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)

Leucovorin (LV) is commonly used as a modulator of 5-fluorouracil (5-FU) cytotoxicity. In patient with colon cancer, the addition of LV to 5-FU improves response rates, and in some trials has improved survival in advanced disease and in the adjuvant setting. Leucovorin is generally administered as a racemic mixture, but the isomers differ substantially in pharmacokinetics and biological activity, with 6S-LV the predominant active component. The current study was undertaken to determine the effect of 6R on the pharmacokinetics of 6S-LV, and to characterize the toxicity and antitumor effect of 5-FU when administered with 6S-LV to patients with advanced colorectal carcinoma. Thirty patients were treated with weekly 5-FU plus high dose 6S-LV. To determine the effects of 6R-LV on the pharmacokinetics of S6-LV, 20 patients were randomly assigned to receive either 250 mg/m2 6S-LV or 500 mg/m2 6R,S-LV as a 2 hour IV infusion on day -2, and the other preparation on day -1, with pharmacokinetics measured each day. The presence of 6R-LV had no effect on the AUC, Clp, Cmax, or terminal phase t1/2 of 6S-LV. The overall response rate was 40% (C.I. 23-60%). The most frequent toxicities were gastrointestinal. In this small cohort, scheduled and delivered dose intensity was positively associated with response (p = 0.05). These results show that there is no pharmacokinetic advantage to the use of 6S-LV rather than 6R,S-LV as a modulator of 5-FU.
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PMID:A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patient with colorectal carcinoma. 861 78

Folinic acid (leucovorin) is frequently used to augment and modulate the clinical activity of 5-fluorouracil (5-FU) in patients with advanced gastrointestinal (Gl) cancer. However, there are conflicting opinions concerning the optimal doses for these patients, and whether folinic acid modulates the clinical activity of 5-FU in patients with non-Gl cancer. To elucidate these questions, model experiments have been performed on human tumor cell lines in vitro to determine the modulatory activity of various concentrations of folinic acid on 5-FU mediated cytotoxicity using a clonogenic assay. Three cell lines of colon cancer and 3 of glioblastoma origin were exposed to 5-FU alone or with folinic acid for 24 hours. It was observed that relatively low concentrations of folinic acid enhanced the cytotoxicity of 5-FU against the colon cancer lines whereas higher concentrations were less effective. Folinic acid did not enhance the 5-FU mediated killing of the glioma cell lines at any concentration (0.01-100 micrograms/ml). On the contrary, folinic acid seemed to counteract the cytotoxic effect of 5-FU in a reasonably dose-dependent fashion. These results may suggest that the value of folinic acid in the treatment of non-Gl cancer with 5-FU should be evaluated within the framework of controlled clinical trials, and that high doses of folinic acid may not necessarily be more effective than low.
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PMID:Dual effects of folinic acid in 5-fluorouracil induced killing of human tumor cell lines in vitro. 891 76

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.
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PMID:[A case of recurrent advanced colon cancer treated with CPT-11 for second-line chemotherapy]. 927 52

Thymidylate synthase (TS), a critical enzyme in the de novo synthesis of thymidylate, is an important target for fluoropyrimidines and folate-based TS inhibitors. In a panel of 13 nonselected human colon cancer cell lines, we evaluated the role of TS levels in sensitivity to 5-fluorouracil (5FU) and four folate-based TS inhibitors that have been introduced recently into the clinic: ZD1694 (Tomudex, Raltitrexed, TDX), GW1843U89 (GW), LY231514 (LY), and AG337 (Thymitaq, AG). Because the latter compounds have different transport and polyglutamylation characteristics, we also related these parameters with drug sensitivity, measured by the sulforhodamine B assay after 72 h of drug exposure. For 5FU, the IC50s varied from 0.8 to 43.0 microM. Leucovorin (LV) potentiated the activity of 5FU in only 4 of 13 cell lines. Sensitivity to folate-based TS inhibitors was variable; IC50s were in the range of: 5.3-59.0 nM TDX; 11.0-1570 nM LY; and 0.5-8.9 nM GW. Eleven of 13 cell lines had an IC50 for AG between 1.3 and 5.3 microM. Two cell lines were resistant to AG, Colo201 and SW1116, with IC50s of 27 and 29 microM, respectively. TS catalytic activity (conversion of dUMP to dTMP) varied from 62 to 777 pmol/h/10(6) cells. The number of FdUMP binding sites varied from 32 to 231 fmol/10(6) cells. Regression analysis showed a significant relation between TS catalytic activity and IC50s for 5FU and 5FU/LV. Kis for FdUMP showed a significant Spearman rank correlation with the IC50s of AG and GW. The role of antifolate transport, accumulation, and polyglutamylation was determined with [3H]methotrexate (MTX) as a reference compound. [3H]MTX influx via the reduced folate carrier varied from 18.6 to 150 fmol/10(6) cells/min. Folylpolyglutamate synthetase (FPGS) activity showed a range from 47 to 429 pmol/10(6) cells/h. A total of 24 h of [3H]MTX accumulation showed a 20-fold variation, from 1.2 to 21.8 pmol/10(6) cells. FPGS levels showed a Spearman rank positive correlation with cytotoxicity to TDX. In conclusion, in a heterogeneous nonselected human colon cancer cell line panel, the best predictor for sensitivity to 5FU and 5FU/LV was TS activity. Multiple sensitivity determinants were of importance for antifolate TS inhibitors, including FPGS activity and TS enzyme kinetics.
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PMID:Thymidylate synthase level as the main predictive parameter for sensitivity to 5-fluorouracil, but not for folate-based thymidylate synthase inhibitors, in 13 nonselected colon cancer cell lines. 1010 Jul 18

We demonstrated in this study that inhibition of intra-hepatic growth of colon cancer by TAC-101 is mediated by inhibition of angiogenesis. In vitro experiments showed that TAC-101 inhibited the proliferation of murine hepatic sinusoidal endothelial (HSE) cells induced by coculture with murine colon 26-L5 (L5) cells. HSE cell proliferation was also enhanced by conditioned medium of L5 cells (CM-L5), and this enhancement of proliferation was abrogated by anti-vascular endothelial growth factor antibody. CM-L5 also induced in vitro tube formation of HSE cells on Matri-gel, and this activity of CM-L5 was abrogated by TAC-101 in a concentration-dependent manner. On the other hand, p.o. administration of TAC-101 inhibited tumor-induced angiogenesis in vivo and decreased the weights of L5 tumors in the mouse liver. Reverse transcriptase-PCR analysis using in vivo tumor tissue suggested that repression of vascular endothelial growth factor expression by TAC-101 was associated with the antiangiogenic activity. TAC-101 alone and 5-fluorouracil (5-FU)/D,L-leucovorin (LV) significantly inhibited the intrahepatic growth of L5 tumors (P = 0.002 and 0.001, respectively), whereas 5-FU alone did not (P = 0.088). When TAC-101 was administered with 5-FU/LV, marked enhancement of antitumor activity was observed (95% inhibition; P<0.001). This enhanced antitumor effect was also observed in experiments using Co-3 human colon adenocarcinoma. Concurrent treatment with TAC-101 and 5-FU/LV and sequential treatment with 5-FU/LV followed by TAC-101 resulted in significant augmentation of antitumor activity against Co-3 (overall P = 0.007 and 0.015, respectively). These findings indicate that TAC-101 inhibits tumor angiogenesis and suggest that it may be effective against hepatic metastasis of colon cancer.
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PMID:Inhibition of angiogenesis and intrahepatic growth of colon cancer by TAC-101. 1049 97

It has been said that there is no standard chemotherapy for gastrointestinal malignancies. However, standard guidelines are essential to increase the level of medical treatment, and the death rate from gastrointestinal malignancies is very high in Japan. FAMTX, standard therapy for gastric cancer abroad, cannot be standard in Japan due to its toxicities. A combination of 5-FU and cisplatin (FP) is most commonly used as the the first choice for chemotherapy, but it's regimens vary. For colon cancer, it is said that a combination of 5-FU and Leucovorin (LV) is standard, but CPT-11, made in Japan, is a promising agent. There is no recommended drug for advanced pancreatic cancer, so palliative care or no chemotherapy are also available alternatives.
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PMID:[Standard chemotherapy for gastrointestinal malignancies based on evidence]. 1070 Aug 86

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

We treated a patient with intra-peritoneal recurrent tumor from colon cancer who responded completely to chemotherapy of combined low-dose Leucovorin (LV) and 5-fluorouracil (5-FU). The patient was a 75-year-old man. He underwent resection of the transverse colon, sigmoid colon and distal stomach for colon and gastric cancers. Nine months after the operation, his CEA level increased to 39.5 ng/ml and a CT scan revealed an intra-peritoneal tumor measuring about 5 cm. He received chemotherapy of 30 mg/day of LV that was injected in a bolus and 500 mg/day of 5-FU that was given i.v. by continuous infusion for 10 days. At the end of 2 cycles of this regimen, CT scan demonstrated complete tumor remission and the patient's CEA level decreased to normal level. After an additional cycle of this regimen, he received modulated chemotherapy combined with l-Leucovorin and 5-FU as an outpatient. However, after 3 months of treatment, a recurrent tumor was detected in the same portion and the first regimen was re-started for 5 days. After 4 cycles of treatment the tumor disappeared completely from a CT scan. It is important to investigate effective regimens that do not reduce the quality of life of the patient. This clinical experience suggests that a low-dose LV/5-FU therapy may be beneficial to patients with recurrent colon cancer. Further investigation is necessary to establish an effective regimen that can be given for a long period without adverse effects on quality of life.
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PMID:[A case of intra-peritoneal recurrence of colon carcinoma that responded remarkably to combined therapy of low-dose leucovorin and 5-fluorouracil]. 1157 43

A 51-year-old man underwent right hemicolectomy due to ascending colon cancer with multiple liver metastases. Administration of modified pharmacokinetic modulating chemotherapy (PMC) using Leucovorin (intravenous infusion of 5-FU, 600 mg/m2/24 hours; oral administration of UFT, Taiho Pharmaceutical Co., Tokyo, Japan, 400 mg/day; and Isovorin, Wyeth Lederle Co., Tokyo Japan, 250 mg/body) was started postoperatively. Two months of modified PMC produced a drastic tumor reduction without any adverse reactions such as diarrhea or myelosuppression observed. At present the patient continues to tolerate the chemotherapy and is being followed as an outpatient clinic. This case suggests the usefulness of modified PMC using Leucovorin for progressive recurrent colon cancer.
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PMID:[A case of multiple liver metastases from colon cancer successfully treated with modified pharmacokinetic modulating chemotherapy using Leucovorin]. 1246 6

A 61-year-old man underwent curative low anterior resection for rectosigmoid colon cancer. Follow-up ultrasonography revealed unresectable multiple liver metastases at 10 months after surgery. Arterial infusion therapy with 5-fluorouracil (5-FU) was given at 1,500 mg every 2 weeks up to a total dose of 37.5 g, resulting in complete remission (CR) of the liver metastases. However, recurrence was seen 4 months after CR. Following partial hepatectomy and local ablation therapy, he received multidisciplinary treatment including local ablation therapy, arterial infusion of 5-FU and mitomycin C, and systemic chemotherapy with 5-FU/Leucovorin/CPT-11. The patient died of liver failure at 3 years and 7 months after the detection of hepatic metastases. If arterial infusion therapy achieves CR of unresectable hepatic metastases from colorectal cancer, the patient may survive for several years with multidisciplinary treatment including surgery, local ablation therapy, and systemic chemotherapy.
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PMID:[A case of unresectable liver metastases from rectosigmoid colon cancer with survival for over 3 years after multidisciplinary treatment]. 1461 6


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