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

5-Fluorouracil (5-FU) is an effective enhancer of radiation therapy (RT) in head and neck cancers. Due to rapid, predominantly hepatic metabolism by dihydropyrimidine dehydrogenase (DPD) and suggested clinical benefit from prolonged drug exposure, 5-FU is commonly given by continuous infusion. Eniluracil is a novel DPD-inactivator designed to prolong the half-life of 5-FU and provide sustained plasma concentrations of 5-FU with oral dosing. We conducted a Phase I study of the safety and efficacy of eniluracil given with oral 5-FU in patients receiving concurrent RT for recurrent or advanced squamous cell carcinomas of the head and neck. Thirteen patients with recurrent, metastatic, or high-risk (defined as an expected 2-year survival rate of <10%) head and neck cancer were enrolled and treated with concomitant chemoradiotherapy on an every-other-week schedule. Eniluracil at a fixed dose [20 mg twice a day (BID)] was given for 7 consecutive days (days 1-7). 5-FU and RT were given on 5 consecutive days (days 2-6). One patient was treated with once-daily RT (2.0 Gy fractions). The remaining patients received hyperfractionated RT (1.5-Gy fractions BID). The initial dose of 5-FU was 2.5 mg/m2 given BID. Dose escalation in patient cohorts was scheduled at 2.5-mg/m2 increments, with intrapatient dose escalation permitted. Lymphocyte DPD activity and serum 5-FU and uracil concentrations were monitored during two cycles. DPD activity was completely or nearly completely inactivated in all patients. Sustained, presumed therapeutic concentrations of 5-FU were observed at a dose of 5.0 mg/m2 given BID. Cumulative dose-limiting myelosuppression (both neutropenia and thrombocytopenia) was observed during the fourth and fifth cycles following administration of 5.0 mg/m2 5-FU BID. One patient died of neutropenic sepsis during cycle 4. Other late cycle toxicities included diarrhea, fatigue, and mucositis. Grade 3 mucositis was observed in 4 patients, but no grade 4 mucositis or grade 3 or 4 dermatitis was observed. A second patient death occurred during cycle 1 of treatment. No specific cause of death was identified. The study was subsequently discontinued. Cumulative myelosupression was the significant dose-limiting toxicity of oral 5-FU given with the DPD-inactivator eniluracil on an every-other-week schedule. Clinical radiation sensitization was not observed, based on the absence of dose-limiting mucositis and dermatitis. Alternative dosing schedules need to be examined to determine the most appropriate use of eniluracil and 5-FU as radiation enhancers.
 ...
PMID:Phase I study of eniluracil, a dihydropyrimidine dehydrogenase inactivator, and oral 5-fluorouracil with radiation therapy in patients with recurrent or advanced head and neck cancer. 1003 77

This study set out to evaluate, in patients with metastatic colorectal carcinoma, the efficacy and toxicity of S-1, which contains tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate, based on a biochemical modulation of 5-fluorouracil (5-FU) targeted at inhibition of dihydropyrimidine dehydrogenase (DPD). Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled into the study. None of the patients had received prior chemotherapy except for adjuvant setting. S-1 was administered orally twice daily at a standard dose of 80 mg m(-2) day(-1) for 28 days followed by a 14-day rest. This agent is continued until disease progression, unaccepted toxicity, or patient refusal. Twenty-two (35%) of the 62 eligible patients achieved PR with a 95% confidence interval of 25-48%. Five of the 10 patients with a history of adjuvant chemotherapy achieved partial remission. The median survival time was 12 months. Major adverse reactions included myelosuppressive and gastrointestinal toxicities, though their incidence of grade 3 or 4 being 13% in neutropenia and less than 10% in the others. None of the 53 patients treated as outpatients required hospitalization due to adverse reactions: These results suggest that S-1 achieves similar responses to those of infusional 5-FU plus leucovorin and shows the potential of another biochemical modulation with easily manageable toxicity.
 ...
PMID:Phase II study of S-1, a novel oral fluorophyrimidine derivative, in patients with metastatic colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. 1090 61

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.
 ...
PMID:Pharmacology of fluorinated pyrimidines: eniluracil. 1108 73

5-fluorouracil (5-FU) is irreversibly catabolized to dihydrofluorouracil, an inactive metabolite, by the enzyme dihydropyrimidine dehydrogenase (DPD). This catabolic pathway is a critical step in determining 5-FU availability for conversion to nucleotides and eventual incorporation into either RNA or DNA. Inactivation of DPD, therefore, is an approach to enhance the availability of 5-FU for potential improved therapeutic effect. Preclinical animal and human studies have demonstrated that eniluracil is an effective inactivator of DPD. Phase I studies have been completed showing the tolerability of two dosing schedules, including (1) a chronic schedule with twice-daily administration of eniluracil plus oral fluorouracil (5-FU) (10:1 ratio) for 28 days, and (2) a schedule of eniluracil administered daily on days 1-7 with oral 5-FU once daily on days 2-6. The phase I trials have demonstrated limited toxicities including diarrhea, mucositis, and neutropenia. Follow-up clinical trials have targeted colon and breast cancers in particular.
 ...
PMID:Oral eniluracil/5-FU for advanced colon and breast carcinomas. 1121 79

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.
 ...
PMID:[New oral anticancer drug, TS-1 (S-1)--from bench to clinic]. 1143 58

A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40 mg m(-2) b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg m(-2) depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg m(-2), because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg m(-2). In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1-8). The incidences of severe (grades 3-4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9-90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity.
 ...
PMID:Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. 1467 96

There is no chemotherapy considered to be standard treatment for advanced gastric cancer worldwide, and there is no consensus as to whether combination or single agent therapy is preferred. In the phase I portion, a dose-escalation study of cisplatin (CDDP) combined with TS-1, new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). TS-1 was given orally at 40 mg/m2 bid for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg/m2, depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg/m2, because 33.3% of patients (2/6) developed DLTs; mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg/m2. In the phase II portion, 19 patients including 6 patients of the RD phase I portion were evaluated. The median administered courses was 4 (range: 1-8). The incidence of haematological and non-haematological toxicities (> or = grade 3) was 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95%) confidence interval: 54.9 (90.6%), and the median survival days were 383. This regimen is considered to be active against AGC with acceptable toxicity. In addition, currently, a randomized phase III study (JCOG 9912) for AGC patients not treated previously with chemotherapy is underway in Japan. It compares three arms: 5-FU alone, TS-1 alone and CPT-11 with CDDP therapy. We also initiated a randomized phase III study comparing TS-1 alone, and with CDDP for AGC. From those two phase III studies, we may be able to evaluate the clinical benefit of TS-1 in combination with CDDP versus TS-1 single, or 5-FU combined with CDDP therapy in terms of survival benefits and improving the QOL for AGC patients.
 ...
PMID:[Combination chemotherapy of TS-1 +cisplatin for inoperable gastric cancer]. 1557 Sep 20

Drug-metabolizing enzymes are responsible for the activation or detoxification of cytotoxic drugs. Allelic variants are present with a variable frequency in different populations around the world and have an important role in the therapeutic index of such drugs. It is known that polymorphisms in thiopurine methyltransferase and dihydropyrimidine dehydrogenase have been associated with altered drug metabolism and increased risk of severe toxicity from 6-mercaptopurine and 5-fluorouracil, respectively. Additionally, a variant number of dinucleotide-repeat sequences in the promotor for uridine 5'-diphosphate glucuronosyltransferase 1A1 influences the glucuronidation of SN-38, the active metabolite of irinotecan, which is associated with severe toxicity, including diarrhea and neutropenia. In the same way, polymorphisms in thymidylate synthase have been associated with pyrimidine-associated toxicity and also with response to chemotherapy. The examples shown in this review demonstrate the usefulness of pre-screening patients for well-characterized polymorphism to identify the best-tolerated and most-effective treatment.
 ...
PMID:Genetic determinants of cancer drug efficacy and toxicity: practical considerations and perspectives. 1616 69

We present a patient with pulmonary metastasis from breast cancer who received S-1 (TS-1) and maintained complete response for approximately 10 years after recurrence. A 51-year-old woman underwent modified radical mastectomy for left breast cancer in November 1991. Her cancer was postoperatively classified as pT2 pN0 M0 Stage IIA. As postoperative adjunctive treatment, tamoxifen and hexylcarbamoyl 1-5-FU (HCFU) were given. During the administration period (30 months after surgery), a solitary pulmonary metastasis occurred. Three months after the start of S-1 (100 mg/body/day), the tumor disappeared on images. Thereafter she took S-1 orally for approximately 10 years, and the pulmonary metastatic focus maintained complete response. In addition, no recurrent focus was observed. The adverse events observed during S-1 treatment were nausea, low-grade neutropenia and pigmentation of fingers. All were mild, and S-1 could be continued. Our case illustrates two important characteristics of S-1. First, S-1 was effective even though this patient had a lung metastasis during adjuvant treatment with HCFU. S-1 is a combined formulation containing 5-chloro-2, 4-dihydroxypyrimidine (CDHP; gimestat), which inhibits an enzyme that metabolites 5-FU, dihydropyrimidine dehydrogenase (DPD). Therefore, high 5-FU concentrations are maintained with S-1, and S-1 may be effective in the patients who do not respond to other fluoropyrimidine agents. Second, since S-1 toxicity was mild, long-term treatment for approximately 10 years was possible. Since S-1 contains potassium oxonate (OXO; otastat), gastrointestinal toxicities, the main adverse events of 5-FU agents, could be reduced. The purpose of treatments for metastatic breast cancer is to maintain favorable quality of life (QOL), as well as to improve survival. S-1 could be a valuable agent for breast cancer treatments, since it showed clinical efficacy and mild toxicity, and can be given orally.
 ...
PMID:S-1 (TS-1) maintained complete response for approximately 10 years in a case of metastatic breast cancer. 1675 22

In the present article, we have summarized the phase I/II clinical trials on combination therapy of S-1 and docetaxel. With result of the phase I study, patients were treated with intravenous infusion of 40 mg/m2 docetaxel on day 1 and oral S-1 80 mg/m2/day on days 1 to 14 every 3 weeks. Forty eight patients received a total of 272 treatment cycles. No complete responses (CRs) and 27 partial responses (PRs) were observed for an overall response rate (CR+PR) of 56.2% (95% CI, 38-66%). Eighteen patients (37.5%) had stable disease (SD), and 3 patients (6.2%) had progressive disease (PD) as best response. The tumor control rate (CR+PR+SD) was 93.8% (95% CI, 83-98%). The median overall survival was 14.3 months (95% CI: 10.7-20.3 months) and the median time to tumor progression was 7.3 months (95% CI: 4.2-10.7 months). The most common grade 3-4 hematologic toxicities were neutropenia 58.3%, leukopenia 41.7%, febrile neutropenia 8.3%, and anemia 8.3%. The most common grade 3 nonhematologic toxicities were anorexia 14.6%, stomatitis 8.3%, nausea 6.3%, diarrhea 4.2%, constipation 4.2%, and vomiting 2.1%. No grade 4 nonhematologic toxicities were reported, and all treatment-related toxicities were resolved. The mechanisms underlying these synergistic effects of S-1 and docetaxel were examined by expression and activity analyses of 5-FU metabolic enzymes. The expressions of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) were decreased and that of orotate phosphorybosyl transferase (OPRT) was increased in mRNA, protein level and activity assay after the treatment with docetaxel and 5-FU in the TMK-1 gastric cancer cell. These findings strongly indicate that the combination chemotherapy of docetaxel and S-1 is effective against gastric carcinomas and therefore is a good candidate as a standard chemotherapeutic strategy in treating these tumors.
 ...
PMID:[Combination chemotherapy of S-1 and docetaxel on advanced and recurrent gastric cancer]. 1689 78


1 2 3 Next >>