Biomedical subjects

T Tihan

Publications and source records attributed to T Tihan.

28 records · Page 2Linked to original sources

PubMed1992

Serum lipid peroxide levels in the course of coronary by-pass surgery.

Reperfusion of the ischemic myocardium is associated with the extension of already existing injury. Investigation of the reperfused myocardium under different conditions revealed ultrastructural changes as well as functional disturbances which were identified as free radical-mediated damage. Free radical scavengers and antioxidant agents have been shown to reduce the size of the infarct, in which a temporary regional ischemia was followed by reperfusion. Elaborately designed in vitro and animal models strongly suggest that reperfusion injury might be of clinical significance in operations involving extracorporeal circulation, as in coronary by-pass surgery. However, there is limited information on the relationship between reperfusion injury and subsequent clinical conditions. In our study, we determined lipid peroxide concentrations in timed serum samples of patients who had undergone coronary by-pass surgery. Preoperative lipid peroxide concentrations were 2.50 +/- 0.50 mumol/l. This value increased to 3.30 +/- 1.00 mumol/l after six hours and showed a second increase to 4.20 +/- 0.80 mumol/l 48 hours after the onset of reperfusion. These results suggest that postoperative increases in lipid peroxide concentrations can be of multifactorial origin and may be an indication of reperfusion injury to the myocardium. Further studies are under way to elucidate the relevance of this increase in different groups and clinical conditions.

Aged↗

PubMed1991

Studies on the mechanisms of inhibition of L1210 cell growth by 3,4-dihydroxybenzohydroxamic acid and 3,4-dihydroxybenzamidoxime.

Didox and Amidox inhibit L1210 cell growth in culture. At least one of the mechanisms in the mode(s) of action of the compounds is directed at the ribonucleotide reductase site. Partially purified preparations of ribonucleotide reductase activity are inhibited by Amidox and Didox. The formation of deoxycytidine nucleotides from [14C]cytidine in intact L1210 cells is also blocked. Didox and Amidox cause the decrease in the intracellular pools of the four dNTPs. Hydroxyurea-resistant L1210 cells are not cross-resistant to either Didox or Amidox. These data suggest that Didox and Amidox are not inhibiting ribonucleotide reductase through a mechanism similar to hydroxyurea.

Animals↗

PubMed1990

Effect of ribonucleotide reductase inhibitors on the growth of human colon carcinoma HT-29 cells in culture.

The effects of ribonucleotide reductase inhibitors on the growth of the human colon carcinoma cell line HT-29 were examined. Inhibitors were chosen for these studies that were specifically directed at each of the subunits of ribonucleotide reductase. The concentrations of drugs required to inhibit the growth of HT-29 cells by 50% (IC50) for hydroxyurea, 2,3-dihydro-lH-pyrazole-[2,3a]imidazole (IMPY), and 4-methyl-5-amino-l-formyl-isoquinoline thiosemicarbazone (MAIQ) were 206, 996, and 3.2 microM, respectively. Although the IC50 for deoxyadenosine alone was greater than 2,000 microM, in the presence of 5 microM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), which protects deoxyadenosine from deamination by adenosine deaminase, it was reduced to 112 microM. The IC50 for deoxyguanosine was 1,060 microM. The addition of 8-aminoguanosine to protect deoxyguanosine from phosphorolysis by purine nucleoside phosphorylase did not increase the toxicity of deoxyguanosine in HT-29 cells. The combination of MAIQ or IMPY and deoxyadenosine/EHNA gave strong synergistic inhibition of HT-29 cell growth. The results of these studies indicate that ribonucleotide reductase inhibitors effectively block the growth of human colon carcinoma HT-29 cells and that combinations of inhibitors directed at the individual subunits of reductase result in synergistic inhibition of HT-29 cell growth in culture.

Adenine↗

PubMed1990

Concordant changes of pyrimidine metabolism in blasts of two cases of acute myeloid leukemia after repeated treatment with ara-C in vivo.

Though data from cell lines are abundant, the reason for the development of resistance to 1-beta-D arabinofuranosylcytosine (ara-C) in vivo remains unresolved. A broad interpatient variation of metabolic parameters has further complicated interpretation of the results. The present study compares ara-C metabolism in leukemic blasts of two patients with newly diagnosed disease, before and after repeated treatment with ara-C containing chemotherapy regimens in vivo. Membrane transport of ara-C was unchanged after treatment. In addition, cell-free extracts of blasts obtained after treatment failure showed an unchanged cytidine deaminase activity. Though deoxycytidine kinase activity in cell extracts was unaltered or increased after treatment failure, the activity in situ, measured as the rate of 1-beta-D-arabinofuranosylcytosine triphosphate (ara-CTP) formation, was decreased. This could be shown to be due to an expansion of the deoxycytidine triphosphate (dCTP) pool. The severalfold increase in dCTP pool was accompanied by a decrease in thymidine triphosphate (dTTP) pool and correlated with a decrease in deoxycytidylate deaminase (dCMP-deaminase) activity in cell free extracts. Low dCMP-deaminase activity had been shown to confer an ara-C resistant phenotype to cell lines in vitro. Data presented in this paper show that a selection for leukemic blasts with low dCMP-deaminase activity can also be favored by ara-C containing treatment regimens in vivo. Our data suggest that this mechanism might contribute to treatment failure.

Adolescent↗

PubMed1989

Influence of cell cycle on glutathione-S-transferase, selenium-dependent glutathione peroxidase, superoxide dismutase and glutathione levels in human myeloid leukaemia cell lines.

An important biological function of glutathione (GSH) resides in the detoxication reactions mediated by enzymes such as glutathione-S-transferase (GSTs) and glutathione peroxidase (GPX). An increasing body of evidence implies that GSH and these enzymes play important roles in determining the sensitivity of tumours against cytotoxic drugs like quinone antibiotics, in particular adriamycin (Adr). In the present study, we have analysed the effects of cell-cycle on GSH and GSH-dependent enzymes in an attempt to explain cell-cycle specificity of these antileukaemic drugs which were shown to be involved in free-radical-type reactions. Determination of GSH, GST, GPX and superoxide dismutase in cell-cycle-enriched fractions of five different human myeloid leukaemia cell lines (KG1, K562, U937, ML-1 and ML-2) yielded results identical to those obtained in random cultures, which implies that neither GSH nor GSH-related enzymes are cell-cycle regulated. These findings argue against the presumption that cell-cycle specificity of cytotoxic drugs like Adr could be due to the glutathione-dependent metabolism in myeloid leukaemia cell lines.

Cell Cycle↗

PubMed1989

Effect of cell growth and cell differentiation on 1-beta-D-arabinofuranosylcytosine metabolism in myeloid cells.

Resistance of leukaemic blasts to 1-beta-D-arabinofuranosylcytosine (ara-C) has been shown to be associated with changes in the metabolism of this drug. However, effects of cell growth and maturation stage on ara-C metabolizing enzymes have to be excluded as a possible cause of different enzyme activities in leukaemic blasts between nonresponders and patients achieving complete remission. We evaluated the effects of cell cycle phase and cell differentiation on the activity of cytidine deaminase, deoxycytidylate deaminase and deoxycytidine kinase in myeloid cell lines. Our data indicate that different enzyme profiles in nonresponders might not only be caused by the emergence of mutator phenotypes but may also reflect the growth and maturation stage of leukaemic blasts.

Cell Cycle↗

PubMedDate not supplied

Pathology of lipomatous lesions in Proteus syndrome.

Proteus syndrome is an extremely rare, complex hamartomatous disorder with markedly variable clinical expression. We present a case of Proteus syndrome with multiple disfiguring soft tissue masses that were present since early childhood. The lesions involved predominantly the right side of the body and included scoliosis, macrodactyly, and limited hyperostosis in the right foot. There was no evidence of cranial or skin lesions. The patient underwent multiple resections of soft tissue masses, including an amputation of the right foot because of severe gait disturbance. All specimens exhibited lipomatous lesions that were probably hamartomatous rather than neoplastic. She carried a diagnosis of neurofibromatosis for more than a decade, but a re-evaluation of clinical features and pathological findings prompted the diagnosis of Proteus syndrome. We believe that a more informed evaluation of the pathology material may help to identify this rare entity.

Adult↗

PubMedDate not supplied

Esophagogastric adenocarcinoma in an E1A/E1B transgenic model involves p53 disruption.

We studied tumorigenesis and p53 immunostaining in a murine transgenic model introducing E1A/E1B under the control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR) promoter in which adenocarcinoma occurs at the squamocolumnar junction in the foregut, predominantly in males, and at no other site. Mutations of p53 are frequent in human esophageal adenocarcinoma and the E1B gene product interferes with p53-mediated apoptosis, inhibiting tumor suppression at the G(1)/S checkpoint. Transgenic animals were generated utilizing a purified linear 6.7 kb fragment of plasmid DNA containing MMTV-LTR/E1A/E1B and were confirmed by dot blot hybridization of tail DNA to (32)P-labeled E1A/E1B probe and polymerase chain reaction (PCR) amplification of E1A. Transgenic and control animals were observed for morbidity and weight changes. Eleven of 45 animals were transgenic (24% efficiency) with an estimated 5 to 57 copies of the gene per genome. Profound weight loss (>20%) led to sacrifice or death of one of five females (at 12 weeks) and four of six males (at 16 to 17 weeks). Grossly visible tumors (2 to 10 mm) were noted in the forestomach at the visible margin between the proximal (squamous-lined) stomach and the distal glandular stomach. Histologic sections confirmed adenocarcinoma arising in each case at the squamocolumnar junction with glandular formation, pleomorphism, and frequent mitotic figures. Immunostaining was positive for p53 indicating accumulation of mutated or altered p53 protein. E1A/E1B transgenic animals developed macroscopic and microscopic adenocarcinoma at the squamocolumnar junction, which corresponds to adenocarcinoma at the human esophagogastric junction. Disruption of p53 was present in the transgenic model as in the human cancer.

Adenocarcinoma↗

PubMedDate not supplied

Giant-cell granulomatous hypophysitis.

OBJECTIVE: To describe the clinical features of giant-cell granulomatous hypophysitis and to report on the results of corticosteroid treatment. METHODS: A case of giant-cell granulomatous hypophysitis is presented, and the pertinent literature is reviewed. RESULTS: A 41-year-old woman with anterior pituitary dysfunction had a pituitary mass that was 18 by 16 by 13 mm by magnetic resonance imaging. The pituitary stalk was thickened and enhanced after intravenous administration of gadolinium. A biopsy specimen that was obtained at transsphenoidal pituitary exploration revealed that the patient had giant-cell granulomatous hypophysitis, a rare inflammatory pituitary disorder. High-dose corticosteroid therapy failed to reverse her anterior pituitary dysfunction. CONCLUSION: The coincidence of a contrast-enhancing pituitary mass with a thickened pituitary stalk and the awareness of the rare occurrence of endocrine inactive tumors in women of childbearing age should suggest an inflammatory pituitary condition. Such lesions should also be suspected in otherwise healthy young women with hypopituitarism and no evidence of hormone hypersecretion. On the basis of the literature and our experience, corticosteroid treatment does not seem to improve anterior pituitary function.

Journal Article↗

PubMedDate not supplied

Evidence of androgen receptor expression in squamous and adenocarcinoma of the esophagus.

Androgen receptors (AR) are known to stimulate cellular proliferation in certain tumors. We have assessed the androgen receptor status of esophageal carcinoma in surgically resected specimens as well as in established human esophageal carcinoma cells lines. In these initial studies we sought to characterize the frequency of expression of androgen receptors in squamous versus adenocarcinoma and in male versus female patients, and to assess the possible influence of AR expression on survivaL We analyzed androgen receptor expression utilizing immunohistochemistry in adenocarcinoma and squamous cell carcinoma of the esophagus in surgical specimens from 25 patients treated at Johns Hopkins Bayview Medical Center. Tumors in 7 of 21 males (33%) and 1 of 4 females (25%) showed positive androgen receptor staining with the monoclonal body antibody AR 441. There was no suggestion of a difference in expression of AR between males and females. Five of 11 adenocarcinomas (45%) and 3 of 14 squamous carcinomas were positive. Survival was similar in AR+ and AR- patients. Studies with established tissue culture cell lines showed AR expression by RT-PCR, with stronger expression of AR in adenocarcinoma lines than in squamous carcinoma lines. The presence of AR in human esophageal cancer is an impetus for further studies to assess anti-androgen therapy for treatment and or prevention of these tumors.

Adenocarcinoma↗