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Biomedical subjects

T Ohnuma

Publications and source records attributed to T Ohnuma.

171 records · Page 10Linked to original sources
PubMedDate not supplied

Overexpression of deletion-mutant epidermal growth factor receptor is associated with altered genotoxic stress-provoked p53 mRNA induction in a human glioblastoma cell line.

A distinct 801-bp deletion mutation of the epidermal growth factor receptor (EGFR) gene is frequently present in primary glioblastoma multiforme (GBM), confers enhanced tumorigenicity in vivo and is prognostic of a shorter interval to clinical relapse. This study sought to investigate whether overexpression of deletion-mutant (delta) EGFR affects genotoxic stress-provoked mRNA inductions of p53 and murine double minute 2 (MDM2), two other genes strongly involved in the pathogenesis of GBM. In a set of human wild-type (wt) p53 GBM cell lines (U-87MG and U-87MG.delta EGFR) that exclusively differ in EGFR expression (endogenous wt EGFR expression and exogenous delta EGFR overexpression, respectively), ultraviolet (UV) light irradiation-mediated EGFR, p53 and MDM2 genotoxic stress-provoked mRNA inductions were assessed by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and densitometry of electrophoretically separated and stained RT-PCR products. Although baseline (at 0 J/m2) p53 mRNA expression in U-87MG.delta EGFR was 42-fold reduced, maximum p53 induction (at 8 J/m2) amounted to 130% compared to U-87MG. Thus, ultimate UV light-mediated p53 mRNA induction was 131.5-fold in U-87MG.delta EGFR and 2.8-fold in U-87MG. In contrast, neither wt/delta EGFR nor MDM2 mRNA expressions were significantly inducible, and MDM2 mRNA profiles were essentially the same among U-87MG and U-87MG.delta EGFR. These data suggest that in human GBM overexpression of delta EGFR is associated with differential genotoxic stress-provoked p53 mRNA induction whereas MDM2 mRNA expression is apparently not directly affected by EGFR status.

ErbB Receptors↗
PubMedDate not supplied

Initial clinical study with N-(phosphonacetyl)-L-aspartic acid (PALA) in patients with advanced cancer.

Thirty-seven patients with inoperable malignancies were given 75 courses of N-(phosphonaceteyl)-L-aspartic acid (PALA). Twenty-seven of these patients received PALA as a continuous iv infusion over 24 hours at dose levels ranging from 500 to 10,500 mg/m2 of estimated body surface area. In addition, ten patients were given PALA by continuous iv infusion over 120 hours at total doses ranging from 4000 t0 8700 mg/m2. The dose-limiting toxic effects occurred in the skin (erythema, vesiculation, and bullae) and gastrointestinal mucosa (oral pain, cheilosis, oral mucosal ulceration, diarrhea, and hematochezia). Toxic reactions seemed more pronounced in patients with third-space fluid compartments. Myelosuppression was severe only in patients with pre-existing marrow dysfunction from neoplastic infiltration. No renal, hepatic, cardiac, or neurologic toxicity was seen. No cumulative toxic effects were evident in 14 patients who received repeated courses of PALA at 21-day intervals. For patients without third-space fluid, 8700 mg/m2/24 hours or 6500 mg/m2/120 hours were well-tolerated doses. One patient with chondrosarcoma had a partial response lasting 5 months.

Adult↗
PubMedDate not supplied

A somatostatin analogue (SMS 201-995) alters the toxicity of 5-fluorouracil in Swiss mice.

The somatostatin analogue 201-995 (SMS), given in a short treatment schedule, 1 microgram/mouse, days 1-4, increased the lethal toxicity of a single, day 2, low lethal dose of 5-fluorouracil (FU), 400-500 mg/kg, in Swiss mice. The analogue did not change the time course of toxic deaths and produced neither autopsy evidence of increased gastrointestinal nor of increased bone marrow toxicity. Paradoxically, the analogue protected the peripheral white blood cell count (WBC). The nadir was only half as severe in the animals treated with SMS in addition to FU. The mechanism responsible for more frequent deaths due to combining SMS with FU is unknown. That brief administration of SMS in combination with marginally lethal, intensive therapy can produce unexpected increase in animal deaths bears consideration because these drugs are sometimes given simultaneously to patients, either fortuitously or in trials designed to limit the gastrointestinal side effects of FU.

Animals↗
PubMedDate not supplied

Initial clinical study with pyrazofurin.

Twenty-five patients with inoperable carcinoma and lymphoma were given pyrazofurin (pf) by iv bolus at a dose level ranging from 100 to 300 mg/m2 of estimated body surface area. In addition, five patients with acute leukemia were given PF by infusion at doses ranging from 250 mg/m2/24 hours to 1500 mg/m2/144 hours. PF was well tolerated by most patients at doses of 100 mg/m2 given as an iv bolus weekly or 250 mg/m2 given every 2-3 weeks. However, an infusion of 750 mg/m2 given over a period of 72-120 hours to leukemic patients resulted in severe but reversible toxicity; 1500 mg/m2 of PF given over a 144-hour period to one patient resulted in the development of severe mucocutaneous toxicity and leukopenia. The patient died of hemorrhagic pneumonitis. The major toxic effects observed were mucosal (oral pain, cheilosis, redness, and oral and lip ulcers), cutaneous (erythema, erosion, and bullae), and hematologic (anemia, leukopenia, and thrombocytopenia). The mucosal manifestations appear to be the dose-limiting toxic factors in most patients. Toxic reactions were more pronounced in patients who had previously received radiotherapy; dose-limiting hematologic toxic reactions occurred in four. After treatment with PF, one of the four patients with breast carcinoma had a partial response (greater than 50% regression) lasting 5 weeks. Another patient with breast carcinoma improved for about 1 month.

Adolescent↗
PubMedDate not supplied

Inhibitory effects of telomere-mimic phosphorothioate oligonucleotides on various human tumor cells in vitro.

We tested the cell growth inhibitory effects of telomere-mimic oligomers, 5'-d(TTAGGG)n-3' where n = 1, 2, 3 or 4 in the following 8 human tumor cell lines: 2780 ovarian carcinoma, HEp-2 squamous cell carcinoma, VAMT-1 mesothelioma, DND-1A melanoma, MOLT-3 ALL, Jurkat lymphoma, Daudi Burkitt lymphoma, and JAR choriocarcinoma. As controls, 1 scrambled 6-mer and 2 scrambled 24-mers were tested. Among the compounds tested, the 6-mer and 12-mer were not active in any of the cell lines studied. Increases in the length of oligonucleotides from 18- to 24-mer resulted in increased cell growth inhibitory activity in sensitive cell lines. Cells in suspension cultures, MOLT-3 ALL and Daudi Burkitt lymphoma were generally more sensitive than the monolayers (24-mer ID90 = -3 microM). While the inhibitory effects of authentic 24-mer oligomer were more pronounced than the scrambled oligomers, both of the scrambled 24-mers also showed some degree of inhibitory activity. Except for modest activity of the 24-mer in 2 cell lines, DND-1A and 2780, none of the compounds tested were active against solid tumor cell lines. These data indicate that further study of the telomere-mimic 24-mer is warranted as candidate compound for the treatment of leukemia/lymphoma.

Growth Inhibitors↗