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)

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

Analysis of camptothecins in biologic media is hampered by chemical hydrolysis of the parent lactone (form I) to an inactive hydroxy acid (form II). A solid-phase extraction (SPE) method utilizing C2-bonded silica particles (100 mg, 1 ml) is presented for simultaneous determination of forms I and II of camptothecin (CPT) and SN-38 (active metabolite of clinically used CPT-11) in culture media and cell lysates. A new HPLC separation is described that efficiently resolves all four compounds employing gradient elution with 10 mM ammonium acetate, increasing methanol (20-80% over 15 min), and a 15-cm by 3-mm Symmetry Shield (RP8) column. Components were detected by fluorescence at an excitation wavelength of 380 nm and emission wavelength of 423 nm. Lactones were shown to be unstable at alkaline pH and hydroxy acids unstable at alkaline pH while the following conditions preserved the chemical equilibrium in specimens: samples kept on ice, final pH of eluates 7.4, autosampler temperature 4 degrees C, and analysis cycle <4 h. Quantitative recovery of lactones was achieved from RPMI culture medium over a wide concentration range (93.5-111.6% for 1-400 ng/ml) although greater variability was noted with the hydroxy acids (59.6-110.3%, 1-400 ng/ml). Limit of quantitation (precision and accuracy <20%) was 0.2 ng/ml for CPT lactone, 0.5 ng/ml for SN-38 lactone, and 2 ng/ml for the two hydroxy acids. The method was applied to quantitate the accumulation of SN-38 and CPT (form I and II) in HT29 and HCT116 human colon cancer cells.
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PMID:High-performance liquid chromatographic technique for the simultaneous determination of lactone and hydroxy acid forms of camptothecin and SN-38 in tissue culture media and cancer cells. 1156 23

E7070 (N-(3-Chloro-7-indolyl)-1,4-benzenedisulphonamide) was selected from our sulphonamide compound collections via antitumour screening and flow cytometric analysis. Following treatment with E7070, the cell cycle progression of P388 murine leukaemia cells was disturbed in the G1 phase. The cell-killing effect on human colon cancer HCT116 cells was found to be time-dependent. In the panel of 42 human tumour cell lines, E7070 showed an antitumour spectrum that was distinct from those of other anticancer drugs used in clinic. Animal tests using human tumour xenograft models demonstrated that E7070 could cause not only tumour growth suppression, but also tumour regression in three of five colorectal and two of two lung cancers. In the HCT116 xenograft model, E7070 was shown to be superior to 5-FU, MMC and CPT-11 (irinotecan). Furthermore, complete regression of advanced LX-1 tumours was observed in 80% of E7070-treated mice. All of these observations have promoted this drug to clinical evaluation.
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PMID:E7070, a novel sulphonamide agent with potent antitumour activity in vitro and in vivo. 1167 18

Colorectal cancer is a leading cause of cancer in Western countries. Surgery remains the only way to cure it. Recent trials led to the general acceptance of adjuvant chemotherapy in Dukes C cancer by identifying bolus 5FU and leucovin during 6 months (5 days monthly) as the current standard. The role of adjuvant chemotherapy remains questionable in Dukes B2 (stage II) colon cancer, in rectal cancer and after curative resection of liver metastases. The development of total mesorectum excision (TME) technique has dramatically resulted in improving local recurrence control and will be the standard in rectal cancer surgery; preoperative irradiation is widely used in Europe for stage II and III rectal cancer but its definite place and its optimal regimen await further assessment as well as the role of adjuvant chemotherapy in rectal cancer. New chemotherapeutic combinations based on new effective agents in colorectal cancer such as CPT-11 and oxaliplatine have been currently used for downstaging liver metastases initially unresectable. This new approach, combined with the development of local ablative therapies such as cryotherapy and radiofrequency allows curative strategies in a significant number of patients primarily unfit for surgical resection of liver mets. The present paper aims to review the different aspect of (neo)adjuvant therapies in the multimodal curative management of colorectal cancers.
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PMID:Adjuvant treatment for colorectal cancer. 1168 45

We studied the pharmacokinetics of the intraperitoneal administration of CPT-11 for four patients with peritoneal metastasis (2 gastric cancer cases, 2 colon cancer cases). CPT-11 was administrated in a dose of 40-60 mg and the intraperitoneal and serum levels of CPT-11, SN-38 and SN-38 glucuronized (SN-38 Glu) were measured periodically. Intraperitoneal therapy with CPT-11 was effective for the control of malignant ascites. No serious side effects were observed. The levels of CPT-11, SN-38 were no different 30 min afterwards the administration of CPT-11 either intraperitoneally or intravenously. The high concentration of CPT-11 was achieved with intraperitoneal therapy and a small fraction of CPT-11 changed into SN-38 in the abdominal cavity.
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PMID:[Pharmacokinetic study of the intraperitoneal administration of CPT-11 for patients with peritoneal seedings of gastric and colonic cancers]. 1170 65

A weekly HAI therapy (CPT-11 80 mg, MMC 4 mg, degradable starch microsphere (DSM) 600 mg) was given to a patient with sigmoid colon cancer and multiple liver metastasis (H3) who had been taking tegafur 300 mg/day and 5-FU 750 mg HAI/week, which resulted in PD. This therapy was carried out on an outpatient basis with minimum side effects (< grade 2). After 8 weeks, the tumor marker dropped to one tenth and the liver metastasis decreased in size (PR). The time courses of the concentrations of CPT-11, SN-38 and SN-38G were determined by drawing blood after HAI with or without DSM. The Cmax and AUC inf. of SN-38 at HAI without DSM were 17 ng/ml and 90.55 ng/h/ml, respectively, which was comparable to that at i.v. administration. The Cmax and AUC inf. of SN-38 at HAI with DSM were 12 ng/ml and 129.19 ng/h/ml, respectively, implying that DSM might have an enhancing effect on CPT-11 due to stasis of the hepatic artery that slows the conversion of CPT-11 to SN-38 resulting in a longer existence of SN-38.
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PMID:[Sigmoid colon cancer with multiple liver metastasis (H3) effectively treated with CPT-11 and DSM (degradable starch microsphere) HAI therapy and intensive high dosage 5-FU HAI therapy--a case report]. 1170 29

The patient was a 52-year-old woman who had sigmoid colon cancer with liver metastasis and multiple lung metastases. Resection of curability B was performed, and alternating adjuvant chemotherapy consisting of hepatic artery injection of 5-FU and systemic administration of CPT-11 was performed. Lung recurrence was found and no antitumor effect of chemotherapy was observed, so the CPT-11 which had been administered every other week was given every week in a dose of 60 mg/body, half of the original dose. Moreover, 5'-DFUR was administered in a dose of 800 mg/day every day. As a result, lung metastasis tumors were reduced markedly. Adverse events such as nausea, vomiting and depilation were mitigated, and no other toxicity was observed. The patient could thus be treated extremely safely in the outpatient clinic. This was considered to be a valuable case suggestive of the significance of combination chemotherapy of CPT-11 and 5'-DFUR and the importance of appropriate administration of CPT-11.
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PMID:[A case of lung metastasis from colon cancer treated successfully with combined chemotherapy of CPT-11 and 5'-DFUR]. 1172 88

CPT-11, a DNA topoisomerase I inhibitor, has demonstrated clinical activity in colorectal cancer. Flavopiridol, a cyclin-dependent kinase inhibitor, is rapidly emerging as a chemotherapy modulator. To enhance the therapeutic index of CPT-11 in colon cancer, we studied the combination of these two drugs in relatively resistant human colon cancer cells, Hct116. Exposure of parental Hct116 cells to clinically achievable concentrations of SN-38 (the active metabolite of CPT-11) induces p21 and a G(2) arrest. However, these conditions fail to induce apoptosis. In contrast, Hct116 cells that are p21 deficient (p21-/- Hct116) readily undergo apoptosis after treatment with SN-38. In this study we show that the parental Hct116 cells can be sensitized to undergo apoptosis by the addition of flavopiridol after SN-38 treatment. The induction of apoptosis was greatest with sequential therapy consisting of SN-38 followed by flavopiridol. Clonogenic assays also showed greatest inhibition with this sequence. Sequential treatment with SN-38 followed by flavopiridol was associated with higher activation of caspase-3 and greater cleavage of both p21 and XIAP, an inhibitor of apoptosis, compared with other treatment schedules. CPT-11 induced some tumor regressions but no complete responses in the p21-intact Hct116 xenografts. CPT-11 with flavopiridol more than doubled tumor regression, compared with CPT-11 alone, and produced a 30% complete response rate. Our studies indicate that CPT-11 induces cell cycle arrest rather than cell death and that flavopiridol, by activating the caspase cascade, cleaves the inhibitors of apoptosis and sensitizes the cells to undergo cell death. Thus, flavopiridol combined with CPT-11 may provide a completely new therapeutic approach in the treatment of colon cancer.
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PMID:Augmentation of apoptosis and tumor regression by flavopiridol in the presence of CPT-11 in Hct116 colon cancer monolayers and xenografts. 1175 22

The ONYX-015 virus is a mutated adenovirus that in theory selectively replicates and induces cytolysis in tumor cells lacking functional p53. The present study investigated whether ONYX-015 viral infection alone or in combination with conventional chemotherapeutic agents could significantly increase apoptosis in human colon cancer cell lines, regardless of p53 status, compared to untreated cells. A pair of colon cancer cell lines that differ only in their p53 status (RKO with wild-type p53 and RKOp53 with deficient p53) was tested. Two chemotherapeutic agents, 5-fluorouracil (5-FU) and CPT-11, were tested in combination with ONYX-015. Final concentrations of these agents corresponded to peak plasma levels achievable in patients. ONYX-015 concentration was 10 p.f.u./cell. In RKO and RKOp53 cell lines, ONYX-015 viral infection alone or in combination with 5-FU or CPT-11 induced a significant increase in apoptosis compared to chemotherapeutic agents alone, regardless of p53 status. Moreover, the combination of ONYX-015 and chemotherapeutics induced more apoptosis than chemotherapeutics alone in the two colon cancer cell lines independently of their p53 status. We conclude that ONYX-015 virus infection alone or in combination with 5-FU or CPT-11 induced apoptosis in human colon cancer cell lines, independently of p53 status.
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PMID:Efficient induction of apoptosis by ONYX-015 adenovirus in human colon cancer cell lines regardless of p53 status. 1191 40

We performed PMC-CPT-11 therapy (modified pharmacokinetic modulating chemotherapy plus irinotecan, or modified PMC) in a case of sigmoid colon cancer with local invasion and multiple hepatic metastases. This regimen combined PMC therapy which includes Hartmann's operation, simple hysterectomy and postoperative 5-fluorouracil (5-FU), with intravenous irinotecan, or CPT-11. The multiple hepatic metastatic lesions disappeared after surgery and no local recurrence has been found since. These results indicate that PMC-CPT-11 (modified PMC) therapy could be an effective regimen for cases of progressive colon cancer in the future.
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PMID:[A case of hepatic metastasis from rectal carcinoma successfully treated with pharmacokinetic modulating chemotherapy (PMC)-CPT-11 therapy]. 1191 40


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