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)

Topoisomerase I inhibitors are a new therapeutic class whose clinical evaluation began a few years ago; Irinotecan (CPT-11) gave interesting results in colon cancer; side effects were neutropenia, diarrhea, vomiting and a cholinergic syndrome. Topotecan was useful in lung and ovarian cancer; side effects were mostly hematologic. Undergoing studies concern dose optimization, mode of administration and therapeutic associations.
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PMID:[Topoisomerase I inhibitors. Review of phase II trials with irinotecan (CPT-11) and topotecan]. 749 18

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.
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PMID:Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. 945 91

Although the prognosis of childhood cancers has dramatically improved over the last three decades, new active drugs are needed. Camptothecins represent a very attractive new class of anticancer drugs to develop in paediatric oncology. The preclinical and clinical development of two of these DNA-topoisomerase I inhibitors, i.e. topotecan and irinotecan, is ongoing in paediatric malignancies. Here we review the currently available results of this evaluation. Topotecan proved to be active against several paediatric tumour xenografts. In paediatric phase I studies exploring several administration schedules, myelosuppression was dose-limiting. The preliminary results of topotecan evaluation in phase II study showed antitumour activity in neuroblastoma (response rate: 15% at relapse and 37% in newly diagnosed patients with disseminated disease) and in metastatic rhabdomyosarcoma (40% in untreated patients). Topotecan-containing drug combinations are currently investigated. Irinotecan displayed a broad spectrum of activity in paediatric solid tumour xenografts, including rhabdo-myosarcoma, neuroblastoma, peripheral primitive neuroectodermal tumour, medulloblastoma, ependymoma, malignant glioma and juvenile colon cancer. For several of these histology types, tumour-free survivors have been observed among animals bearing an advanced-stage tumour at time of treatment. The clinical evaluation of irinotecan in children is ongoing. Irinotecan undergoes a complex in vivo biotransformation involving several enzyme systems, such as carboxylesterase, UDPGT and cytochrome P450, in children as well as in adults. Preclinical studies of both drugs have shown that their activity was schedule-dependent. The optimal schedule of administration is an issue that needs to be addressed in children. In conclusion, the preliminary results of the paediatric evaluation of camptothecin derivatives show very encouraging results in childhood malignancies. The potential place of camptothecins in the treatment of paediatric malignant tumours is discussed.
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PMID:Preclinical development of camptothecin derivatives and clinical trials in pediatric oncology. 961 66

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.
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PMID:Comparison of the pharmacokinetics and efficacy of irinotecan after administration by the intravenous versus intraperitoneal route in mice. 965 18

Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine++ +] is a water-soluble analogue of camptothecine used in the second-line treatment of advanced colon cancer. Recently, we identified, in the plasma of patients and in human liver microsomal incubations, the presence of a new metabolite of irinotecan, 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine (NPC), which is produced by cleavage of the distal piperidine ring of irinotecan. The kinetics of biotransformation of the lactone and carboxylate forms of irinotecan into NPC were studied using human liver microsomes. The formation of NPC was characterized by the following parameters: KM = 48.2 +/- 6.8 and 273 +/- 122 microM and Vmax = 74.1 +/- 4.9 and 78.6 +/- 27.7 pmol/min/mg of protein for the lactone and carboxylate forms of irinotecan, respectively. Interestingly, there was no formation of NPC from 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecine, a major metabolite of irinotecan that has an open distal piperidine ring and could be considered a possible metabolic precursor of NPC. The transformation of irinotecan into NPC was found to be catalyzed principally by cytochrome P450 (CYP) 3A, based on three key results, as follows: 1) the CYP3A-selective inhibitors ketoconazole (1 microM) and troleandomycin (100 microM) inhibited NPC formation by 99 and 100%, respectively; 2) of a series of microsomal preparations from transfected lymphoblastoid cells expressing specific CYPs, only those from CYP3A4 cDNA-transfected cells transformed irinotecan into NPC; and 3) incubations with 15 individual preparations of human liver microsomes yielded highly significant correlations between the formation of NPC and both immunoreactivity with anti-CYP3A antibodies and testosterone 6beta-hydroxylation (an activity specifically mediated by CYP3A). The effects of 11 drugs (used at 100 microM) on this metabolism were studied with irinotecan lactone (25 microM). Although ondansetron, loperamide, and racecadotril inhibited this pathway by 75, 95, and 95%, respectively, the concentrations used may not be clinically achievable. However, significant inhibition by ketoconazole and troleandomycin indicates that NPC formation in patients may be influenced by coadministration of drugs with known anti-CYP3A activities.
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PMID:Biosynthesis of an aminopiperidino metabolite of irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] by human hepatic microsomes. 969 91

Given that human cancer xenografts tend to retain chemosensitivities similar to the cancerous tissue of origin, human carcinoma xenografts grown in nude mice were tested for sensitivity to four drug protocols: doxorubicin at 5 mg/kg, i.v., q5d; irinotecan at 60 mg/kg, i.v., q4d; cisplatin 5 mg/kg, i.p., q7d; and topotecan 1.5 mg/kg, p.o., qd (5 of 7 days). Irinotecan and doxorubicin protocols either halted or caused significant regression of the breast cancer cell lines (MCF7, MDA-MB 231 and T47D). None of the protocols tested resulted in significant regression in the lung cancer xenografts (H460, A549 and H226) although both irinotecan and doxorubicin did halt growth of the H226 xenograft. The ability of the irinotecan treatment to cause regression of xenograft size in all three colon cancer cell lines (SW620, COLO205 and HT29) justifies further clinical trials of irinotecan as an especially promising drug for the treatment of colon cancer.
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PMID:Efficacy of treatment of colon, lung and breast human carcinoma xenografts with: doxorubicin, cisplatin, irinotecan or topotecan. 1047 42

Irinotecan (CPT-11) and carboplatin have broad anti-tumor activities. We conducted a Phase I study of CPT-11 combined with carboplatin in previously untreated solid cancers, especially advanced lung cancer. The aim of the study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities in this regimen. In addition, we prospectively evaluated the Chatelut formula for predicting carboplatin clearance. Patients with advanced cancer were treated with CPT-11 (days 1, 8, and 15) and carboplatin (day 1) of a fixed-target area under the concentration-time curve (AUC) of 5 mg x min/ml. Carboplatin dose was determined by multiplying the AUC by the clearance predicted using the Chatelut formula. The CPT-11 dose was escalated from 40 mg/m2 to the MTD by 10 mg/m2. A total of 27 patients, 26 lung cancer patients and 1 colon cancer patient, were enrolled in this study. Dose-limiting leukoneutropenia, thrombocytopenia, and diarrhea, including one treatment-related death, were observed at 60 mg/m2 CPT-11, indicating that this level was the MTD. In 11 patients, the actual AUCs of carboplatin almost achieved the target AUC of 5. Fifteen (60%) of 25 evaluable patients showed an objective response, with an 85% response rate [11 of 13 patients (complete response, 31%; partial response, 54%)] in small cell lung cancers and a 36% response rate (4 of 11 patients) in non-small cell lung cancers. Neutropenia, thrombocytopenia, and diarrhea were the dose-limiting toxicities in this regimen. CPT-11 (50 mg/m2) under the carboplatin target AUC of 5 using the Chatelut formula was the recommended dose for further Phase II study, and this regimen seems to be active for small cell lung cancer.
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PMID:Phase I study of irinotecan combined with carboplatin in previously untreated solid cancers. 1063 26

The combination of irinotecan and fluorouracil (5-FU) is synergistic when applied to human colon cancer cell lines in vitro and appears to be schedule-dependent: maximal activity occurs when irinotecan is administered prior to 5-FU. In this phase I study, irinotecan is administered in combination with UFT and leucovorin in patients with advanced solid tumors. Irinotecan is given as a 90-minute intravenous infusion on day 1 followed by twice-daily UFT plus oral leucovorin on days 2 through 15. Cycles are repeated every 21 days. Five patients have been treated to date; four are evaluable for toxicity. Starting doses were irinotecan 200 mg/m2/day, UFT 200 mg/m2/day, and leucovorin 60 mg/day. Preliminary results indicate that irinotecan in combination with UFT plus leucovorin is well tolerated at the initial doses (described in this article).
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PMID:Irinotecan and UFT/leucovorin in patients with advanced cancers. 1109 4

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

The in vitro and in vivo combination of oxaliplatin and irinotecan was investigated in a panel of four human colon cancer cell lines and their counterpart xenografts. In vitro and in vivo experiments demonstrated a synergistic or additive interaction in three cell lines (HCT-116, HCT-8 and HT-29) and an antagonism in SW-620 cells. Since there were clearly opposite interactions depending on the cell line, we further investigated cellular determinants possibly involved in the interaction between the two drugs in HCT-8 and SW-620 cells. Irinotecan slowed down the early platinum-DNA adducts repair (1 h after oxaliplatin exposure) in the presence of irinotecan only in HCT-8 cells (p=0.03, n=3). Moreover, a decrease of the expression of two proteins of the nucleotide excision repair (NER) system, ERCC1 and XPA, was observed. None of these effects was seen in SW-620 cells. Irinotecan induced apoptosis with an increase of poly(ADP-ribose) polymerase (PARP) cleavage in SW-620 cells (60 versus 7% basal level). Pretreatment of these cells with oxaliplatin abolished the increase in PARP cleavage induced by irinotecan (29%). In HCT-8 cells, a very little PARP cleavage was observed whatever the drug treatment. The persistence of platinum-DNA adducts in the presence of irinotecan could be due to a direct impact of irinotecan on NER gene expression or to an indirect effect on topoisomerase I activity. Complementary studies are required to determine if the cellular parameters identified in this study could be translated at the clinical level to predict clinical response after combined treatment with oxaliplatin and irinotecan in humans.
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PMID:Combination of oxaliplatin and irinotecan on human colon cancer cell lines: activity in vitro and in vivo. 1159 56


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