Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

24 patients with advanced, histologically proven cancer were treated with difluoromethylornithine 2.25 g/m2 orally every 6 h for the first 7 days of each 4-week treatment cycle. These patients also received daily i.m. doses of recombinant human alpha 2a-interferon (IFN) on Days 3 through 7 of each cycle. IFN doses of 3, 6, 12, 24, 36, and 48 X 10(6) units/m2 have been studied utilizing three patients at each daily dose level. Three additional patients have been observed at each of the two highest doses for better toxicity definition. This combination produced slight transient declines in leukocyte and platelet counts and transient rises in serum aspartate aminotransferase; however, these changes were no more pronounced at the higher IFN doses than at daily doses of 6 X 10(6) units/m2. Mild nausea and vomiting occurred in most patients and mild diarrhea also was common at all IFN dose levels. Chills, fever, myalgia, lethargy and fatigue, and anorexia were also observed at all IFN doses; however, lethargy and fatigue (lassitude) seemed to be the major factor which limited patient tolerance of IFN to 48 X 10(6) units/m2 daily. No ototoxicity was identified clinically or audiometrically and no life-threatening toxicity has occurred. Initial Phase II studies in melanoma are currently in progress.
Cancer Res 1988 Nov 15
PMID:Phase I study of difluoromethylornithine in combination with recombinant alpha 2a-interferon. 314 Oct 46

An in vitro model has been devised so that mixtures of human tumor cells can be grown together for studies related to drug-induced or -selected changes in sensitivity. In the studies reported here, two human astrocytoma clones, one sensitive and one resistant to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), were carefully matched for doubling times, cell cycle phase distributions, and colony-forming efficiencies. The clones were mixed and grown together, and after only three weekly treatments with MeCCNU (10 micrograms/ml for 1 h each week) the sensitive cells in the mixture were killed, leaving behind a population that was almost 100% resistant to further exposures to MeCCNU. The loss of the sensitive cells from the mixture each week was easily detected by visual observation of flow microfluorometry histograms since the clones had different DNA indices. Repeated weekly exposures of the unmixed resistant clone (AST 1-1) to MeCCNU caused very little accumulated cell kill. Similar exposures of the unmixed sensitive clone (AST 3-4) produced a linear decrease in survival over the first three weekly treatments with 10 micrograms MeCCNU/ml, but after that time these cells became progressively more resistant to MeCCNU. It is unlikely that the change to resistance in the AST 3-4 clone occurred because of contamination with the resistant AST 1-1 cells, because their DNA index remained stable. These data show that repeated treatments with a single agent can cause a tumor cell population to become more resistant. It remains to be tested whether this resistance was the result of cellular interactions, drug-induced changes in sensitivity, or selection for resistant cells already present in the populations. This mixture model may be useful in studies on how cellular interactions influence growth and drug sensitivity in tumor and normal cell populations.
Cancer Res 1988 May 15
PMID:Treatment-induced changes in sensitivity in a multiclonal human tumor mixture model in vitro. 335 35

10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transaminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.
Cancer Res 1988 Oct 01
PMID:Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer. 341 10

The synthetic factor based on determinations of 10 parameters in sera of patients with ovarian carcinoma, was constructed. The factor was found to be useful in evaluation of the effectiveness of the cytotoxic treatment and in indication of the recurrence of the malignancy. Reduction of the number of biochemical markers to five (haptoglobin, seromucoid, lactate dehydrogenase, alkaline phosphatase, aspartate aminotransferase), according to significance of particular markers in the laboratory diagnostics of ovarian cancer did not affect the diagnostic sensitivity of the synthetic factor.
 ...
PMID:Synthetic factor for evaluation of the effectiveness of the therapy in ovarian carcinoma. 345 51

Age fractionation of erythrocytes is useful for further studies of the pharmacokinetics of methotrexate (MTX) in red blood cells. We separated erythrocytes from five blood donors and four patients at different time points after MTX infusions, using discontinuous Percoll gradients consisting of four solutions with a difference of 3% in density among them. The procedure yielded five distinct fractions of erythrocytes of increasing mean cell age as judged by declining reticulocyte enrichment and erythrocyte aspartate aminotransferase activity among the five fractions. MTX concentrations of the erythrocytes were measured at different times in connection with five 24-h MTX infusions (0.7-4 g/m2) on 14 occasions. Two days after completion of MTX infusion, no MTX was detected in the youngest erythrocyte population in two patients. Seven days after the infusion, the highest MTX concentrations were found in the youngest red blood cells. Ten to fourteen days following the MTX treatment, considerably lower MTX concentrations were found in the young red blood cells, and the MTX-containing erythrocytes seemed to have moved down the gradient. Just before the next MTX infusion (after 28 days) no MTX could be detected in the young erythrocytes. The MTX concentrations at that time were highest in the oldest erythrocyte fractions. This study shows more directly that MTX is incorporated in the red cell precursors of the bone marrow. The pharmacokinetics demonstrated correspond to a maturation time of the erythroblasts of about 7 days.
Cancer Chemother Pharmacol 1986
PMID:Methotrexate pharmacokinetics in age-fractionated erythrocytes. 346 79

The morphological characteristics and the production of biochemical markers were determined for 8 human tumor cell lines grown in artificial capillary culture. Comparisons were made with nude mouse xenografts and conventional monolayer or suspension cultures. Capillary histologies reproduced the features of neoplastic differentiation and glandular formation exhibited by the original human tumors and xenografts. The concentrations of specific biochemical markers, such as carcinoembryonic antigen, aspartate aminotransferase, and immunoglobulin, were higher in the pericellular culture medium in capillary culture. The capillary environment influenced the expression of biochemical heterogeneity by the DLD-1 colon carcinoma cell line and its derivative clones. Spontaneous differentiation of K562 leukemia cells was increased in the capillary system. These results indicate that the artificial capillary is a useful and relevant system for the study of cultured human tumor cells.
J Natl Cancer Inst 1987 Jul
PMID:Artificial capillary culture studies of human tumor cell growth, differentiation, and marker production. 347 51

The value of scalp cooling in the prevention of alopecia was investigated in 32 patients with advanced breast cancer who were given a mean of four courses of 40-80 mg/m2 of epirubicin. None of the 15 patients free from liver metastases who received scalp cooling required a wig, whereas four of eight similar patients who did not receive scalp cooling did require a wig. Abnormalities of aspartate transaminase and alkaline phosphatase pretreatment were predictive for reduced efficacy of scalp cooling, but not a contraindication to its use.
Cancer Treat Rep 1987 Oct
PMID:Effectiveness of scalp cooling in reducing alopecia caused by epirubicin treatment of advanced breast cancer. 347 18

To evaluate the frequency of false positive globular inclusions, 89 autopsy cases with various malignancies and liver metastases have been examined by immunoperoxidase staining of liver sections and isoelectric focusing of sera. Four subjects with AAT globules in their hepatocytes were found, all of whom had the Pi Z phenotype. Globular inclusions were not found in any subject lacking the Pi Z allele on isoelectric focusing, but in 3 subjects with the Pi Z phenotype no hepatocytic globules were found.
 ...
PMID:The Pi Z allele and hepatic alpha 1-antitrypsin globules in patients with secondary liver cancer. 348 14

The occurrence of liver metastases was evaluated by ultrasonic scanning and correlated with prognostic factors, pattern of metastases, clinical examination, biochemical liver function tests from serum, and liver biopsy specimens in 394 consecutive evaluable patients with first recurrence of breast cancer. Fifty-nine patients (15%) had a positive scan, and liver metastases were the only sign of recurrent disease in 11 of these patients. The presence of liver metastases was not associated with age, menopausal status, size of the primary tumor, regional lymph node status, or the length of the recurrence-free interval; but patients with liver metastases were significantly closer to the menopause than those without (P = 0.02). The diagnostic value of clinical examinations was comparable to that of serum bilirubin and serum aspartate aminotransferase (ASAT) analyses, but was significantly better than alkaline phosphatase (AP) and lactate dehydrogenase (LDH) analyses. Analysis of serum AP was not a valuable diagnostic tool in the diagnosis of liver metastases, since it was elevated in 58% of the patients with bone metastases, and since metastases in this site were found in one third of the patients without liver metastases. If all four tests were negative, liver metastases were excluded in 99% of the patients, and if more than two of the four tests were positive, liver metastases were found in 95%. Valid (greater than 80%) diagnosis of liver metastases by serum LDH or serum ASAT alone, required an elevation of three or five times the upper normal limits, respectively. Thirty-nine patients with positive ultrasonography results underwent biopsy. The ultrasonographic diagnosis could not be confirmed histologically in three patients (8%). If ultrasonic scanning had not been performed routinely, only one of 213 patients (0.5%) with soft tissue metastases would have been offered local therapy rather than systemic treatment. These data suggest that ultrasonic scanning of the liver should not be a routine diagnostic tool in examination of patients with first recurrence of breast cancer. However, whenever indicated by clinical signs or elevated blood tests, scanning should be performed to confirm the presence of liver metastases, particularly in patients entering therapeutical trials, since liver metastases demonstrated by ultrasound examinations may serve as a measurable parameter.
Cancer 1987 Apr 15
PMID:Incidence and methodologic aspects of the occurrence of liver metastases in recurrent breast cancer. 354 42

The pharmacokinetics of amsacrine have been studied after the first and third infusions (200 mg . m-2) in 10 patients receiving combined chemotherapy for the treatment of acute myelogenous leukaemia (AML). Postinfusion amsacrine elimination was best described by a biexponential expression with a mean t1/2 alpha of 0.8 h and a terminal t1/2 beta of 5.3 h. After the third infusion there was a significant reduction (P less than 0.05) in the plasma clearance (Cl) and a prolongation of the terminal half-life (t1/2 beta) (P less than 0.01), but no change in the initial half-life (T1/2 alpha) or volume of distribution (Vd). No significant overall changes were recorded in any of the biochemical indices of renal or hepatic function between the first and third infusions, but the patient who exhibited the largest reduction in Cl showed a marked increase in AST levels and a reduction in albumin concentration. Two distinct groups were apparent after the first infusion, patients with a Cl greater than 294 and those with a Cl less than 208 ml . h-1 . kg-1. The latter patients were significantly older (P less than 0.05), and four of the five had subnormal albumin concentrations. Urinary determination of amsacrine indicated that renal elimination plays a minor role in the total clearance of this drug. Amsacrine was also found to be highly bound to plasma proteins (96.4%-97.7%), but changes in binding were not responsible for the reduced Cl and prolonged t1/2 beta observed between the first and third infusions. We suggest that the elimination of amsacrine may be susceptible to small changes in hepatic function, perhaps due to the high amsacrine concentrations (5-18 mumol . l-1) achieved with this regimen, which may be approaching saturation of the capacity for hepatic elimination.
Cancer Chemother Pharmacol 1985
PMID:Pharmacokinetics of amsacrine in patients receiving combined chemotherapy for treatment of acute myelogenous leukemia. 385 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>