Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacological inactivation of dihydropyrimidine dehydrogenase (DPD) represents one strategy to improve 5-FU therapy, which historically has been associated with unpredictable pharmacological behavior and toxicity. This is principally due to high interpatient differences in the activity of DPD, the enzyme that mediates the initial and rate-limiting step in 5-FU catabolism. By inactivating DPD and suppressing the catabolism of 5-FU, eniluracil has dramatically altered the pharmacological profile of 5-FU. The maximum tolerated dose of oral 5-FU given with oral eniluracil (1.0 to 25 mg/m2) is substantially lower than conventional 5-FU doses. In the presence of eniluracil, bioavailability of 5-FU has increased to approximately 100%, the half-life is prolonged to 4 to 6 hours, and systemic clearance is reduced > 20-fold to values comparable the glomerular filtration rate (46 to 58 mL/min/m2). Renal excretion (approximately 45% to 75%), instead of DPD-related catabolism, is the principal route of elimination of oral 5-FU given with eniluracil. Chronic daily administration of oral 5-FU 1.0 mg/m2 twice daily with eniluracil 20 mg twice daily produces 5-FU steady-state concentrations (8-38 ng/mL) similar to those achieved with protracted intravenous administration on clinically relevant dose-schedules. On a daily x 5 regimen, higher 5-FU AUC values are related to neutropenia, whereas elevated 5-FU AUC and steady-state concentrations are related to diarrhea when oral 5-FU is given daily with eniluracil on a chronic schedule. The pharmacokinetic behavior of oral eniluracil is similar to that for oral 5-FU. Administration of eniluracil 10 to 20 mg twice daily completely inactivates DPD activity both in peripheral blood mononuclear cells and in colorectal tumor tissue, and prolonged inhibition of DPD after discontinuation of eniluracil treatment has been noted. In the presence of eniluracil, oral administration of 5-FU is feasible and variation in 5-FU exposure is reduced, with the anticipation of further reduction in variation as dosing guidelines based on renal function are formulated.
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PMID:Pharmacology of fluorinated pyrimidines: eniluracil. 1108 73

The prognosis of locally advanced or recurrent carcinomas of the penis (PE) and of the anal canal (AC) after conventional treatment is dismal. We report 16 patients (eight with AC carcinomas and eight with PE cancers) treated by intra-arterial (IA) chemotherapy. Fifteen of them were treated for locally advanced or recurrent disease and one in an adjuvant setting. The chemotherapy was administered via a femoral IA catheter with its tip located above the aortic bifurcation, under the inferior mesenteric artery. It consisted of eight push injections, given over a 48-h period, of the following drug combination: cisplatin 8.5 mg m(-2), 5-FU 275 mg m(-2), methotrexate 27.5 mg m(-2), mitomycin C 1.2 mg m(-2), and bleomycin 4 mg m(-2). Leucovorin was given po, 4 x 15 mg day(-1), during the chemotherapy and for 3 days thereafter. A total of 52 cycles of treatment were administered. Of the 15 patients evaluable for response, six obtained a CR (three PE, three AC) and eight a PR. Among the complete responders, four are alive and disease-free 2-15 years after treatment. The other patients enjoyed an objective response lasting 3-25 months (median 7 months). Four patients developed grade III/IV haematological toxicity with three episodes of febrile neutropenia, one of them with a fatal outcome due to patient's failure to obtain medical attention at the onset of his fever, one a grade III mucositis of the glans, and four a grade III/IV cutaneous toxicity, the latter caused by the IA administration of bleomycin. In conclusion, IA chemotherapy is effective and potentially curative in locoregionally advanced or recurrent carcinomas of the penis and of the anus. Its contribution in the primary management of advanced penile or anal carcinoma should be prospectively investigated.
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PMID:Intra-arterial chemotherapy in locally advanced or recurrent carcinomas of the penis and anal canal: an active treatment modality with curative potential. 1110 58

The purpose of this prospective study was to assess the efficacy, clinical benefit and safety of irinotecan (CPT-11) in patients with 5-fluorouracil-resistant metastatic colorectal cancer (CRC). Sixteen patients with World Health Organization (WHO) performance status < or = 2 were treated with CPT-11 350 mg/m2 every 3 weeks. The observed partial response (PR) rate was 6.3 per cent with a high rate of stable disease (SD) (43.7%) which was of long duration (21.1 weeks for the best response; 1PR, 7SD). The median survival time for the 16 patients entered into this study was 69.6 weeks. There was no toxic death. The most frequent adverse events were neutropenia (31% grade 3/4) and delayed diarrhea (9.7%). CPT-11 has definite activity in the treatment of progressive metastatic CRC truly resistant to 5-FU which translated into clinical survival benefit. Median survival from first administration of CPT-11 was 78.6 weeks for patients with best response (PR + SD) compared with 28.1 weeks for patients with progressive disease (PD) (P = 0.01). With the appearance of new active drugs in this highly chemotherapy-resistant disease, the definition of response should be reassessed in CRC.
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PMID:Clinical activity and benefit of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma pre-treated with fluorouracil-based chemotherapy. 1114 84

Despite the long clinical history of 5-FU in gastrointestinal cancer, the development of oral agents has been a productive endeavor, and oral fluoropyrimidine agents are likely to play an important role in the management of colorectal cancer. Results of recent trials in advanced/metastatic colorectal cancer have shown equivalence of response rates, time to disease progression, and median survival and reduced rates of neutropenia and stomatitis with oral capecitabine (Xeloda) or UFT/leucovorin compared with standard fluorouracil (5-FU)/leucovorin regimens. Evaluation of these oral agents in adjuvant therapy, in combination chemotherapy, and in combination with radiation therapy is ongoing.
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PMID:Role of oral chemotherapy in colorectal cancer. 1119 16

Fluorouracil (5-FU) has remained the standard therapy for the treatment of advanced colorectal cancer for over 40 years. Unfortunately, only a minority of patients experience objective clinical response. Discussed herein are attempts to improve on the activity of 5-FU by biochemically modulating its action. In addition, novel agents for the treatment of advanced colorectal cancer (oral fluoropyrimidines, oxaliplatin, and irinotecan) are discussed. Oral fluoropyrimidines (UFT plus leucovorin, capecitabine, eniluracil plus oral 5-FU) provide the convenience of oral delivery with a marked reduction in febrile neutropenia and mucositis. Recent randomized trials with these agents have demonstrated therapeutic activity that is comparable with intravenous schedules of 5-FU plus leucovorin. Compared to 5-FU, both oxaliplatin and irinotecan have uniquely different mechanisms of action and have demonstrated clinical activity in patients whose disease has progressed with 5-FU treatment. Combinations of either irinotecan or oxaliplatin plus 5-FU/leucovorin have demonstrated that the addition of these agents to 5-FU/leucovorin improves response rates and time to progression compared to 5-FU/leucovorin alone. Combination chemotherapy regimens with these novel agents are rapidly being introduced into the adjuvant setting.
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PMID:Colorectal cancer: chemotherapy treatment overview. 1120 Jan 48

Two randomized phase III trials with irinotecan as second-line treatment of metastatic colorectal cancer have shown that irinotecan (CPT-11, Camptosar) significantly improves survival when compared with best supportive care or continuous infusion of fluorouracil (5-FU) after failure of 5-FU. The combination of irinotecan and 5-FU/leucovorin produced a significantly higher response rate (40.8% vs 23.1%, P < .001), longer time to progression of disease (6.7 vs 4.4 months, P < .001), longer median survival (17.4 vs 14.1 months, P = .03), and a greater chance of survival at 1 year (69% vs 59%, P = .03) than 5-FU/leucovorin treatment alone. Such benefits have not previously been demonstrated in this setting. Although the use of irinotecan in combination with 5-FU/leucovorin increased the likelihood of neutropenia, the incidence of febrile neutropenia and infection remained low. Other toxic effects were manageable, noncumulative, and reversible.
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PMID:Irinotecan and high-dose fluorouracil/leucovorin for metastatic colorectal cancer. 1120 Jan 50

The aim of this study was to examine the efficacy and safety of both oxaliplatin as a single agent and oxaliplatin in combination with dailyx5 bolus 5-fluorouracil and folinic acid (5-FU/FA, Mayo clinic regimen) in the first-line treatment of metastatic colorectal cancer (CRC) patients. 73 advanced CRC patients were randomised to receive either oxaliplatin 85 mg/m(2) every 2 weeks (35 patients), or the same treatment combined with 5-FU 425 mg/m(2)/day and FA 20 mg/m(2)/dayx5 days every 4 weeks (38 patients). Treatment was continued until disease progression or unacceptable toxicity. All patients had documented inoperable disease and no previous chemotherapy for advanced disease. Based on the investigators' assessment of best response, objective response rate was 9% (95% confidence interval (CI) 2-24%) in the oxaliplatin arm, and 45% (95% CI 27-64%) in the oxaliplatin+5-FU/FA arm. Median progression-free survival (PFS) was 2 months (95% CI 1.7-2.4 months) in the oxaliplatin arm and 3.9 months (95% CI 2.9-5 months) in the oxaliplatin+5-FU/FA arm. Severe neutropenia was seen in 23% of patients in the oxaliplatin+5-FU/FA arm, and none in the oxaliplatin arm. There were two treatment-related deaths, both in the oxaliplatin+5-FU/FA arm. In the oxaliplatin+5-FU/FA arm, severe diarrhoea, vomiting and stomatitis were seen in 34, 14 and 14% of the patients, respectively. In conclusion, oxaliplatin at a dose of 85 mg/m(2) given every 2 weeks was well tolerated and has limited activity in metastatic CRC, while the combination of this treatment with the full-dose Mayo clinic regimen (5-FU bolus 425 mg/m(2)/day+FA 20 mg/m(2)/dayx5 days every 4 weeks), although active, was unfeasible due to a high level of myelosuppression and gastrointestinal toxicity. Alternative lower dosing or other regimens are to be explored to ascertain the value of bolus 5-FU/FA combined with oxaliplatin.
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PMID:A randomised phase II study of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo Clinic regimen) in previously untreated metastatic colorectal cancer patients. 1133 26

We describe in this paper a therapeutic modality which is based on a self-rescuing concept (SRC) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent, tegafur (FT); a DPD inhibitor (CDHP: 5-chloro-2, 4-dihydroxypyridine) which is about 200-fold more potent than uracil used in UFT; and an ORTC inhibitor (Oxo: potassium oxonate) which is localized in the gastrointestinal tract. We devised a novel oral anticancer agent, S-1, as a combination drug with a molar ratio of 1:0.4:1 for FT, CDHP, and Oxo, respectively. To compare S-1, FT, and UFT in terms of their anticancer activity and adverse reactions, a colon cancer implantation model in rats was used for 4-week consecutive oral administration from the time when the postimplantation tumor weight become about 2 g. The tumor disappeared on day 16 at a given dose of S-1 (as 22.5 mg/kg FT), and the tumor did not reappear for at least three months. Antitumor activity was more marked with S-1 than FT and UFT. Adverse reaction, i.e., stomatitis, depilation, and weight loss, were less frequent in the S-1 group than in the other groups. A clinical pharmacology study examined blood concentrations of 5-FU after twice-a-day administration after meals of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were 60 to 200 ng/ml in all twelve patients examined. Late phase II clinical trials of S-1 were conducted in patients with advanced and recurrent stomach cancers, in the same regimen as for the clinical pharmacology study. It basically consisted in four cycles, each of which comprised 4-week, twice-a-day, consecutive oral administration with a 2-week withdrawal. The overall response rate was 44.6% (45/101). Median survival time (MST) was 224 days. S-1 was given manufacturing approval by the Ministry of Health and Welfare of Japan after a priority review, with indications for advanced and recurrent stomach cancers. A late phase II clinical study of S-1 in patients with advanced/recurrent head and neck cancer was conducted in 59 eligible patients. Objective responses were 4 complete response (CR) and 13 partial response (PR), for a response rate of 28.8% (17/59). MST was 344 days. Grade 4 hemoglobin decrease was observed in one case; however, this returned to normal after the termination of drug administration and blood transfusion. Therefore, this event was confirmed to be reversible. A late phase II clinical trial of S-1 was conducted to evaluate the efficacy and toxicities in patients with metastatic colorectal carcinoma. Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled in this clinical trial. The overall response rate was 35.5% (22/62), and the MST was 378 days. The main adverse reactions were myelosuppression and GI toxicities. The incidence of neutropenia (Grade 3 or 4) was 13%, while the incidence of other adverse reactions was 10% or below. None of 53 outpatients required to be hospitalization due to adverse reactions. Late phase II clinical trials of S-1 are in progress for colorectal cancer, breast cancer and non-small cell lung cancer. To establish the standard therapeutic modality for cancers, including gastrointestinal cancers, in Japan, the conduction of clinical trials combining S-1 and other anticancer drugs holds promise for the future.
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PMID:[New oral anticancer drug, TS-1 (S-1)--from bench to clinic]. 1143 58

5-Fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin (35 mg/m(2)) and cyclophosphamide (400 mg/m(2)) were administered from day 2 to day 4, every 4 weeks. All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity.
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PMID:Combined 5-fluorouracil infusion with fractionated epirubicin and cyclophosphamide in advanced breast cancer. 1147 71

To date, in cases of advanced or recurrent breast cancer, combination chemotherapy including anthracycline have been used for 1st-line treatment. Mitomycin C and oral 5-FU were used for cases refractory to such treatment, but the response rate was not satisfactory. Docetaxel is one of the most promising drugs to have emerged in recent years, with phase II studies in previously untreated metastatic breast cancer indicating a high overall response rate of approximately 60%, in the refractory cases for anthracyclines, indicating an overall response rate of 40% using docetaxel at 75 to 100 mg/m2 as a 1-hour intravenous infusion every 21 days. In Japan, the overall response rate was reported as about 50% using single docetaxel given at 60 mg/m2 every 21 days. The dose-limiting toxicity is myelosuppression, which is dose-but not schedule-dependent. In most published studies, there is a 90-95% incidence of grade 3 or 4 neutropenia when docetaxel is administered every 3 weeks. In recent studies, for the purpose of reducing the severity of myelosuppression, weekly docetaxel seems to be an effective and feasible treatment for advanced or recurrent breast cancer.
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PMID:[Docetaxel]. 1168 Dec 43


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