of the chemotherapy-induced apoptosis. In this study, we have focused on colorectal cancer, which is known to be highly resistant to genotoxic chemotherapy and gamma irradiation. We show that the topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) activates NF-kappaB in most colorectal cancer cell lines. We then examine a therapeutic strategy that uses adenovirus-mediated transfer of the super-repressor IkappaBalpha to inhibit NF-kappaB activation as an adjuvant approach to promote chemosensitivity in colorectal tumor cells to treatment with CPT-11. These data demonstrate that the protection from apoptosis induced in response to CPT-11 treatment is effectively inhibited by the transient inhibition of NF-kappaB in a variety of human colon cancer cell lines and in a tumor xenograft model, resulting in a significantly enhanced tumoricidal response to CPT-11 via increased induction of apoptosis. These findings indicate that the activation of NF-kappaB by chemotherapy is an important underlying mechanism of inducible chemoresistance.
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PMID:Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothe cin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-kappaB activation. 1081 Nov 1

We reviewed the results of chemotherapy for gastrointestinal cancer. In Western countries, FAMTX or ECF is recognized as the standard therapy for gastric cancer. In Japan, no standard chemotherapeutic regimen has been established yet, but FP or MTX/5-FU are often used as a first line chemotherapy. There have been only a few clinical trials of adjuvant chemotherapy for gastric cancer in which this regimen was identified as having a statistically significant effect. For colon cancer, 5-FU plus LV are now used as the standard therapy. Recently, however, it has been shown that 5-FU + LV combined with CPT-11 is more active than 5-FU + LV alone. The efficacy of oral anticancer agents such as UFT + LV, S-1, and capecitabin have also been shown to be equally or more active than i.v. administration of 5-FU and LV, so that the standard therapy for colon cancer will be changed in near future.
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PMID:[State of the treatment for gastrointestinal cancer]. 1094 22

BNP1350, 7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, is a novel semi-synthetic, highly lipophilic, silicon-containing camptothecin and an inhibitor of topoisomerase I. It has been supercomputer engineered for superior oral bioavailability, superior lactone stability, broad anti-tumor activity, increased potency and insensitivity to Pgp/MRP/LRP drug resistance. We determined the efficacy of BNP1350 in experimental human colon cancer and compared its anti-tumor effects with those of CPT-11/SN-38. We also determined a possible influence of Pgp, MRP and LRP on the efficacy of BNP1350. The in vitro anti-proliferative capacity of the compounds using various exposure times was assessed in five colon cancer cell lines and indicated that BNP1350 was similarly effective or slightly more potent than SN-38. Four cell lines of other origin with sublines expressing Pgp, MRP and/or LRP showed that BNP1350 was significantly more effective than SN-38 (p < 0.05) and that the activity of BNP1350 was not reduced in multidrug-resistant cells. For in vivo experiments, BNP1350 was given 1.0 mg/kg i.p. or 1.5 mg/kg p.o. daily x 5 and CPT-11 20 mg/kg i.p. daily x 5 being equitoxic schedules in nude mice bearing s.c. human tumor xenografts. The schedules were studied in colon cancer xenografts COLO320, COLO205 or WiDr as well as in two Pgp-positive xenografts 2780AD and BRO/mdr1.1 and the parental Pgp-negative A2780 ovarian cancer xenografts and BRO melanoma xenografts. Growth inhibition of >50% was obtained for BNP1350 given i.p. in six out of the seven xenografts studied. BNP1350 was similarly effective when given i.p. or p.o. CPT-11 was as effective as BNP1350, except in BRO and BRO/mdr1.1 xenografts. Pgp expression in xenografts in vivo confirmed that there was no negative influence on the efficacy of BNP1350. In conclusion, BNP1350 shows a broad spectrum of activity in experimental human tumors and is a suitable candidate for oral treatment of cancer.
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PMID:New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer. 1100 78

To evaluate the significance of surgical adjuvant chemotherapy, randomized controlled trials (RCTs) of adjuvant chemotherapy after curative resection for colorectal cancer were reviewed. Several multi-drug systemic chemotherapies (MOF, MMC/FT, 5-FU, UFT p.o.) were useful as adjuvant treatment to improve survival or disease-free survival of patients with colorectal cancer. Moreover, a worldwide meta-analysis suggested that continuous intraportal 5-FU infusion improves survival. Combination chemotherapy trials utilizing 5-FU and levamisol (LEV) demonstrated a survival advantage in patients with high risk colon cancer. Recently, many RCTs have substantiated the benefits of treatment with 5-FU/Leucovorin (LV) and this treatment is widely used as adjuvant treatment for the patients with Dukes C resected colon cancer in Europe and the U.S.A. Now, with the increasing use of oral chemotherapy drugs, new trials comparing oral UFT/LV with intravenous 5-FU/LV are being implemented to investigate these drugs in terms of QOL, toxicity and cost. Furthermore, the new drug irinotecan (CPT-11) is now under investigation to see if it brings added efficacy to 5-FU/LV. In Japan, two major groups (N-SAS-CC and TAC-CR) are comparing surgery alone and UFT alone in patients with Dukes C colon and rectal cancer. From these results, surgical adjuvant chemotherapy seems to be effective in the treatment of patients with high risk colon cancer and those with rectal cancer.
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PMID:[Recent advances is surgical adjuvant chemotherapy for colorectal cancer]. 1114 63

Though the first choice of treatment for liver metastasis in colon cancer is surgical resection of liver, 30-60% of such patients experience a recurrence of liver metastasis. Even if reoperation is done optimally, the surgical resection of liver metastasis may not be a definitely curative treatment. For cases of liver metastasis from colon cancer that are non-resectable due to multiple liver metastases, other organ metastases (lung, bone, brain etc.), the advanced age of the patient, or other complications (cerebrovascular disease, diabetes mellitus, heart disease etc.), hepatic arterial infusion or systemic combination chemotherapies are selected. In the present paper, we report 3 cases of effective systemic chemotherapy utilizing CPT-11 for liver metastases from colon cancers. The method was UFT + irinotecan (CPT-11), cisplatin (CDDP) + tegafur + CPT-11, UFT + CPT-11 + etoposide (ETP) + pirarubicin (THP). The result obtained was a partial response (PR) in each case. As there were few adverse effects, we could provide treatment during a short-term admission or an outpatient basis. We thus obtained good post-chemotherapeutic QOL, and these regimens may be effective forms of chemotherapies in the future.
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PMID:[Three cases of liver metastasis of colon cancer responding to systemic combination chemotherapy utilizing CPT-11]. 1114 72

Identification of the molecular determinants of 5-fluorouracil (5-FU) and irinotecan (CPT-11) efficacy and toxicity is critically important for the development of more efficient and less toxic treatment strategies for patients with colon cancer. We have identified molecular predictors of response to chemotherapy with 5-FU and survival in patients with advanced colorectal cancer. Low gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) are associated with response and survival. Preliminary data suggest that gene expression levels of topoisomerase I, p21, bcl-2, and ICE may be predictive of response to therapy with CPT-11. Increased toxicity seen in patients treated with CPT-11 may be explained by polymorphism in the UGT1A1 gene, which is responsible for glucuronidation of the active metabolite of CPT-11.
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PMID:Determinants of prognosis and response to therapy in colorectal cancer. 1117 41

Preclinical studies at Roswell Park Cancer Institute by Minderman, Cao, and Rustum (unpublished results) showed that a combination of SN-38 and 5-FU against HCT-8 human colon carcinoma cells in vitro was synergistic, with the best interaction occurring when the drugs were added sequentially, SN-38 first. Their in vivo studies using HCT-8 tumor xenografts implanted s.c. in nude athymic mice demonstrated superior efficacy for a sequential i.v. administration of CPT-11, 24 hr before 5-FU. On the basis of these studies, our group has begun to evaluate effects of RFS2000 (9-nitro-20(S)-camptothecin) (9-NC) in combination with a series of other antitumor agents. Using a panel of human tumor cell lines including A121 ovarian cancer, HCT-8 colon cancer, H-460 NSCLC, HT-1080 fibrosarcoma, and MCF7 mammary cancer, we found that a 2-hr exposure to 9-NC resulted in ID50 values of < 1.0 microM, whereas continuous exposure to drug resulted in ID50 values of < 1.0 nM. Tumor growth inhibitory activities of 5-FU, gemcitabine, and paclitaxel were determined for comparison. Combinations of these agents were evaluated with 9-NC using the human HCT-8 colon tumor cell line. Concurrent and sequential combinations of 9-NC with 5-FU had some regions of the concentration-effect surface with local synergy and some with local antagonism. However, sequential combination of 9NC or SN-38 followed by 5-FU, 24 hr later appeared to be highly synergistic at high dose-effect levels (i.e., ID90), suggesting that sequential drug administration may be more efficacious at high effect level and that the order of drug addition is very important. Overall, our results were similar to that found earlier by Rustum's group with CPT11 (or SN-38) and 5-FU, suggesting that sequential combination of 9-NC (or other camptothecin analogues) followed by 5-FU has potential for the treatment of cancer in man.
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PMID:In vitro antitumor activity of 9-nitro-camptothecin as a single agent and in combination with other antitumor drugs. 1119 4

Adjuvant therapy, believed by some to be of no benefit for colorectal cancer as recently as 10 years ago, now offers thousands of patients considerable hope after surgical resection. The first effective adjuvant regimen--combined fluorouracil (5-FU) and levamisole--described in 1989, was soon supplanted by a variety of 5-FU-based regimens, usually combined with leucovorin. Although most recent research in the adjuvant setting has focused on refining chemotherapy doses, schedules, and combinations, with the aim of improving efficacy and decreasing toxicity, investigators have also explored other approaches, such as portal vein infusion, monoclonal antibodies, interferon-alpha, and vaccines. Future directions being evaluated for adjuvant therapy of colon cancer include the use of oral fluorinated pyrimidines, which may replace current intravenous treatments, as well as the incorporation of new agents, such as oxaliplatin and CPT-11, into adjuvant chemotherapy programs.
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PMID:Adjuvant therapy of colon cancer. 1119 81

The current recommendation for adjuvant chemotherapy for patients with newly diagnosed stage III colon cancer involves 6 months of fluorouracil (5-FU) plus low- or high-dose leucovorin. In clinical trials performed throughout the world, several drugs have demonstrated either improved toxicity profiles or antitumor activity for patients with advanced colorectal carcinoma. Uracil and tegafur (UFT) and capecitabine (Xeloda) are two examples of new oral chemotherapy compounds with acceptable side-effect profiles in early adjuvant or advanced disease trials. Irinotecan (CPT-11, Camptosar) and oxaliplatin, when administered intravenously in combination with a 5-FU regimen, have both demonstrated significant antitumor effects for patients with advanced-stage disease. Other immunotherapies, including monoclonal antibodies and cancer vaccines, are being evaluated to help stimulate immune responses in patients with resected colon cancer. These agents are just a few examples of the new compounds being tested in the next generation of clinical trials for resected stage III colon cancer. Future and ongoing investigations will look to integrate these new therapies as we attempt to move beyond the era of 5-FU and leucovorin.
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PMID:Future directions in adjuvant therapy for stage III colon carcinoma. 1130 38

Epidermal growth factor (EGF) receptors are expressed at high levels in about one third of epithelial cancers, and autocrine activation of EGF receptors appears to be critical for the growth of many tumors. We hypothesized that blockade of the binding sites for EGF and transforming growth factor-alpha on EGF receptors with an antireceptor monoclonal antibody (mAb) might be an effective anti-cancer therapy. We produced murine mAb 225 against EGF receptors and demonstrated blockade of receptor function, as well as inhibition of cell growth in cultures and in nude mouse xenografts. mAb C225 is the human:murine chimeric version of mAb 225. Cell cycle inhibition occurred in G(1) phase, and was due to upregulation of p27(Kip1), resulting in inhibition of cyclin E/cyclin dependent kinase-2 activity and hypophosphorylation of Rb. In addition, the amount and/or activities of a number of proapoptotic molecules were enhanced. The antitumor activity in vivo against xenografts was at least partly attributable to reduced vascularization, resulting from decreased vascular endothelial growth factor and basic fibroblast growth factor production by the tumor cells. Metastasis of xenografts was curtailed with mAB C225 treatment, accompanied by a decrease in tumor production of MMP-9. Further studies showed that mAbs 225 and C225 enhanced the cytotoxicity of chemotherapy against xenografts of a variety of human cancer cell lines. Well established xenografts resistant to either mAb or drug treatment alone were eradicated by the combination therapy. Drugs for which this has been demonstrated include doxorubicin, paclitaxel, cisplatin, and topotecan. Antibody treatment also potentiated the responsiveness of human tumor xenografts to radiation therapy. These findings led to clinical trials of human:murine chimeric mAb C225 in combination with chemotherapy or radiotherapy. Results from phase I and II trials involving more than 500 patients are quite promising, in particular in advanced head and neck cancer treated with C225 plus cisplatin or radiation, in advanced colon cancer treated with C225 plus CPT-11, and in advanced pancreatic cancer treated with C225 plus gemcitabine. Phase III trials are now underway.
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PMID:The epidermal growth factor receptor as a target for cancer therapy. 1135 Jul 23


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