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)

Colorectal cancer affects around 5% of the population in Westernised countries and is associated with a high level of morbidity and mortality. Overall, around 50% of patients can expect to be fully cured by surgery, along with recent improvements in survival due to the use of adjuvant therapy. However, in patients who develop metastatic disease, the prognosis is poor, and the appropriateness of anticancer chemotherapy in such patients has been controversial. Nevertheless, there is increasing evidence that chemotherapy can extend life expectancy in colorectal cancer and that in metastatic disease patients achieve a significant benefit from early rather than late chemotherapy. For first-line treatment of metastatic colorectal cancer, the best available regimens have been those which include 5-fluorouracil (5-FU) and folinic acid; a meta-analysis of nine randomised clinical studies of such regimens produced a mean response rate of 23%. However, in those who fail or relapse, there has been no established second-line alternative. The development of CPT-11 (Campto, irinotecan), a specific inhibitor of topoisomerase I, represents a significant advance in the management of colorectal cancer. Following encouraging observations of sustained activity in colon cancer cell lines, including those having the MDR phenotype, clinical studies of CPT-11 monotherapy in both chemotherapy-naive and pretreated patients with advanced colorectal cancer demonstrated response rates at least equivalent to those achieved with first-line 5-FU/folinic acid combination therapy. This indicates that CPT-11 does not exhibit cross-resistance with 5-FU, making it the first effective second-line agent in this setting. Further studies are ongoing to define the optimum dosage schedule for CPT-11 and to assess the utility of CPT-11 as a single agent in second-line therapy, or combined with 5-FU and other anticancer agents as first-line therapy. In conclusion, CPT-11 offers a different cytotoxic approach that may complement the use of 5-FU/folinic acid in colorectal cancer in the future.
 ...
PMID:Current status of colorectal cancer: CPT-11 (irinotecan), a therapeutic innovation. 894 58

We studied the antiproliferative effect of recombinant human interferon-alpha/beta/gamma (rHuIFN-alpha/beta/gamma) and CPT-11 against human colon cancer xenografts in nude mice. CPT-11 (25 mg/kg) alone exhibited significant antiproliferative effects. Although rHuIFN-alpha/beta/gamma alone did not show antiproliferative activity, it markedly enhanced the antiproliferative activity of CPT-11. rHuIFN-alpha/beta/gamma significantly increased in the population of cells in the S-phase. rHuIFN-alpha/beta/gamma progressed cell cycle in the S-phase under the existence of CPT-11, which exhibited no effect on cell cycle progression. Because CPT-11 is known to exhibit antiproliferative effect on S-phase cells, IFNs, especially rHuIFN-alpha and beta, can enhance the antiproliferative effect of CPT-11 mediated by cell accumulation in the S-phase.
 ...
PMID:Interferon potentiates antiproliferative activity of CPT-11 against human colon cancer xenografts. 901 94

CPT-11, a new semisynthetic derivative of camptothecin, is active in a number of tumor types in the clinic, including colon cancer. CPT-11 is a drug that is converted into the active metabolite SN-38 by a carboxylesterase. Experiments were performed to obtain more insight in the cellular characteristics in 5 unselected human colon-cancer cell lines that account for the differential sensitivity to CPT-11 and SN-38. In vitro, the sensitivity to CPT-11 and SN-38 was highest in LS174T and COLO 320 cells, intermediate in SW1398 cells and lowest in COLO 205 and WiDr cells. SN-38 was 130 to 570 times more active than CPT-11. CPT-11 induced complete remissions in 6 out of 12 COLO 320 tumors grown as subcutaneous xenografts, but was not effective in WiDr tumors. The cellular carboxylesterase activity did not relate to the sensitivity to CPT-11. The enzyme activity was higher in normal mouse tissues, i.e., serum and liver, than in COLO 320 or WiDr xenografts, indicating that tumor carboxylesterase is of minor importance for CPT-11 efficacy. The topoisomerase-1 mRNA expression in tumor cells was not predictive of the antiproliferative effects of CPT-11 or SN-38. We observed a positive relationship between the DNA topoisomerase-1 activity and the cellular sensitivity to carboxylesterase-activated CPT-11 (r = 0.75, p < 0.1) as well as to SN-38 (r = 0.89, p < 0.05). The higher topoisomerase-1 activity in COLO 320 cells and tumors when compared with that in WiDr cells and tumors reflected the differences in sensitivity to the drug(s). In conclusion, the DNA topoisomerase-1 activity was the best determinant for CPT-11/SN-38 sensitivity in this panel of unselected human colon-cancer cell lines.
 ...
PMID:CPT-11 in human colon-cancer cell lines and xenografts: characterization of cellular sensitivity determinants. 903 37

A 59-year old male patient had been operated on for sigmoid colon cancer in July, 1990. Operative findings were, P0, H0, S1, N (-), Stage I, and histological findings were ss, ly 2, v0, n (-). In July 1994, the CEA level elevated, and be was diagnoted as having para-aortic LN swelling and stenosis of anastomosis of colon. He was admitted for treatment of recurrent colon cancer. Initially, he was treated with continuous injection of 5-FU, low-dose CDDP and Leucovorin. His CEA level decreased and para-aortic LN diminished in size. But, in December 1995, the CEA level and para-aortic LN relapsed. 5-FU, CDDP and Leucovorin were administered, but the CEA level became more and more elevated. This regimen was not considered responsible for drug resistance. CPT-11 was administered at 60 mg/week 6 times, and 80 mg/week 3 times. The side effects disappeared, LN sightly diminished in size, and the CEA level decreased. Judging by the anticancer effect without severe side effect, we found CPT-11 a useful drug for second-line chemotherapy.
 ...
PMID:[A case of recurrent advanced colon cancer treated with CPT-11 for second-line chemotherapy]. 927 52

Oxaliplatin is a new platinum analog of the DACH family. Recent preclinical data have confirmed its non overlapping spectrum of activity with cisplatin, including acquired and intrinsic platinum resistant cell lines (as KB-CP, A 2780, HT29, CaCo2 colon cancer). When combined with other cytotoxic agents (5FU, SN38, CDDP, carboplatin), oxaliplatin has additive and/or synergistic antitumoral effects on various in vitro and in vivo models (colon, breast, ovarian and epidermoid tumors). Phase II trials have confirmed a sensorial peripherical neuropathy as its limiting toxicity while neither ototoxicity nor renal toxicities and only limited myelotoxicity were noted. Available phase II studies have established its antitumoral activity as single agent in 5FU refractory colon carcinoma while preliminary results suggest efficacy in cisplatin resistant ovarian cancer, in non small cell lung cancer, non Hodgkin lymphoma. Antitumoral activity has been observed during phases 1 in melanoma, glioma, breast and oesophageal cancers. A high response rate (28-65%) with the triple association (FU/folinic acid/oxaliplatin) has been reported in advanced colon cancer treated in first and second line settings. The results of two randomized phase III studies (FU/folinic acid +/- oxaliplatin) are expected. The oxaliplatin/cisplatin combination as salvage regimen had produced significant antitumoral activity (response rate: 45%) in resistant/refractory ovarian cancer. Finally, recent experimental and clinical data have outlined the potential interest in the development of this new original platinum compound. New single agent phases II are expected in other tumor types as well as new oxaliplatin combinations are ongoing (phase I trials of oxaliplatin/CPT-11 and of oxaliplatin/carboplatin, phase II study of oxaliplatin-vinorelbine in lung cancer.
 ...
PMID:[Oxaliplatin: the first DACH platinum in clinical practice]. 929 71

Irinotecan (CPT-11) is a water-soluble analogue of camptothecin showing activity in colon cancer. Recently, we identified a major metabolite of CPT-11 in patients' plasma, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC), which is produced by the oxidation of the distal piperidine ring (P. Rivory et al, Cancer Res., 56: 3689-3694, 1996). As with all active camptothecin derivatives, CPT-11 is subject to spontaneous interconversion between a lactone and a carboxylate form in aqueous media. The kinetics of biotransformation of the two forms of CPT-11 into APC was studied using pooled human liver microsomes. The formation of APC was characterized by the following parameters: Km = 18.4 +/- 1.4 and 39.7 +/- 11.6 microM; and Vmax = 26.0 +/- 0.6 and 13.4 +/- 1.7 pmol/min/mg protein for the lactone and carboxylate forms of CPT-11, respectively. This reaction was found to be catalyzed principally by cytochrome P-450 (CYP) 3A because of three key results: (a) the CYP 3A-selective inhibitors ketoconazole (1 microM) and troleandomycin (100 microM) inhibited APC formation by 98 and 100%, respectively, mostly in a competitive way; (b) using microsomes from transfected lymphoblastoid cells expressing specific CYPs, we found that only those from CYP 3A4 cDNA-transfected cells transformed CPT-11 into APC; and (c) using 15 individual preparations of human liver microsomes, we observed highly significant correlations between the activity of CPT-11 metabolism into APC and both immunoreactivity with anti-CYP 3A antibodies and testosterone 6beta hydroxylation, an activity specifically mediated by CYP 3A. The effect on this metabolism of 11 drugs used at 100 microM was studied with CPT-11 lactone at 25 microM. Amikacin, Bactrim, ciprofloxacin, rocephine, 5-fluorouracil, metoclopramide, morphine, and paracetamol had no effect, but ondansetron, loperamide, and racecadotril inhibited this pathway by 25, 50, and 50%, respectively. These concentrations exceed those expected in vivo. APC formation in patients may thus be influenced by coadministered ketoconazole therapy and may decline after administration of CPT-11 because of the lactonolysis of the latter.
 ...
PMID:Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. 945 91

Oxaliplatin, the first available diaminocyclohexane platinum, has clinical activity in colorectal and ovarian cancers. Its mechanism of action is thought to be similar to that of cisplatin, its main mechanism being the intrastrand DNA adduct between two adjacent guanins or two adjacent guanine and adenine adducts. Ongoing molecular pharmacological studies of the mechanism of action of cisplatin suggest that platinated adducts are recognized by proteins of the mismatch repair system, including the products of the hMLH1 and hMSH2 genes. DNA mismatch repair defects occur in a wide variety of sporadic human cancers, are the main genetic factor in hereditary non-polyposis colon cancer and a frequent de novo or acquired phenomenon in ovarian cancer and other solid tumours. Moreover, they have recently been reported to be a cause of resistance to cisplatin but not to oxaliplatin, as diaminocyclohexane platinum adducts do not appear to be recognized by the mismatch repair complex. These findings explain the oxaliplatin activity in some cisplatin-resistant tumours. In addition, the good safety profile of oxaliplatin makes it a drug of choice for combination therapy, and it has been shown to be synergistic with other cytotoxic agents, including 5-fluorouracil, cisplatin, carboplatin, topotecan, gemcitabine and CPT-11. The results of several ongoing trials are awaited, but available data demonstrate that oxaliplatin is highly effective in the treatment of advanced colorectal and ovarian cancers. Promising early results suggest that it is also efficacious in non-Hodgkin's lymphoma, breast and non-small-cell lung cancers. As a result of its mechanism of action, its favourable safety profile and the differential profile of its antitumoral activity, the full potential of oxaliplatin as an active, versatile antitumoral agent is yet to be fully explored.
 ...
PMID:Ongoing and unsaid on oxaliplatin: the hope. 964 13

Irinotecan (CPT-11) is a new drug active in colorectal cancer. A comparison was made of the efficacy and pharmacokinetics of CPT-11 after i.p. versus i.v. administration to mice. We found that i.p. administration of CPT-11 to mice bearing C26 colon cancer was more efficient and less toxic than i.v. administration; a 100-mg i.p. dose induced an increase in life span equivalent to that produced by a 300-mg i.v. dose, and toxic deaths appeared after doses of 400 mg/kg given i.v. and 800 mg/kg given i.p. Pharmacokinetic parameters of CPT-11 and SN-38 were compared after i.v. or i.p. administration in mice bearing P388 leukemia ascites. Peritoneal CPT-11 and SN-38 AUC values were higher after i.p. administration than after i.v. injection. Plasmatic AUC values remained equivalent. Moreover, peritoneal CPT-11 clearance was 10-fold lower after i.p. versus i.v. administration. If the survival and pharmacologic advantage of i.p. CPT-11 in the murine model considered can be translated to a safe and practical mode of therapy in patients and if local toxicity does not prove to be a major adverse effect, then a potentially useful agent could be added to the drugs known to be active when given by the i.p. route for adjuvant therapy in colon cancer.
 ...
PMID:Comparison of the pharmacokinetics and efficacy of irinotecan after administration by the intravenous versus intraperitoneal route in mice. 965 18

The induction of severe diarrhea limits the usefulness of the DNA topoisomerase I inhibitor irinotecan (CPT-11) in the treatment of advanced colon cancer. We investigated whether oral administration of the new synthetic bacterial lipopeptide, JBT 3002, encapsulated in phospholipid liposomes could prevent damage to the intestinal epithelium and lamina propria and thus allow for the parenteral administration of high-dose irinotecan to mice with established syngeneic CT-26 colon cancer liver metastases. Treatment of mice with four daily i.p. injections of 100 mg/kg irinotecan was effective against liver metastases but also resulted in loss of body weight and early death. Histopathological examination of the intestines after this treatment revealed loss of villi, epithelial vacuolation, decrease in the number of cells in the crypts in S-phase, increase in the number of apoptotic cells, and reduction in the number of lymphocytes in the lamina propria. In contrast, treatment of mice with the same irinotecan regimen after oral administration of JBT 3002 produced highly significant inhibition of liver metastases without detectable damage to the intestines. Studies that used irinotecan administered once a week for 3 weeks after pretreatment with oral JBT 3002 demonstrated significantly intensified eradication of established CT-26 liver metastases compared with treatment with once-weekly irinotecan alone. Histological studies revealed that the liver metastases in mice treated with oral JBT 3002 and i.p. irinotecan contained a higher number of macrophages than metastases in mice treated with either drug alone. In vitro studies revealed that irinotecan produced direct antiproliferative effects but JBT 3002 did not. Tumor cells exposed to both irinotecan and macrophages activated by JBT 3002 were highly susceptible to lysis. These data show that oral administration of JBT 3002 can prevent irinotecan-induced gastrointestinal toxic effects and maintain the integrity of the lamina propria, thus allowing for intensification of irinotecan therapy against liver metastases from colon cancer.
 ...
PMID:Prevention of intestinal toxic effects and intensification of irinotecan's therapeutic efficacy against murine colon cancer liver metastases by oral administration of the lipopeptide JBT 3002. 974 19

This study determines the prognostic role of c-fos protein expression in patients with colon cancer who previously failed therapy with 5-fluorouracil (5-FU). Patients with advanced colorectal who were refractory to 5-FU therapy received irinotecan (CPT-11) by a 90-minute intravenous infusion at a dose of 125 mg/m2 weekly for four weeks followed by a 2-week rest period were eligible for oncogene assessment. C-fos protein expression was evaluated using archival formalin-fixed, paraffin-embedded tumor tissue, and an automated immunoperoxidase histochemical technique. Thirty-five patients were found to have > 25% positive c-fos activity. Nine patients had no detectable c-fos expression. Characteristics of patient subgroups were not different, however, the median survival of patients with elevated c-fos expression from the time of treatment with CPT-11 was 436 days, whereas patients with no detectable c-fos expression had a median survival of 365 days (p = 0.045). C-fos exhibits a casual role in the initiation of apoptosis and is implicated in differentiation and proliferation. It has been shown to correlate with poor survival in breast cancer, but improved survival in patients with astrocytic glioma. In this analysis, there is a suggestion that elevated c-fos expression is a good prognostic marker for patients with refractory colorectal carcinoma.
 ...
PMID:Improved survival in patients with advanced colorectal carcinoma failing 5-fluorouracil who received irinotecan hydrochloride and have high intratumor C-fos expression. 978 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>