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Biomedical subjects

T C Chou

Publications and source records attributed to T C Chou.

At least 199 records · Page 11Linked to original sources
PubMed1982

Incorporation of metabolites of 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine into deoxyribonucleic acid of neoplastic and normal mammalian tissues.

The radioactivity of 14C-labeled 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine ([2-14C]-FIAC), a new and potent antiherpetic agent, was shown previously to be incorporated into the DNA fractions of mammalian and neoplastic tissues. The present work was undertaken to learn the nature of the incorporated moieties. Enzyme degradation of highly purified DNA from the small intestine of mice treated with [2-14C]FIAC and analysis of the resulting nucleosides failed to reveal the presence of unchanged FIAC. Rather, three metabolites were found, namely, the 2'-fluoro-1-beta-D-arabinofuranosyl nucleosides of cytosine (FAC), thymine (FMAU) and 5-iodouracil (FIAU). Labeled metabolites of FIAC were also found in the DNA isolated from P815 leukemic cells in mice given [2-14C]FIAC. It is of interest to note that FMAU, FIAU and FAC are, like FIAC, potent antiherpetic agents.

Animals↗
PubMed1982

Therapy of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas with combinations of 5-fluorouracil and 2 alpha-methyldihydrotestosterone propionate.

This investigation was undertaken to determine whether a combination of a cytotoxic drug with a sex hormone would provide efficacious therapy for mammary carcinomas. Established, 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas were treated with 5-fluorouracil (5-FUra) and 2 alpha-methyldihydrotestosterone propionate (MDTP) for 4 weeks. At end of therapy, pooled data showed 21% of the tumors in complete remission (CR) in rats given 5-FUra at 17.5 mg/kg/day and 3% in those given 8 mg/kg/day. Administration of MDTP at 1.25 to 5 mg/kg/day yielded 15 to 48% tumor CR. The combination of 5-FUra at 17.5 mg/kg/day with MDTP at 5, 2.5, and 1.25 mg/kg/day induced, respectively, 96, 91, and 75% CR. Maxima of 100, 100, and 92% CR were obtained in single tests at these respective doses. Therapy with combinations of 5-FUra at 8 mg/day and MDTP at 2.5 and 1.25 mg/kg/day yielded, respectively, 69 and 61% tumor CR. Appearance of new tumors during and after therapy was controlled more effectively by combinations of the two agents. Analysis of percentage of tumor CR showed marked synergism for 5-FUra and MDTP. A second course of combination therapy effectively prolonged duration of CR. Therapy with the cytotoxic drug 5-FUra in combination with the androgen analog MDTP is highly efficacious against induced mammary carcinomas.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Clinical evaluation of succinylated Acinetobacter glutaminase-asparaginase in adult leukemia.

We treated 13 adult patients with acute leukemia or chronic myelocytic leukemia (CML) in blast phase using succinylated Acinetobacter glutaminase-asparaginase (SAGA) administered on a daily dose schedule. SAGA reduced the peripheral blast count in two patients with acute lymphoblastic leukemia and two with blastic CML; however, no patient achieved either complete or partial remission. Marked central nervous system toxic effects (encephalopathy and coma) were observed, limiting treatment in patients whose disease appeared responsive; this effect finally prompted early discontinuance of the trial. Other toxic effects observed included nausea, hyperglycemia, and respiratory alkalosis. Hypersensitivity reactions to the enzyme were not seen. Pharmacologic analyses showed that prolonged blood glutamine depletion was achieved only by daily enzyme administration; however, we noted the importance of performing amino acid analysis on blood which was deproteinized immediately following phlebotomy. Our results demonstrate excessive central nervous system toxicity when glutaminase-asparaginase is administered on a daily schedule. Because of this effect, we propose that future trials of similar enzymes be limited to short courses of enzyme therapy, possibly with the addition of antimetabolites or amino acid analogs, which could enhance the antitumor effect without increasing toxicity.

Acinetobacter↗
PubMed1982

Activity of 2-fluoro-5-methylarabinofuranosyluracil against mouse leukemias sensitive to and resistant to 1-beta-D-arabinofuranosylcytosine.

A new pyrimidine nucleoside, 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil, previously has been shown to be active against the herpes group of viruses in vitro and in vivo. It is also active against mouse and human leukemic cells in culture and against mouse leukemias L1210, P388, and P815 in vivo. In contrast to other 1-beta-D-arabinofuranosylcytosine (ara-C) derivatives, 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil, when given either i.p. or p.o., is highly active against lines of leukemias P815 and L1210 made resistant to ara-C. Against P815/ara-C and L1210/araC, it is more effective than is 5-azacytidine, a drug which has shown definite effectiveness in patients with acute leukemia whose disease has become resistant to ara-C. For these reasons, 2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil would seem to merit clinical trial in patients with acute nonlymphocytic leukemia whose disease has become resistant to ara-C.

Animals↗
PubMed1981

Electrocardiographic diagnosis of right ventricular infarction.

The electrocardiographic findings in 11 cases of acute right ventricular infarction associated with acute left ventricular inferior wall myocardial infarction are described. The diagnosis of right ventricular infarction was proved by autopsy findings in five cases and supported by hemodynamic data in the other six. Ten of the 11 patients had typical electrocardiographic changes of acute inferior myocardial infarction and one had that of inferior wall injury. Transient S-T segment elevation was present in one (lead V1) or more of the right precordial leads in eight cases. In the absence of other explanations for the S-T segment elevation, acute right ventricular infarction was most likely the cause. Therefore, when acute inferior myocardial infarction is accompanied by S-T segment elevation in the right precordial leads, the coexistence of right ventricular infarction should be suspected. The sensitivity and specificity of this electrocardiographic sign are yet to be determined.

Aged↗
PubMed1980

Phase I evaluation of succinylated Acinetobacter glutaminase-asparaginase in adults.

Succinylated Acinetobacter glutaminase-asparaginase (SAGA) has broader antitumor activity than Escherichia coli L-asparaginase in experimental systems; moreover, drug resistance does not develop in tumor cell lines initially sensitive to this enzyme. We have investigated the pharmacology and toxicology of SAGA after both single-dose and serial daily dose injections in 20 adult patients. Glutaminase activity in plasma after i.v. injection of single doses did not follow simple first-order kinetics (half-life during the initial 24 hr was 21 +/- 9 hr. A linear relation was observed between increasing doses of SAGA and resultant levels of plasma enzyme activity and blood glutamate. Assay of whole blood which had been deproteinized immediately following phlebotomy showed that single doses of SAGA lowered glutamine only transiently to nondetectable levels; serial daily doses were required to achieve and maintain continuous glutamine depletion. Reversible depression of the central nervous system, ranging from encephalopathy to coma, occurred in a dose-related manner and was dose limiting. Other prominent reactions included respiratory alkalosis, hyperglycemia, nausea, and vomiting. Transient antitumor effects were noted in two patients with solid tumors and in two patients with leukemia. SAGA causes considerable neurotoxicity in adults which requires close patient monitoring. Phase II studies in leukemic patients are in progress.

Acinetobacter↗
PubMed1980

Biochemical, pharmacological, and phase I clinical evaluation of pseudoisocytidine.

Pseudoisocytidine (psi ICyd) is a C-nucleoside with enhanced stability and resistance to enzymatic deamination when compared to 5-azacytidine and 1-beta-D-arabinofuranosylcytosine. Elimination kinetics in plasma using [14C]psi ICyd showed a beta-phase for t1/2 for 14C of 2 hr and a beta-phase t1/2 of unchanged psi ICyd of 1.5 hr. Net recovery of radioactivity in urine over 24 hr varied between 40 and 80% of the administered dose; 50 to 90% was unchanged drug and the rest was pseudouridine. Human leukemic cells in vitro deaminated psi ICyd very slowly, formed appreciable quantities of pseudoisocytidine triphosphate, and incorporated small amounts into RNA and DNA. Clinical trials were done using a daily i.v. injection for 5 consecutive days. Hematological or intestine toxicities were not seen, nor was depression of white blood cell count observed in leukemic patients. Hepatic toxicity proved to be dose limiting; this was characterized by an early phase with elevation of prothrombin time and aspartate aminotransferase. A later phase with cirrhosis was observed in two patients. Autopsy showed massive hepatic necrosis in patients dying of acute toxicity and micronodular cirrhosis in one patient dying with the chronic form.

Antineoplastic Agents↗
PubMed1979

Metabolism and effects of 5-(beta-D-ribofuranosyl)isocytosine in P815 cells.

5-(beta-D-Ribofuranosyl)isocytosine (psi l Cyd), a C-nucleoside, has been shown to be active against P815 leukemia in mice. In P815 cells treated with [2-14C]psi l Cyd, we have detected radioactivity in nucleotide fractions and in RNA and DNA. Degradation to nucleosides of the labeled triphosphate nucleotide fraction and of RNA showed that the radioactivity present was chromatographically identical to psi l Cyd. Half-saturation concentrations for the incorporation of [2-14C]psi l Cyd into the triphosphate nucleotide fraction and into RNA and DNA were 370, 280, and 94 microgram/ml, respectively, which were greater than 100-fold higher than those for tritiated cytidine. The incorporation of psi l Cyd was competitively inhibited by cytidine. Phosphorylation and incorporation of psi l Cyd into nucleic acids of P815 cells and of a P815 subline resistant to 1-beta-D-arabinofuranosylcytosine are about 2- to 20-fold higher than in P815 sublines resistant to psi l Cyd or to both 5-azacytidine and 1-beta-D-arabinofuranosylcytosine. These data suggest that the phosphorylation of psi l Cyd and possibly its incorporation into nucleic acids are essential for therapeutic activity in P815 leukemias. In vitro metabolic studies also suggest that psi l Cyd and 5-azacytidine are cross-resistant and that P815 cells resistant to psi l Cyd are collaterally sensitive to 1-beta-D-arabinofuranosylcytosine. These predictions were confirmed by therapeutic experiments carried out in mice bearing P815 leukemias.

Animals↗
PubMed1978

The importance of R on T phenomenon.

The onset of ventricular tachycardia was examined in 44 patients with various types of heart disease. In only six patients (14%) the ventricular tachycardia was initiated by an ectopic ventricular complex interrupting the T wave. The findiings suggest that the importance of R on T phenomenon may have been over-emphasized.

Adolescent↗
PubMed1977

A simple generalized equation for the analysis of multiple inhibitions of Michaelis-Menten kinetic systems.

The summation of the effects of two or more reversible inhibitors of various types on the initial velocity of enzyme systems obeying Michaelis-Menten kinetics is described by the the general relation: (formula: see text) wherein v1,2,3...n is the velocity of reaction in the simultaneous presence of n inhibitors, vi is the velocity observed in the presence of each individual inhibitor, and v0 is the velocity in the absence of inhibition. The derivation is based on the assumption that each enzyme species can combine with no more than one of the inhibitors (i.e. the inhibitors are mutually exclusive). The above relationship holds irrespective of the number of inhibitors, the type of inhibition (competitive, noncompetitive, or uncompetitive), or the kinetic mechanism (sequential or ping-pong) of the enzyme reaction under consideration. Deviations from this equality define synergism or antagonism of inhibitors depending on whether the value of the left side of the above equation is greater or smaller than the right, respectively. Knowledge of the kinetic constants for substrates and inhibitors is not required. If two or more inhibitors act independently (i.e. are not mutually exclusive), their combined effects are necessarily synergistic. Under certain circumstances, described in the text, mutually nonexclusive inhibitors obey the fractional velocity product relationship: v1,2,3...n/v0 = (v1/v0) x (v2/v0) x (v3/v0)...(vn/v0).

Enzyme Inhibitors↗