Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preclinical and clinical studies demonstrate that the selective antitumor activity of fluorouracil (5-FU) is enhanced by agents which perturb certain intracellular nucleotide pools. We previously demonstrated that the combination of N-phosphonacetyl-L-aspartate (PALA), which depletes pyrimidine nucleotide pools, and 5-FU yielded a 43% response rate among 37 assessable patients with colorectal carcinoma. In preclinical tumor models, 6-methylmercaptopurine riboside (MMPR), an inhibitor of purine synthesis, elevates phosphoribosylpyrophosphate (PRPP) pools and promotes the anabolism of 5-FU to fluorinated nucleotides. In vivo, the addition of MMPR enhances the therapeutic efficacy of PALA-5-FU. In a phase I trial, we sought to determine the optimal dose and schedule of MMPR in combination with PALA (250 mg/m2 on day 1) and 5-FU (1300 mg/m2 by 24-hour infusion on day 2). MMPR (75-225 mg/m2) was given intravenously on day 1 to 27 patients with solid tumors (15 colorectal, seven breast, five other). Toxic effects were mild to moderate and included leukopenia, mucositis, nausea, or rash. Two of seven patients given MMPR at 225 mg/m2 had grade 3 diarrhea. PRPP was measured using a [14C]orotic acid 14CO2 release assay in tumor biopsy specimens obtained before and 12 hours and 24 hours after MMPR doses were given to 20 patients. The addition of MMPR elevated PRPP pools in human solid tumors. At 12 hours after treatment, two (50%) of four patients showed a twofold or greater elevation of PRPP at the MMPR dose level of 75 mg/m2; a similar elevation was observed in five (71%) of seven patients given 150 mg/m2 MMPR and in three (43%) of seven patients given 225 mg/m2 MMPR. At 24 hours after treatment, results for the respective dose levels of MMPR were two (33%) of six patients, one (20%) of five patients, and four (57%) of seven patients. Administration of the two highest MMPR dose levels appeared to result in a greater increase in tumor PRPP levels. However, toxicity was greater at the 225 mg/m2 dose level; therefore, the 150 mg/m2 dose level was favored. Tumor levels of PRPP decreased between 12 hours and 24 hours in nine (56%) of 16 patients. This time course indicates that MMPR should be administered at the beginning of the 24-hour infusion of 5-FU.
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PMID:Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine riboside: optimization of 6-methylmercaptopurine riboside dose and schedule through biochemical analysis of sequential tumor biopsy specimens. 171 7

Little is known about the in vivo effects of inhibition of the mitochondrial pyrimidine de novo synthesis enzyme dihydroorotic acid dehydrogenase (DHO-DH). In mice a new inhibitor of DHO-DH, Brequinar sodium (DUP-785, NSC 368390) depleted the plasma uridine concentration to 40% within 2 h, followed by a small rebound after 7-9 days. The drug was subsequently evaluated in a Phase I clinical trial, during which it was possible to follow its biochemical effects in 24 patients (27 courses). In addition to the measurement of plasma uridine concentrations, we also measured in lymphocytes of 9 patients (10 courses) the duration of DHO-DH inhibition. Brequinar sodium was administered every 3 weeks as an i.v. infusion at dose levels of 15-2250 mg/m2. The biochemical effects were studied following the first administration of the drug. In sonicated extracts of lymphocytes from 7 healthy volunteers the activity of DHO-DH varied from 2.0 to 3.9 nmol/h per 10(6) cells, while in the lymphocytes of 9 patients obtained immediately before treatment this value was between 0.5 and 4.8 nmol/h per 10(6) cells. Within 15 min of drug administration DHO-DH activity was not detectable and was still low up to 1 week later. Duration of the inhibition appeared to be related to the extent of clinical toxicity, e.g., myelosuppression, nausea, vomiting, diarrhea, and mucositis. Severe lymphopenia was observed in patients receiving Brequinar sodium at the maximum tolerated dose. At dose levels of greater than or equal to 600 mg/m2, uridine depletion (40-85%) was observed between 6 h and 4 days, followed by a rebound of 160-350% after 4-7 days. The extent of the depletion and of the accompanying rebound of uridine levels and the extent and duration of DHO-DH inhibition in the individual patients could be partially associated with drug toxicity in these patients. This is the first report describing biological effects of DHO-DH inhibition in humans in relation to the degree and duration of inhibition of this enzyme.
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PMID:In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. 216 43

Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms. Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.
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PMID:Phase I and pharmacokinetic study of brequinar sodium (NSC 368390). 236 34

A phase I study of a new fluorinated pyrimidine compound, 5'-deoxy-5-fluorouridine (5'-DFUR), was performed in 37 patients with various malignant cancers. Starting dose was 600 mg/m2/day (900 mg/body/day) and escalated up to 3900 mg/body/day. The dose given was divided into 3 administrations a day for 5 consecutive days. Subjective symptoms were observed in cases given a dose of over 2,100 mg/body/day. Gastro-intestinal disturbances such as nausea, vomiting and anorexia were the major side effects. In the hematological and urinary examinations, no severe abnormal signs were observed. The maximum tolerated dose was considered to be 2.100 mg/body/day, and the dose-limiting factor was gastro-intestinal disturbance. 5-FU levels were determined in the serum and tumor tissues. 5'-DFUR was well absorbed. The 5-FU level in tumor tissue was very high at 2 to 3 hours post-dose and then rapidly decreased, being 0.05 microgram/g 12 hours after administration. The optimal dosage for a phase II study was suggested to be less than 2,100 mg/body/day.
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PMID:[Phase I study of 5'-deoxy-5-fluorouridine (5'-DFUR)]. 293 58

A phase II trial of 5'-deoxy-5-fluorouridine (5'-DFUR), a new fluorinated pyrimidine analog which has been demonstrated to have potential superiority over 5-FU and tegafur for chemotherapy of murine tumors, was performed in patients with advanced non-small cell carcinoma of the lung and metastatic pulmonary tumors. 5'-DFUR at a dose of 800 mg/m2 was given per os every day for more than four weeks. None of 15 evaluable patients with non-small cell carcinoma of the lung and 15 evaluable patients with metastatic pulmonary tumors showed a complete or partial response. Toxic effects of 5'-DFUR included anorexia (29%), diarrhea (26%), nausea (23%), vomiting (10%), leukocytopenia (10%), general fatigue (10%), liver disorder (6%) and thrombocytopenia (6%).
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PMID:Phase II study of oral administration of 5'-deoxy-5-fluorouridine (5'-DFUR) for solid tumors. 624 May 46

5-Fluorouracil (FUra) is a clinically useful antineoplastic agent. Preclinical studies suggest that the therapeutic effects of FUra can be enhanced by pretreatment with N-(phosphonacetyl)-L-aspartic acid (PALA), an inhibitor of aspartate transcarbamylase. The objective of treatment with PALA is to increase the activation of FUra by inhibiting the normal pathway of de novo pyrimidine biosynthesis. Theoretically, the optimal dose of PALA should produce effective blockade of this pathway without increasing toxic effects of FUra. Using pyrazofurin-induced orotic aciduria and orotidinuria as a measure of this pathway, it as determined that PALA (250 mg/sq m) is effective in inhibiting total-body pyrimidine synthesis. Sixty-eight adult patients with cancer were treated with combinations of PALA and FUra. High doses of PALA (1 to 2 g/sq m) prevented the use of full dosage of FUra; however, PALA (250 mg/sq m) can be administered 24 hr before FUra (750 mg/sq m) once weekly for at least 3 weeks. The toxicity observed using that combination of doses was mild to moderate myelosuppression, mucositis, diarrhea, nausea, and vomiting. Further clinical studies are warranted.
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PMID:Phase I and clinical pharmacological evaluation of biochemical modulation of 5-fluorouracil with N-(phosphonacetyl)-L-aspartic acid. 683 57

A new fluorinated pyrimidine, TAC-278, was studied for its safety, anti-tumor activity and pharmacokinetics in patients with solid tumors of various types. Single oral administration was done in 43 patients with dose range of 50 to 1200 mg. These single administrations caused no side effects but nausea in only one patient daily given 900 mg. Repeated oral dose tolerance was assessed in 79 patients in daily doses of 100 to 1800 mg. Side effects were reported by 26 (33.3%) of the 79 patients. Major side effects were mild gastrointestinal symptoms. The maximum tolerated dose was considered to be 1200 mg/day, over which CNS symptoms as dose limiting factor for TAC-278 developed in some patients. As to the therapeutic effect, minor response was obtained in 2 of the 24 evaluable patients. Concentration of 5-FU in body fluid and tumor tissues were high following oral administration of TAC-278, but the disappearance was relatively rapid. Excretion of TAC-278 occurred predominantly in urine.
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PMID:[Phase I clinical study of a new fluorinated pyrimidine antineoplastic agent, TAC-278]. 718 8

A phase I study of a new fluorinated pyrimidine, 1-hexylcarbamoyl-5-fluorouracil (HCFU), was performed by a multi-institutional clinical study group using a total of 111 patients with histologically proven malignancies. The characteristic toxic effects were a transient hot sensation and pollakiuria, which occurred 15-120 minutes after oral administration of the drug, continued for 30 minutes to 4 hours, and subsided spontaneously. Gastrointestinal disturbances such as nausea, vomiting, diarrhea, and anorexia, which are common with 5-FU administration, also occurred with HCFU but did so less frequently. The maximum tolerated dose for a single oral administration was estimated to be between 12 and 15 mg/kg and the optimal daily dose for continuous administration was considered to be between 9 and 18 mg/kg, with divided daily administration. Fifty-seven patients received 5-19 mg/kg/day of HCFU for > 4 weeks, including 31 patients with > 60 days' treatment. Cumulative doses were from 9.5 to 166.2 g, with a mean of 26.3 g. Hematopoietic toxicity was slight and hepatic toxicity was questionable. No renal or other cumulative toxicity was observed. In ten of the 57 patients, favorable clinical effects were seen: an active decrease in the size of the solid tumor (three patients), the disappearance of ascites (six), and the improvement of intestinal obstruction due to peritoneal carcinomatosis (one).
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PMID:Phase I study of a new antitumor drug, 1-hexylcarbamoyl-5-fluorouracil (HCFU), administered orally: an HCFU clinical study group report. 744 23

Fazarabine (Arabinofuranosyl-5-azacytosine) is a synthetic pyrimidine nucleoside which combines the arabinose sugar of cytosine arabinoside with the triazine base of 5-azacytidine. It has demonstrated activity against a variety of human solid tumor xenografts including colon, lung and breast cancers. Eighteen patients with refractory metastatic colon cancer were enrolled in a phase II trial of fazarabine. The drug was administered as a 72 hr continuous infusion every 3-4 weeks; the starting dose was 2 mg/m2/hr as established in a previous phase I study. The major toxicity was neutropenia, as predicted from the phase I study. The median time to nadir for cycle 1 was 20 days, with a median granulocyte count of 437/microliters (range 36-1600/microliters); recovery was within 2-4 days, with only one incidence of fever and neutropenia in 42 cycles. Especially noted for their absence were thrombocytopenia, nausea, vomiting and stomatitis. No objective clinical responses were seen; one patient had stabilization of rapidly growing liver metastases for a period of 7 months. In view of fazarabine's narrow range of toxicities, future dose intensification trials utilizing fazarabine in combination with hematopoietic growth factors are worthy of consideration.
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PMID:Phase II study of fazarabine (NSC 281272) in patients with metastatic colon cancer. 768 14

Fazarabine (1-beta-D-arabinofuranosyl-5-aza-cytosine, or Ara-AC) is a nucleoside analogue that consists of the arabinoside ring of 1-beta-D-arabinofuranosylcytosine and the pyrimidine base of 5-azacytidine. In Phase I and Phase II trials, neutropenia was dose limiting, with minimal nonhematological toxicity. The in vitro cytotoxic concentrations of Ara-AC could not be achieved in these studies; neutropenia precluded dose escalation. The objectives of this study were: to determine either the maximum tolerated dose of Ara-AC or to safely achieve target plasma levels of 2-5 microgram/ml when Ara-AC was administered as a 24-h infusion with granulocyte colony-stimulating factor (G-CSF) to patients with advanced refractory malignancies; to characterize the pharmacokinetic behavior of Ara-AC with G-CSF; and to define the relationship of Ara-AC pharmacokinetics to toxicity. Twenty-four patients received 67 courses of Ara-AC at doses of 54-112 mg/m2/h. Dose-limiting toxicity was approached but not reached. Grade 3 or 4 neutropenia and nausea were the principle side effects. Steady-state plasma concentrations exceeded the minimum target concentration of 2 microgram/ml in all patients who received >/=78 mg/m2/h for 24 h. The maximum target concentration was approached during administration of 112 mg/m2/h for 24 h. The mean steady-state clearance was 475 +/- 103 ml/min/m2 and did not change with dose. One partial response was seen. One patient received 16 courses and another received 7 courses of therapy before progression. Ara-AC can be safely administered in doses that result in plasma concentrations of 2-5 microgram/ml, if it is given with G-CSF. Phase II trials of Ara-AC in selected malignancies are planned.
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PMID:Phase I and pharmacological trial of fazarabine (Ara-AC) with granulocyte colony-stimulating factor. 981 35


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