Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TAS-103 is a novel anticancer agent targeting both topoisomerase (Topo) I and Topo II, that stabilizes cleavable complexes of Topo-DNA at the cellular level. In this study, the in vitro antitumor effects of TAS-103 were compared with those of other known Topo I and Topo II inhibitors. TAS-103 inhibited DNA synthesis more strongly than RNA and protein synthesis, and induced an increase of cell population in the S-G2/M phase. The cytotoxicity of TAS-103 was strongest against S-phase cells, but its cell cycle phase specificity was not clear, and depended on drug concentration and exposure time. The cytotoxicity of TAS-103 (IC50: 0.0030-0.23 microM) against various tumor cell lines was much stronger than that of VP-16 and comparable to that of SN-38. The cytotoxicity of TAS-103 seemed to be more related to the amount of protein-DNA complexes than to the accumulation of TAS-103 in the cells. P-Glycoprotein (P-gp)-mediated MDR, CDDP-resistant and 5-FU-resistant cell lines did not show cross-resistance to TAS-103. Although PC-7/CPT cells bearing a Topo I gene mutation showed cross-resistance to TAS-103, the sensitivity of P388/CPT, HT-29/CPT and St-4/CPT cells, showing decreased Topo I expression, was not changed. KB/VM4 and HT-29/Etp cells, showing decreased Topo II expression, were slightly cross-resistant to TAS-103. These results suggest that TAS-103 may act as an inhibitor of both Topo I and Topo II at the cellular level. This property may be responsible for its strong antitumor effect and broad-spectrum, growth-inhibitory effect on drug-resistant cell lines.
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PMID:In vitro antitumor activity of TAS-103, a novel quinoline derivative that targets topoisomerases I and II. 1039 Oct 99

Over the past 10 years, a number of topoisomerase I inhibitors have entered into clinical trials and several of these have been evaluated in phase II and III studies to determine their activity in patients with advanced colorectal cancer. The most extensively studied of these has been irinotecan (CPT-II). In phase II trials in patients with colorectal cancer that was recurrent or refractory to 5-Ruorouracil (5-FU)based front-line therapy, response rates of 14% to 22% and median survival times of 8 to 10 months have been consistently reported by groups from Japan, Europe, and the United States using avariety of drug administration schedules Two recently reported phase III trials comparing CPT-II against infusional 5-FU or best supportive care demonstrated that CPT-II confers a survival advantage over either of the two other approaches. In front-line treatment of colorectal cancer, CPT-II produces response rates of 19% to 32% and median survival times of 11 to 12 months, figures quite similar to those achievable with bolus 5-FU and leucovorin. Further evaluation in the front-line setting has concentrated on the integration of CPT-II with 5-FU-based regimens. The role of other topoisomerase I inhibitors in colorectal cancer has been more difficult to characterize. Using a standard daily x 5 schedule, topotecan has little objective activity against relapsed or refractory colorectal cancer. Infusional topotecan appears more promising in the treatment of patients with advanced colorectal cancer. The development of an oral formulation of topotecan may make this approach more feasible and is likely to undergo dinical evaluation in the near future. Phase II evaluation of 9-aminocamptothecin (9-AC) has focused on infusional schedules of varying lengths Despite this, little antitumor activity has been observed against colorectal cancer. Other topoisomerase I inhibitors, such as DX-8951f and 9-nitrocamptothecin (9-NC, RFS2000), have not been formally tested in phase II trials against colorectal cancer. In summary, extensive evaluation of topoisomerase I inhibitors has identified a significant degree of variability in clinical activity in patients with advanced colorectal cancer. To date, only one topoisomerase I inhibitor, CPT-II, has demonstrated a level of activity sufficient for it to become an integral component of treatment for patients with 5-FU-refractory colorectal cancer. Current and future studies will focus on the development of front-line regimens combining CPT-II and 5-FU for treatment of patients with advanced-stage disease, moving topoisomerase I inhibitors into the adjuvant therapy setting, and developing combined modality regimens of surgery, radiation, and topoisomerase I inhibitors for patients with locally advanced colorectal cancer.
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PMID:Topoisomerase I inhibitors in the treatment of colorectal cancer. 1060 56

The dawn of chemotherapy for gastrointestinal cancers including colorectal cancer was the inception of 5-fluorouraci (l 5-FU), produced by Dr. Heidelberger in 1957. 5-FU had been playing the leading role in chemotherapy for colorectal cancer for four decades until the Nineties. The second wave of chemotherapy was biochemical modulation. For the enhancement of 5-FU effects, the sequential combination with methotrexate and leucovorin (LV) was devised. Among them, 5-FU/LV was established in standard chemotherapy for colorectal cancer, due to several meta-analyses. Oral 5-FU such as UFT, TS-1 and capecitabine derivatives are gaining an important position in chemotherapy for colorectal cancer based on the accumulation of evidence. The third wave enveloped chemotherapy. Irinotecan was developed for gastrointestinal cancer. In 2000, CPT-11+5-FU/LV became the standard and first-line chemotherapy for colorectal cancer in the U.S. and Europe. Unfortunately, we in Japan have lagged behind the U.S. and Europe, because, 5-FU with LV was not approved here until 1999. Oxaliplatin was accepted in Europe first. FOLFOX, including continuous infusion of 5-FU, and LV were approved in 1998. In 2004, oxaliplatin + 5-FU/LV, named FOLFOX 4, was approved as the first-line chemotherapy treatment for colorectal cancer in the U.S. Oxaliplatin was the synthesized in Japan. At last, it was approved with usage restrictions the past March. We are now able to use FOLFOX 4, and this chemotherapy strategy for colorectal cancer in Japan is spreading rapidly. Recently, several new molecular targeted agents, which we call the fourth wave of chemotherapy, have been available in clinical studies,and promising data have been presented. Among them, evacizumab and cetuximab were tested in large phase III studies, their efficacies were upheld, and the drugs were approved in the U.S. Median survival time(MST) has been gradually prolonged through 5-FU/LV with irinotecan and oxaliplatin. Now, with the addition of molecular targeted agents, over 20 months of MST was reported.
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PMID:[Recent progress of chemotherapy for colorectal cancer]. 1635 22

The 3-drug regimen of CPT-11+5-FU+l-LV is generally used for metastatic and/or recurrent colorectal cancer. We have applied this treatment as the first-line intervention in our hospital. However,when the efficacy is reduced we try chemotherapy using CPT-11+TS-1 for 5 outpatients as second- or third-line chemotherapy. Decreased CEA levels were subsequently observed in 4 of 5 cases. In addition, 2 cases exhibited grade 1 or 2 adverse effects, but no case developed neutropenia. We could expect such effects even for patients after only 5-FU, and this treatment may be performed safely on ambulatory patients.
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PMID:[Second-or third-line chemotherapy with CPT-11+TS-1 for 5 cases of metastatic and recurrent colorectal cancer]. 1743 54

The patient was a 79-year-old a man who had a sigmoid colon resection for sigmoid colon carcinoma in another hospital 11 years ago. Four years later,he was noted to have multiple unresectable hepatic metastases on CT. Therefore,intrahepatic arterial and portal infusion with CDDP 10 mg + 5-FU 250 mg, respectively,were started. His CEA level decreased to the normal range,and a partial response (PR) was achieved. But two years later, the CEA level increased again,so radiofrequency ablation (RFA) therapy was given during abdominal surgery. Then, IFL, CPT-11+S-1, and FOLFOX were administered. Currently, the patient is being treated as an outpatient with CPT-11+S-1. The patient's multiple hepatic metastases were treated with multidisciplinary therapy, and the man has lived for 6 years 11 months since his first hepatic metastases were noted. The multidisciplinary therapy that was used lengthened this patient's life.
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PMID:[Long survival of a colon cancer case with multiple liver metastases cured by multidisciplinary therapy]. 1756 64

A 68-year-old woman was on dialysis for the treatment of chronic renal failure. FOLFOX 4 therapy was performed following CPT-11+UFT+Leucovorin for liver metastasis after resection of cancer of the sigmoid colon. The dose of oxaliplatin was 40 mg/m2, while 5-FU was given as a bolus of 300 mg/m2, and a continuous intravenous infusion of 500 mg/m2. Hemodialysis was performed 1 hour after administration of oxaliplatin on day 1 and was repeated two days later after the completion of drug administration. Vomiting (grade 2),anorexia and leukopenia (both grade 3) were observed after the first treatment. A total of 4 courses were administered thereafter by reducing the dose of oxaliplatin to 32 mg/m2, the intravenous bolus of 5-FU to 240 mg/m2, and continuous infusion of 5-FU to 400 mg/m2. Measurement of drug concentrations showed that free platinum was immediately eliminated by dialysis. It was considered possible to safely perform FOLFOX 4 therapy in patients with chronic renal failure by reducing the doses and by providing dialysis. It is desirable to measure drug concentrations in these patients. Also,more cases should be monitored to investigate the safe dose,the blood drug concentration profile, and the accumulation of chemotherapy agents.
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PMID:[FOLFOX 4 in a patient with metastatic colorectal cancer on hemodialysis due to chronic renal failure]. 1768 18

The ACTS-GC trial suggested that adjuvant chemotherapy with S-1 should be adopted as the standard treatment for stage II/III gastric cancer after curative D2 gastric dissection. In the JCOG9912 trial (5-FU vs CPT-11+CDDP (CP), 5-FU and vs S-1), the MSTs were 9.0, 12.1, and 10.5 months for 5-FU, CP, and S-1, respectively, with S-1 demonstrating significant non-inferiority to 5-FU, while CP did not show statistically significant superiority to 5-FU. In the SPIRITS trial comparing S-1 alone with S-1+CDDP, the MSTs were 11.0 and 12.0 months for S-1 and S-1+CDDP, respectively, and S-1+CDDP showed statistically significant superiority to S-1 monotherapy. The GC0301/TOP-002 trial compared CPT-11+S-1(IRI-S)to S-1 alone in advanced gastric cancer patients. An analysis revealed an ORR of 26.9% for the S-1 monotherapy arm and 41.5% for the IRI-S arm (p=0.035). However, IRI-S did not show statistically significant superiority to S-1 alone in OS. On the basis of these results, S-1+CDDP was adopted as the standard cancer chemotherapy regimen for inoperable and recurrent gastric cancer in Japan. Thus, in the next revision, the contents of the description of the Japanese Guidelines for Treatment of Gastric Cancer (2nd Edition) will be changed. Now, the second-line treatment and the biological molecular targeting agents-based drug medicine treatment development are continued with an eye to the future.
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PMID:[Clinical development of chemotherapy for advanced gastric cancer]. 1879 98

We evaluated the efficacy of chemotherapy using S-1 after gastrojejunostomy for unresectable gastric cancer with pyloric stenosis. We performed gastrojejunostomy to relieve obstruction in 40 patients from 1993 to 2007. After gastrojejunostomy, 15 patients were treated with S-1(S-1 group), 12 patients were treated with another anticancer drug(non S-1 group)and the other 13 patients received no chemotherapy. After informed consent was obtained, S-1(80 mg/m(2)day)and another anticancer drug was administered. The mean period of administered was 16(range 2-56)weeks in the S-1 group. In the non S-1 group, 5-FU was used in 1 patient, 5'-DFUR in 2, UFT in 3, FP chemotherapy in 3, CPT- 11/CDDP chemotherapy in 1, and 5-FU/PTX chemotherapy was conducted in 2 patients. The one-year survival rate was 63% and the median survival time was 394 days in the S-1 group, against 33% and 169 days, respectively, in the non S-1 group. Appetite loss of grade 3 was observed in one(7%)patient with nonhematological toxicity, but no patient suffered grade 3 hematological toxicity. We observed the course of all patients on an outpatient basis. In conclusion, S- 1 administration after gastrojejunostomy appears to be an effective treatment modality for far advanced gastric cancer patients with pyloric stenosis in view of toxicities, antitumor effects and QOL of the patients.
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PMID:[Administration of S-1 after gastrojejunostomy for unresectable gastric cancer with pyloric stenosis]. 1938 Oct 30