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Biomedical subjects

T Ohnuma

Publications and source records attributed to T Ohnuma.

At least 109 records · Page 6Linked to original sources
PubMed1985

Combined cytotoxicity effect of hyperthermia and anthracycline antibiotics on human tumor cells.

The effects of temperature on the anthracycline antibiotics-induced cell kill of DND-1A human malignant melanoma (MM) and DND-39A Burkitt's lymphoma (BL) cell lines were studied by means of a clonogenic assay. The two cell lines differed in sensitivity when exposed to heat: The MM cells were unaffected by hyperthermia (42 degrees C), whereas BL cells were sensitive to this temperature. With the MM cells, hyperthermia potentiated the cytotoxic effects of doxorubicin (ADM), daunorubicin, mitoxantrone (DHAD), and quelamycin but did not enhance that of aclacinomycin (ACM). Conversely, the exposure of cells to the anthracycline compounds at 0 degree C resulted in almost complete disappearance of cell kill effects except with ACM; ACM retained substantial cell kill effects even at the given low temperature. For BL cells, ADM- or DHAD-induced cell lethality was also potentiated by hyperthermia; ACM produced only additive cell kill. At 0 degree C, ACM's effects virtually disappeared. These data indicate that human tumor cell lines have a substantial variety in heat sensitivity and that not every anthracycline antitumor agent is potentiated by temperature. ACM's thermoresponse is unique among anthracycline antibiotics studied. Additionally, it was shown that normothermic cell kill by ADM was not affected by hyperthermic preheating; however, preheating of appropriate duration produced important influence on subsequent hyperthermic ADM-induced cell kill.

Antibiotics, Antineoplastic↗
PubMed1985

Evolution of methotrexate resistance of human acute lymphoblastic leukemia cells in vitro.

A human acute lymphoblastic T-cell line, MOLT-3, was fed with Roswell Park Memorial Institute Medium 1640 supplemented with 10% fetal bovine serum and antibiotics which contained increasing concentrations of methotrexate (MTX). The development of drug resistance was associated initially with progressive decrease in MTX transport. When the cells became 200-fold resistant, a rise in the dihydrofolate reductase was noted which was short-lived in the absence of the drug. A 10,000-fold increase in MTX resistance was accompanied, in addition to further decrease in MTX transport, by a 10-fold increase in the dihydrofolate reductase activity. While the purely transport-related resistant cell lines had a collateral sensitivity to lipid-soluble antifols, the sublines which had both transport- and enzyme-related MTX resistance contained a subpopulation highly resistant to these antifols. Chromosome analysis of the subline with increased dihydrofolate reductase activity showed an expanded abnormally banded region in chromosome 5.

Cell Line↗
PubMed1985

Pharmacokinetic and biochemical studies on acivicin in phase I clinical trials.

Acivicin pharmacokinetics were studied in Phase I patients receiving i.v. treatment on single-dose or daily x5 (daily times five doses) regimens repeated every 3 weeks. In 14 patients, the time course of plasma concentrations was characterized by a biexponential equation with a terminal (elimination-phase) half-life of 9.92 +/- 3.91 h (mean +/- SD), distribution phase half-life of 0.32 +/- 0.28 h, total body clearance of 1.69 +/- 0.48 liters/h/m2, and volume of distribution of 21.79 +/- 2.94 liters/m2. Acivicin kinetics appeared to be dose-independent over the range of 8.5-150 mg/m2/day. Urinary excretion of intact acivicin in nine patients ranged from 2-42% in the first 24 h following administration; interpatient variability in urinary excretion was large, but daily urinary recovery within patients on the daily x5 schedule was quite consistent. Measurements of acivicin effects on the activity of carbamyl phosphate synthetase II (CPS II) were conducted using leukocytes and/or malignant ascites of three colon cancer patients. Acivicin given to one patient at 8.5 mg/m2/day on the daily x5 schedule caused a 70% reduction in leukocyte CPS II activity within 5 h after therapy was initiated. Leukocyte CPS II activity remained suppressed at this level over the 5-day dosing regimen. In this patient, CPS II activity in malignant ascitic cells had decreased by 75% on day 4 of the daily x5 regimen. On the single dose schedule, treatment of two patients with 100 mg/m2 caused leukocyte CPS II activity to decrease by greater than 90% within 4 h of treatment with gradual recovery over the next 2 days.

Antibiotics, Antineoplastic↗
PubMed1985

Pharmacokinetics of vindesine given as an intravenous bolus and 24-hour infusion in humans.

The pharmacokinetics of vindesine was examined after the determination of serum drug levels by radioimmunoassay in patients who received the drug either as an i.v. bolus or a 24-hr infusion. After i.v. bolus, vindesine was eliminated from the serum by triphasic decay. The central compartment was approximately 6 times the serum volume. The peak serum level achieved by i.v. bolus was approximately 16 times that achieved by the 24-hr infusion. The post-24-hr-infusion serum decay followed biphasic decay. Pharmacokinetic modeling, assuming a prolonged infusion period, resulted in a triphasic decay curve, with an extremely short distribution phase which would not be clinically detectable. This was due to the incorporation of the distribution phase into the infusion period. This explains the experimental data of a biphasic decay curve observed after 24-hr infusion. Pharmacokinetic parameters for the two phases observed after 24-hr infusion were similar to values calculated from i.v. bolus data. The c X t for 24-hr infusion was identical to that after i.v. bolus; theoretically, the c X t appears constant regardless of infusion time. It is concluded that the rate of elimination and/or the c X t, rather than the peak serum level, played a role in the degree of hematological toxicity.

Antimetabolites, Antineoplastic↗
PubMed1985

Pharmacology and toxicology of a seven-day infusion of 1-beta-D-arabinofuranosylcytosine plus uridine in dogs.

In vitro studies of certain lymphoid tumor cells show potentiation of 1-beta-D-arabinofuranosylcytosine (ara-C) effects by uridine because it elevates intracellular uridine triphosphate, resulting in increased ara-C triphosphate levels. Seven-day continuous i.v. infusions of uridine at 123 mg/kg/h (2.5 g/sq m/h) were studied in 5 male beagles. Steady state levels of uridine were reached within 4 to 6 h and ranged from 2 to 5 X 10(-4) M over the course of the infusion. Steady state uracil levels ranged from 4 to 10 X 10(-4) M. After the end of infusion, uridine and uracil levels fell with a half-life of approximately 15 and 18 min, respectively. Toxicity in 2 dogs treated at this dose was limited to minimal diarrhea and a transient rise of alkaline phosphatase to 2 to 3 times normal. No drug toxicity was evident at sacrifice on Days 7 or 72. Three dogs received a 7-day infusion of ara-C plus uridine followed approximately 4 weeks later by an infusion of ara-C alone (or the same drugs in the reverse sequence). Coinfusion of 2.5 or 5.0 mg/kg/day (50 or 100 mg/sq m/day) of ara-C had no significant effects on uridine plasma levels or postinfusion half-lives. Similarly, no consistent effect was seen of uridine on ara-C plasma levels. Uridine coinfusion with ara-C resulted in a definite potentiation of myelosuppression; at 5.0 mg/kg/day X 7 of ara-C white blood cell and platelet nadirs (X 10(3)/microliters) were 0.8 and 15 as compared to 3.6 and 66, respectively, with ara-C alone. One-third of the dogs developed reversibly elevated transaminases with the combination treatment. The results show that a minimally toxic dose of uridine enhances bone marrow and probably hepatic toxicity of coadministered ara-C.

Adenosine Triphosphate↗
PubMed1984

Adoptive autoimmunotherapy. Cytotoxic effect of an autologous long-term T-cell line on malignant melanoma.

The in vitro and in vivo cytotoxic effects of an autologous long-term T-cell (LTTC) line were evaluated in a 65-year-old man with metastatic malignant melanoma. The patient's own T-cells were grown from a peripheral blood sample in a lymphocyte-conditioned medium. The cytotoxic effect of the LTTC against the patient's cultured melanoma cells was determined in vitro using the method of 51Cr release. Long-term T-cells produced specific lysis of 34% at an effector:target ratio of 30:1. Using allogeneic melanoma target cells, comparable or greater lysis was obtained in vitro. Long-term T-cells were injected into the infratumor and peritumor regions of two subcutaneous melanoma metastases of a lower extremity. A second injection of one of these lesions was followed 3 days later by an excisional tumor biopsy. Histologic examination showed many lymphocytes and necrotic areas in the injected lesions. Electron microscopic examination revealed numerous areas of lymphocyte-melanocyte membrane contact, membrane thickening, disintegration, hydropic cytoplasmic changes, and irreversible nuclear degenerative changes of melanocytes. Dividing lymphoblasts were also seen. These changes did not occur in noninjected tumor nodules. Long-term T-cell cultures yield immunologically functional cells capable of cytotoxic activity against allogeneic and autochthonous melanoma in vitro and against autochthonous melanoma in vivo. In vivo use after in vitro expansion of autologous immunocompetent cells (adoptive autoimmunotherapy) appears to be a feasible new approach to the study of human tumor immunology and treatment.

Aged↗
PubMed1984

Bleomycin infusion followed by cyclophosphamide, methotrexate, and 5-fluorouracil in advanced squamous carcinoma of the head and neck.

Twenty-seven patients with squamous cell carcinoma of the head and neck were treated with bleomycin 7.5 U/m2/day continuous infusion X 3 days (days 1-4, 8-11), followed by cyclophosphamide 300 mg/m2, methotrexate 30 mg/m2 and 5-fluorouracil 300 mg/m2 on days 5 and 12 (bleo-CMF). Treatment was repeated every 28 days. All but two had a performance status of 0-2 and all but 3 patients had received prior surgery, radiotherapy, and/or chemotherapy. Of 24 evaluable patients, 1 had a complete remission (1.9 months) and 4 had partial remissions (3.7, 3.9, 3.9, 4.1 months, respectively) for an overall response rate of 21%. If one excludes 7 patients with prior chemotherapy, the response rate is 5 of 17 (29%). All responders had received both radiotherapy and surgery. The median survival was 4.4 months for the responders and 3.5 months for the nonresponders. Marked hematologic toxicity occurred in eight patients, and contributed to the death of two. Severe pulmonary toxicity occurred in two patients and caused the death of one. Bleo-CMF did not produce a higher response rate than historical single-agent trials and caused significant toxicity. Furthermore, there was no important difference in the survival of responders and nonresponders.

Adult↗
PubMed1984

Chemotherapeutic susceptibility of human bone marrow progenitor cells and human myelogenous leukemia cells (HL-60) in co-culture: preliminary report.

We determined the chemotherapeutic susceptibility of normal human granulocyte progenitor cells (CFU-C) and acute myelogenous leukemia cells (HL-60) in co-culture. Nucleated bone marrow cells and HL-60 cells were mixed in 0.3% agar containing McCoy's 5A medium, fetal bovine serum, human placenta-conditioned medium, and various concentrations of chemotherapeutic agents. They were incubated in 5% humidified CO2 at 37 degrees C for 8-10 days. CFU-C and HL-60 colonies were differentiated morphologically. The formation of CFU-C was progressively inhibited with the increasing number of HL-60 cells, whereas the presence or absence of bone marrow cells did not influence the number of HL-60 colonies. In separate culture, HL-60 cells were more sensitive to vincristine than were CFU-C cells. In co-culture, however, the CFU-C became more sensitive to vincristine than in the separate culture. Similarly, co-culture CFU-C were more sensitive to daunorubicin than in separate culture. These data indicate that HL-60 leukemic cells exert inhibitory effects on normal bone marrow CFU-C; in such an inhibited state, normal bone marrow is more susceptible to certain chemotherapeutic agents.

Bone Marrow↗
PubMed1984

Chemotherapeutic sensitivity of acute lymphoblastic leukemia cells in culture: correlation with clinical efficacy on donor patients.

The establishment of permanent acute lymphocytic leukemia (ALL) lines of different phenotypes permits the study of their sensitivity to chemotherapeutic agents. The sensitivity of four ALL cell lines, two T-cell lines and one each of B- and non-T/non-B cell lines, to eight chemotherapeutic agents was studied by means of clonogenic assay. Response data were analyzed by two criteria--one based on concentrations obtainable from the elimination phase and the other based on peak concentration--both derived from pharmacokinetic studies in man. The overall correlation between the two criteria was good and only in 5 of 32 occasions were there major discrepancies. A retrospective analysis of the clinical course of the four donor patients showed that although the one set of criteria gave a positive correlation of asparaginase response in vivo, the other positively correlated the daunorubicin response, but not vice versa. No new cut-off line could be drawn to satisfy completely in vitro/in vivo correlation for all the drugs. Although the possibility exists that a leukemic cell line may not actually be predictive of chemotherapeutic responsiveness in the donor patients, our data indicate a need to reexamine the in vitro system in predictive testing of antileukemic agents.

Adult↗
PubMed1984

Phase I study of mitoxantrone on a daily X 5 schedule.

Mitoxantrone (NSC-301739) is a synthetic amino anthraquinone DNA intercalater active in several experimental tumor systems. Thirty-three patients with advanced cancer received the drug on a daily X 5 schedule. Myelosuppression, especially leukopenia, was the dose-limiting toxicity and was reversible. Nausea and vomiting occurred sporadically. No definite hepatic, renal, or cardiac toxicities were noted. The recommended dose for phase II evaluation in solid tumor patients with little or no prior therapy is 4.2 mg/m2/day X 5. Patients with prior myelosuppressive therapy but adequate bone marrow reserve may be started at 2.6 mg/m2/day X 5.

Adult↗
PubMed1984

Visual fatigue phenomenon and prescribing tinted lenses in patients with optic neuritis.

The fatigue phenomenon of grating visual acuity was examined in 36 patients with optic nerve disorders by means of a laser interferometric acuity device. The phenomenon was found in 6 of 36 cases even under a luminance corresponding to the Japanese standards of office illumination. This fact indicated that the patients suffered visual fatigue in their everyday vision. After they were prescribed tinted lenses to eliminate the fatigue, the patients had comfortable sustained vision in their daily work.

Adult↗
PubMed1984

[Differential cell growth inhibition and terminal differentiation induction by chemotherapeutic agents of a human acute myelogenous leukemia cell line (HL-60) in vitro].

The relationship between cell growth inhibitory effects and terminal differentiation-inducing effects of nine clinically active chemotherapeutic agents was evaluated using HL-60, a human acute myelogenous leukemia cell line. Continuous exposure to HL-60 cells of adriamycin, daunorubicin, mitoxantrone, m-AMSA, cytosine arabinoside, 6-thioguanine (6-TG), actinomycin-D (Act-D) and vincristine resulted in percentage increase of morphologically differentiated cells and phagocytic cells. Hydrocortisone at a concentration of up to 10(-4) M failed to produce this effect. Examination of actual numbers per flask of morphologically differentiated cells and phagocytic cells revealed, however, that all these agents except Act-D and 6-TG failed to produce a numerical increase in differentiated cells in comparison with those of control groups at day 6. Only Act-D and 6-TG were able to produce increases in the percentage, as well as actual number, of differentiated cells. These data indicate that the percentage increase in terminal differentiation-induced cells by certain chemotherapeutic agents is due not to their ability to increase differentiated cells but to their ability to inhibit the growth of primitive cells preferentially.

Anthraquinones↗
PubMed1984

Distinctive sensitivity of some T-leukemia cell lines to L-asparaginase.

Forty-two human hematopoietic cell lines were assessed for sensitivity to a four-day incubation with L-asparaginase. Eight of 13 T-leukemia cell lines and 1 of 7 non-T, non-B common acute lymphoblastic leukemia cell lines exhibited an ID50 (50% growth inhibition dose) of less than 0.0001 IU/ml. Seven of these sensitive cell lines were further cultured in L-asparagine-free medium and were found not to proliferate. Five T-leukemia cell lines, 6 non-T, non-B common acute lymphoblastic leukemia cell lines, 10 "abnormal" B-cell lines, 4 "normal" B-cell lines, 3 myeloma cell lines and 5 myeloid leukemia cell lines had ID50 values between 0.1 and 1.0 IU/ml. Twelve of these resistant cell lines were able to proliferate in L-asparagine-depleted medium. The results indicate that some patients with T-cell acute lymphoblastic leukemia might respond to this enzymatic antineoplastic drug, L-asparaginase, at low dose.

Asparaginase↗
PubMed1983

Implications of a 5'-nucleotidase inhibitor in human leukemic cells for cellular aging and cancer.

5'-Nucleotidase activity of normal human embryonic lung fibroblasts (IMR-90) was found to be inhibited by the homogenates of seven different cell lines originated from patients with different kinds of leukemia and of fresh lymphocytes from a patient with Sezary syndrome (circulating T-cell lymphoma). About 97% of the inhibiting activity was found in the soluble fraction of RPMI 8402 cells, a cell line originated from the lymphocytes of a patient with acute lymphocytic leukemia. This inhibiting activity was not destroyed by dialysis, heating at 56 degrees C for 30 min, nor digestion with RNAase or DNAase. About 85% of the inhibiting activity was destroyed by digestion with papain at 37 degrees C for 1 h and it was destroyed completely by heating at 100 degrees C for 30 min. When the heated (56 degrees C for 30 min) soluble fraction of RPMI 8402 cells was mixed with the homogenate of IMR-90 cells, it had no effect on the activities of alkaline, neutral or acid phosphatases, nor of N-acetyl-beta-D-glucosaminidase or cytochrome c oxidase of IMR-90 cells. Preincubating the mixed samples for 1, 20 and 45 min, respectively, before adding the substrate, the heated soluble fraction of RPMI 8402 cells did not increase the percentage of inhibition for 5'-nucleotidase of the homogenate of IMR-90 cells. No inhibition of other enzyme activities was observed under similar conditions. These data suggest that the inhibiting activity is due to a protein(s) that is not a protease. The inhibiting activity was found in a single peak after the soluble fraction was fractionated by Sephadex G-100 chromatography and sedimentation centrifugation. The molecular weight of the inhibitor was found to be approx. 35,000 by comparing its retention volume and sedimentation rate with those of proteins of known molecular weight. The present study suggest that the previously reported undetectability of 5'-nucleotidase in permanent cell lines could be due to the presence of a protein inhibitor for 5'-nucleotidase in these human leukemic cell lines. It also supports the hypothesis that the increased 5'-nucleotidase activity in normal senescent cells in vitro may be a control in cellular aging that is missing from leukemic cells in vitro.

5'-Nucleotidase↗
PubMed1983

Phase I study of L-alanosine (NSC 15353).

L-alanosine (NSC 15353) is a newly developed antitumor antibiotic which acts as an inhibitor of purine intermediary metabolism. Experimental antitumor activity was demonstrated in a variety of murine neoplasms. A Phase I trial was undertaken on a daily x 5 (d x 5) schedule in 22 evaluable patients. Dose limiting toxicity was an oral mucositis characterized by beefy red oral, lingual and pharyngeal erythema. The maximum tolerated dose is 320 mg/m2/d x 5 every three weeks. The recommended dose for Phase II evaluation is 160 mg/m2/d x 5 every three weeks.

Adult↗