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)

Leucovorin and interferon are capable of modulating the cytotoxicity of fluorouracil (5-FU). Preclinical studies demonstrate that d,l-leucovorin is rapidly metabolized in human breast and colon cells into the various one-carbon substituted folate pools and to the polyglutamated state. While increases in intracellular folate pools are proportional to the exposure concentration of leucovorin, relatively large increases in leucovorin concentrations (50- to 100-fold) are required to produce small intracellular changes (twofold). Polyglutamation is favored by prolonged exposures to leucovorin. Polyglutamate forms have a prolonged intracellular retention and a higher affinity for the target enzyme, thymidylate synthase. Ratios of up to 20:1 inactive to active leucovorin stereo-isomers had essentially no effect on the intracellular metabolism of the active isomer. Interferon gamma interacts with 5-FU in H630 colon cancer cells at the level of thymidylate synthase and enhances cytotoxicity of 5-FU by eliminating the 5-FU-induced acute overexpression of the target enzyme. No alterations in the intracellular metabolism or nucleic acid incorporation of 5-FU could be demonstrated with the addition of interferon gamma. A clinical trial combining interferon-alfa-2a (IFN-alpha-2a) (subcutaneous days 1 to 7) with 5-FU and leucovorin (given IV days 2 to 6) demonstrated that these agents could be combined with acceptable toxicity. While the addition of interferon did not allow dose escalation of 5-FU, it resulted in a significant increase in drug exposure (1.5-fold) compared with matched cycles of 5-FU plus leucovorin without interferon. The overall response rate in this pilot study of 13 untreated patients with gastrointestinal adenocarcinoma was 46%, including two complete responses. There were no responses in eight patients who had previously failed therapy with 5-FU.
 ...
PMID:Biochemical modulation of fluorouracil with leucovorin and interferon: preclinical and clinical investigations. 155 56

5-Fluorouracil (5-FU) remains the most effective chemotherapeutic agent in the management of patients with metastatic colorectal cancer. Leucovorin enhances its efficacy, but also its toxicity. Cited data suggest modulation of 5-FU toxicity by high dose allopurinol. In a prospective randomized trial we assessed the ability of allopurinol in a conventional dose to modulate the toxicity of 5-FU-leucovorin combination without compromising its efficacy in 50 patients with advanced colorectal cancer. Twenty-seven patients were randomized for allopurinol but had no benefit in terms of response or reduced toxicity over the other 23. Survival of responders with colon cancer was longer than that of non-responders (p = 0.013). Although allopurinol failed to reduce 5-FU-leucovorin toxicity, it did not lower its expected efficacy.
 ...
PMID:Treatment of advanced colorectal cancer by 5-fluorouracil-leucovorin combination with or without allopurinol: a prospective randomized study. 180 86

The establishment of reliable preclinical test is essential for the reasonable clinical trial. As a methodology for the screening of new active anticancer agents, disease oriented strategy using human tumor cell lines has been proposed in USA. The important questions in DOS are to determine the representative cell lines of specific cancer and it is also extremely important to decide the numbers of cell lines used for the screening. CPT-11, topoisomerase I inhibitor, developed in my country has been demonstrated to be active against lung cancer cell lines compared with mice tumors such as S-180 and P-388. However, no compound is demonstrated to be clinically active so far by this methodology. The criteria for the application of clinical trial are obscure and each drug company decides empirically by themselves. We have proposed to use PEI (predictive efficacy index) for the prediction of antitumor activity of new compounds. The clinical effect of new platinum analogue well correlated with this value. We have conducted phase II trial of 5-FU + LV against NSCLC without no prior chemotherapy. No responder was observed in the trial. Augmentive effect of leucovorin on the cytotoxicity of 5-FU and FdUrd was examined in vitro against NSCLC and colon cancer cell lines. Leucovorin stimulated the cytotoxicity of both drugs only against colon cancer cell lines. We tried to predict the response rate of new platinum derivative based on the data of bioassay of patient's serum administrated with platinum compounds. The predicted response rates of 254-S were 57-67% and 16-27% against SCLC and NSCLC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Preclinical trials from the standpoint of clinical trials]. 185 17

We evaluated the efficacy of the combination therapy of UFT with Leucovorin (LV) against mouse colon adenocarcinomas and human colon adenocarcinoma. In vitro studies, it was shown that LV potentiated the cytotoxicity of FUra against 7 out of 9 cell lines used in this experiment. In vivo studies, the antitumor activity of UFT against mice bearing colon 38 adenocarcinoma was increased following administration of LV either before, after or at the time of treatment with UFT. Further studies were performed on the combination effect of UFT and LV against mouse colon 26 adenocarcinoma and human colon adenocarcinoma KM20C. Consequently, the combined treatment of UFT with LV was more effective than UFT alone against two cell lines. Our studies suggest that combination chemotherapy of UFT with LV is a promising approach for the treatment of a human colon cancer in clinical practice.
 ...
PMID:[Combination chemotherapy with orally administered UFT and leucovorin (LV)]. 187 23

Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days, beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients, there were no complete or partial regressions, although there was one minor response lasting 4 months. Three patients had stable disease for 5, 20, and 21 months, respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients, and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range, 1.4 to 9.6) x 10(3)/microL, and the median platelet nadir was 147.0 (range, 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.
 ...
PMID:Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. 187 24

The substantial recurrence rate of colorectal cancer following potentially curative resection has fuelled the search for effective adjuvant therapy. Previous trials using 5-fluorouracil (5-FU) as a single agent or in combination chemotherapy regimens have not demonstrated meaningful benefits, an impression reflected in the results of a meta-analysis encompassing large patient numbers. Newer developments utilizing intraportal chemotherapy and the combination of 5-FU and levamisole have resulted in lower recurrence rates and improved survival in patients with colon cancer. In advanced disease, the biochemical modulation of 5-FU by Leucovorin has been shown to prolong survival in some studies. Combined chemotherapy and radiotherapy or chemotherapy alone have showed promising results in rectal cancer. These developments have now been incorporated into ongoing trials.
 ...
PMID:Adjuvant therapy of colorectal cancer: an overview. 199 78

Sixteen patients with metastatic carcinoma of the colon were treated with a regimen of leucovorin 200 mg/m2, given as a 10-min infusion followed by a median dose of 833 mg/m2 (range 500-1000 mg/m2) 5-fluorouracil every two weeks. For the 16 patients with proven metastatic disease, two-year survival exceeds 50%. Responses were: 2 complete; 4 partial; 4 minor; 3 progression; and 3 not evaluable but without progression to date. Toxicities include: 8 (50%) leukopenia; 9 (56%), 1 severe thrombocytopenia; 9 (56%), 2 severe, diarrhea; 9 (56%), 3 severe, nausea/vomiting; 8 (50%), 1 severe, stomatitis; 7 (44%) conjunctivitis; 6 (38%) alopecia; and 13 (81%), 3 severe, neurotoxicity. Leucovorin appears to exert a dose-dependent beneficial effect on both the response and survival produced by the intermittent high-dose 5-fluorouracil schedule. This benefit first appears to increase substantially when the leucovorin dose is increased from 120 to 200 mg/m2. Findings identify a testable candidate regimen for selected good risk patients. Full selection criteria remain to be identified.
 ...
PMID:Dose-dependent leucovorin efficacy with an intermittent high-dose 5-fluorouracil schedule. 220 56

We reported 2 patients treated with Methotrexate (MTX)-Fluorouracil (5-FU) sequential therapy combined with Doxifluridine (5'-DFUR). The method of administration was as follows: MTX 60 mg was given intravenously (iv) followed by 5-FU 600 mg iv 2 hours later in colon cancer and 5 hours later in gastric cancer. Leucovorin 20 mg was administered 3 times every 6 hours beginning 6 hours after 5-FU infusion. This cycle was repeated once a week for 5 weeks. 5'-DFUR 1,200 mg was given orally daily and continued after MTX.5-FU therapy. Patient 1 was a 60-yr-old female with recurrent colon cancer developed four years after sigmoidectomy. She was referred to our hospital for further examinations of elevated serum carcinoembryonic antigen (CEA). The enlarged intraabdominal lymph nodes due to recurrence were demonstrated on computer tomography and the chemotherapy was performed as described above. The swelling of lymph nodes showed marked reduction in size and CEA value was normalized. Patient 2 was a 59-yr-old man with advanced gastric cancer accompanied by giant liver metastasis. Both primary and metastatic lesion responded favorably to this regimen. There was no remarkable side effect in either patient. These results suggest that this method is worth performing in further clinical trials for cancer patients.
 ...
PMID:[Two cases of gastrointestinal cancers with major responses to sequential methotrexate 5-FU plus 5'-DFUR]. 252 5

Recurrence of gastric cancer or colon cancer was observed in some patients who received 5-fluorouracil (5-FU) high-dose continuous Methotrexate (MTX)-Leucovorin (LV) therapy (FML therapy) previously. 5-FU high-dose 48-hours continuous therapy (5-FU therapy) as maintenance therapy for the patients was performed in the hospital and successively at home. The patients included 3 with recurrent gastric cancer and 2 with recurrent colon cancer: there were 4 males and 1 female, the mean age was 51.8 years (33-59 years). All patients had received FML therapy during the hospital stay before the maintenance chemotherapy at home. 5-FU therapy (30 mg/kg/day x 2 days/w), 30.2 courses on an average (11-40 courses), was performed through a catheter (Port-A-Cath), which was introduced into the right subclavian vein and placed under the skin, with a Baxter infusion pump. The concentration of 5-FU was 197 +/- 172-401 +/- 127 ng/ml between the 2nd and 48th hour. Adverse reaction included anorexia in 5 patients, stomatitis in 4, pigmentation in 4, leukopenia in 3, neuropathy in 2 and alopecia in 1. The therapy was effective for 10.4 months on an average (4-18 months) and the mean survival period was 12.0 months (7-18 months).
 ...
PMID:[Usefulness of 5-FU high-dose continuous therapy at home in patients with recurrent gastric and colon cancer]. 780 45

Changes of granulocyte macrophage colony forming units (CFU-GM) were assessed in peripheral blood of patients treated with 5-Fluorouracil-Leucovorin adjuvant chemotherapy after removal of colon cancer. The clinical and hematological state of the patients was steady and as far normal as possible. Leucocyte counts did not show significant changes. The mean peripheral blood level of CFU-GM significantly decreased following 5FU-LV infusion, reaching nadir by day 15. These changes of hemopoietic progenitors, not detected by routine hematic cell counts, point to a perturbation of the granulopoietic system by the 5FU-LV association also at doses used in adjuvant chemotherapy.
 ...
PMID:Hematotoxicity of 5-fluorouracil-leucovorin in a setting of adjuvant chemotherapy. 784 May 17


1 2 3 4 5 6 7 8 Next >>