Search PubMed⌕ Search

Biomedical subjects

N Nara

Publications and source records attributed to N Nara.

At least 91 records · Page 5Linked to original sources
PubMed1989

Effects of recombinant granulocyte colony-stimulating factor (rG-CSF) and recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) on acute radiation hematopoietic injury in mice.

We have attempted to evaluate in vivo effects of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on acute radiation hematopoietic injury in mice. BDF1 mice, irradiated with 7.5-Gy x-rays, were injected i.p. twice daily for 10 days with 10(5) U recombinant human G-CSF, 3.75 x 10(5) U recombinant murine GM-CSF, or a combination of both. G-CSF significantly enhanced the recovery of not only peripheral leukocytes but also platelets and hematocrit on days 14 and 21 after irradiation. GM-CSF significantly enhanced the recovery of platelets on day 14 and peripheral leukocytes on day 21. G-CSF markedly enhanced the recovery of spleen colony-forming units (CFU-S), colony-forming units in culture (CFU-C), erythroid burst-forming units (BFU-E), and megakaryocyte colony-forming units (CFU-Meg) both in bone marrow and in the spleen. GM-CSF significantly enhanced the recovery of CFU-Meg in bone marrow on day 14. We found synergistic effects between G-CSF and GM-CSF on CFU-S, CFU-C, and CFU-Meg in the spleen on day 14, although we found antagonistic effects between G-CSF and GM-CSF on CFU-S and CFU-C in bone marrow on day 7, and on platelet counts on day 7. These results indicate that the administration of recombinant G-CSF and GM-CSF may be useful in accelerating hematopoietic recovery in patients with acute radiation hematopoietic injuries.

Acute Disease↗
PubMed1989

[Multidrug resistance in acute leukemia].

Despite substantial recent advances in leukemia therapy, most leukemia patients eventually relapse and die of recurrent or refractory leukemia. Important issues are how to treat the patients in relapse of leukemia and how to overcome drug-resistant leukemic cells. Multidrug resistance of tumor cells has been vigorously studied in terms of P-glycoprotein, which may play important roles in the transport of antitumor drugs through cell membrane. In the present article, the author has reviewed the recent advances in understanding the pathophysiology of drug-resistance in leukemic cells and discussed the clinical approaches to drug-resistant leukemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Effects of recombinant human tumor necrosis factor on the self-renewal capacity of leukemia blast progenitors in acute myeloblastic leukemia.

The effects of human recombinant tumor necrosis factor type alpha (rTNF alpha) on the blast progenitors from 14 acute myeloblastic leukemia (AML) patients and 1 chronic myelogenous leukemia patient in blastic crisis were studied in methylcellulose and suspension cultures. Blast progenitors renew themselves and/or undergo terminal divisions. Plating efficiency of primary colony formation (PE1) in methylcellulose, which is considered to reflect the terminal divisions of blast progenitors, was suppressed by rTFN alpha in a dose-dependent manner in all cases. Plating efficiency of secondary colony formation (PE2) and the recovery of clonogenic cells in suspension culture, which are considered to reflect the self-renewal capacity of blast progenitors, were also suppressed by rTNF alpha in a dose-dependent manner in almost all cases. rTNF alpha also inhibited both PE2 and clonogenic cells in suspension culture, even in relapsed AML patients who were very refractory to intensive chemotherapies. The results demonstrate that rTNF alpha inhibits not only terminal divisions but also the self-renewal capacity of leukemic blast progenitors. The finding that rTNF alpha suppressed the self-renewal capacity of leukemic blast progenitors proposes the utility of rTNF alpha to AML therapy.

Cell Division↗
PubMed1988

Production of growth potentiating factor(s) for autologous blast cells by acute myeloblastic leukemia cells.

The effects of media conditioned by leukemic cells from 11 acute myeloblastic leukemia patients on the growth of autologous blast progenitors were studied. First, it was shown that T-cell-depleted leukemic cells from some patients release high levels of colony-stimulating activity into the culture medium, whereas following further depletion of phagocytic cells, the levels of colony-stimulating activity become undetectable. Second, media conditioned by purified blast cell fraction depleted of both T-cells and phagocytic cells potentiated autologous blast progenitor growth both in methylcellulose and suspension cultures stimulated by optimal concentration of media conditioned by human bladder carcinoma line 5637. Third, media conditioned by these purified blast cells generally did not contain measurable colony-stimulating activity or interleukin 1, whereas substantial levels of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interleukin 1 were observed in media conditioned by human bladder carcinoma line 5637 using bioassays and specific immunological assays. Therefore, purified blast cell fraction from acute myeloblastic leukemia patients appears to produce factor(s) other than granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or interleukin 1, which potentiate the growth of autologous blast progenitors both in methylcellulose and suspension cultures.

Adult↗
PubMed1988

Cytotoxicity of 4-hydroperoxycyclophosphamide for the blast progenitors of acute myeloblastic leukemia.

The effects of 4-hydroperoxycyclophosphamide (4-HC), an analogue of cyclophosphamide, on the blast progenitors from eight acute myeloblastic leukemia patients were studied in methylcellulose and suspension cultures. Leukemic blast progenitors undergo terminal divisions in methylcellulose culture, making blast colonies. Cells in primary colonies can make secondary colonies after replating in fresh methylcellulose medium. Leukemic blast progenitors grow exponentially in suspension culture for periods of weeks. The ability to form secondary colonies and the exponential growth in suspension culture are considered to reflect the self-renewal of blast progenitors. 4-HC suppressed primary blast colonies in a dose-responsive manner. Secondary colonies were not significantly affected by 4-HC. Although the clonogenic cell recovery was suppressed by 4-HC, leukemic blast progenitors were less sensitive to 4-HC in suspension culture than in methylcellulose culture. The results suggest that 4-HC is effective in suppressing the terminal divisions of blast progenitors but not as effective against the self-renewal of blast progenitors.

Adult↗
PubMed1988

Effects of purified human native granulocyte colony-stimulating factor (G-CSF) on proliferation of blast progenitors in acute myeloblastic leukemia.

Blast progenitors in acute myeloblastic leukemia (AML) grow in methylcellulose and suspension cultures. Blast colony formation in methylcellulose culture reflects the terminal divisions of blast progenitors, while secondary colony formation, by replating in methylcellulose and recovering clonogenic cells in suspension culture, reflects the self-renewal of blast progenitors. To analyze the regulatory mechanisms of the proliferation of leukemic blast progenitors, the effects of highly purified native granulocyte colony-stimulating factor (G-CSF) obtained from human squamous cell carcinoma line (CHU-2) on blast progenitors in AML patients were studied in methylcellulose and suspension cultures. Purified G-CSF stimulated the growth of blast progenitors in both culture systems, although sensitivity to G-CSF varied from patient to patient. No obvious maturation of leukemic blasts was noted in suspension culture in the presence of G-CSF. The data suggest that a normal hemopoietic regulator may play a role in the growth of blast progenitors in AML patients.

Adult↗
PubMed1988

Effects of recombinant G-CSF and GM-CSF on the growth in methylcellulose and suspension of the blast cells in acute myeloblastic leukemia.

The effects of two recombinant human CSFs (G-CSF and GM-CSF) on the growth of blast progenitors from 36 acute myeloblastic leukemia patients were studied in methylcellulose and suspension cultures. Blast colony formation in methylcellulose and the growth of blast progenitors in suspension were stimulated by G-CSF or GM-CSF. Their responses to CSFs were different from those of normal myeloid progenitors. First, the sensitivity of blasts to 0.01 ng/ml of G-CSF and 0.001 ng/ml of GM-CSF was significantly increased compared with normal. Second, in more than 70% of patients, the pattern of the responsiveness to the two CSFs was aberrant compared with ordered response in normal subjects. Third, in about half of the patients, combination of G-CSF and GM-CSF showed synergism for the growth of blast progenitors in both culture methods, whereas negligible or no synergism was observed in normal subjects. Finally, when stimulated by G-CSF, GM-CSF, or both, a significant relationship was noted between blast colony formation in methylcellulose and blast progenitor growth in suspension, suggesting that CSFs do not affect the balance between self-renewal and terminal divisions of blast stem cells.

Adult↗
PubMed1988

Relationship between the in vitro sensitivity to cytosine arabinoside of blast progenitors and the outcome of treatment in acute myeloblastic leukaemia patients.

The sensitivity to cytosine arabinoside (Ara-C) of blast progenitors from 22 acute myeloblastic leukaemia (AML) patients was studied in methylcellulose and suspension cultures. Primary colony-formation (PE1) in methylcellulose reflects the terminal divisions of blast progenitors, while secondary colony formation (PE2) in methylcellulose and the clonogenic cells recovery in suspension are considered to be based on the self-renewal of blast progenitors. In any patient, PE2 or clonogenic cells in suspension were more sensitive to Ara-C than PE1. The results indicate that Ara-C effectively suppresses not only terminal divisions but also self-renewal of blast progenitors D10 Ara-C value, the dose required to reduce survival to 10% of control, for PE1, PE2 and clonogenic cells in suspension showed marked patient-to-patient variation. No significant correlation was found between D10 Ara-C in methylcellulose or suspension culture and the response to treatment with a combination chemotherapy of 6-mercaptopurine, Ara-C and daunorubicin. However, a relapsed patient whose D10 values in methylcellulose and suspension cultures were very high showed poor response to a high-dose Ara-C protocol, where Ara-C was given alone at a high dose. The application of chemosensitivity test as a prediction of the clinical outcome may be dependent on the treatment protocol.

Adult↗
PubMed1988

Effect of recombinant human M-CSF on the proliferation of leukemic blast progenitors in AML patients.

We studied the effects of recombinant human macrophage colony-stimulating factor (M-CSF) on the leukemic blast progenitors from 10 acute myeloblastic leukemia patients. Recombinant human (rh)M-CSF stimulated leukemic blast progenitors in methylcellulose in four patients, but the colonies by rhM-CSF were smaller in size and number than those by rh-granulocyte-CSF or human bladder carcinoma cell line 5637 conditioned medium. rhM-CSF did not increase the number of clonogenic cells in long-term suspension culture. The blast colony formation in methylcellulose and the exponential growth of clonogenic cells in long-term suspension culture are considered to reflect the terminal divisions and the self-renewal of blast progenitors, respectively. The results show that M-CSF stimulates terminal divisions weakly but does not stimulate self-renewal of leukemic blast progenitors. M-CSF did not induce differentiation of blasts either in methylcellulose or in suspension culture.

Cell Differentiation↗
PubMed1987

Effects on leukemic clonogenic cells in murine myeloid leukemia of 1-beta-D-arabinofuranosylcytosine and the anthracyclines adriamycin, daunomycin, aclacinomycin A, and 4'-epidoxorubicin.

M-3 murine myeloid leukemic cells undergo terminal divisions making colonies in methylcellulose culture and also renew themselves in methylcellulose and suspension; leukemic clonogenic cells are characteristic as stem cells. The effects of 1-beta-D-arabinofuranosylcytosine and four anthracyclines (Adriamycin, daunomycin, aclacinomycin A, and 4'-epidoxorubicin) on M-3 leukemic clonogenic cells were studied. 1-beta-D-Arabinofuranosylcytosine was effective in reducing primary and secondary colonies in methylcellulose and the growth of clonogenic cells in suspension. In contrast, the anthracyclines were not so effective in reducing secondary colonies in methylcellulose or clonogenic cells in suspension as to suppress primary colonies in methylcellulose. The results suggest that 1-beta-D-arabinofuranosylcytosine but not the anthracyclines is effective for not only terminal divisions but also self-renewal of leukemic clonogenic cells. The study will be used as a practical screening test to examine the effects of antitumor agents on leukemic blast progenitors.

Aclarubicin↗
PubMed1986

A comparison of the growth supporting capacities of fresh and cultured leukemic blast cells.

Clonogenic progenitors of the blast population in acute myeloblastic leukemia (AML) grow exponentially in suspension in the presence of a source of growth factors (media conditioned by the continuous cell line HTB9) and provided a high cell density is maintained. We investigated this latter requirement by comparing blasts freshly obtained from patients to others that had been maintained in culture. We found that cultured cells lost their growth-promoting capacity. Further, membranes from fresh cells but not cultured cells were active in stimulating growth. Repeated additions of fresh cells to suspension cultures prolonged the exponential phase but did not permit continuous culture.

Cell Count↗
PubMed1986

The sensitivity to cytosine arabinoside of the blast progenitors of acute myeloblastic leukemia.

Two culture methods are available for the study of the blast cells of acute myeloblastic leukemia (AML). One is an assay for clonogenic precursors; it depends on their ability to form blast colonies in culture in the presence of methylcellulose and suitable growth factors. The other assesses the growth of blast cells in suspension culture, where growth is measured by increasing numbers of clonogenic cells. We have compared the two methods as assays for the cytotoxic effects of the chemotherapeutic drug cytosine arabinoside (Ara-C). Marked patient-to-patient variation was found using either method; however, the slopes of the dose-response curves were usually greater when cells were exposed to drug in suspension rather than in methylcellulose. Control experiments showed that the difference could not be explained by drug carry-over from the suspension cultures to the methylcellulose plates when clonogenic cells in the suspensions were assessed. Further, the survival curves for Adriamycin were very similar, regardless of which assay was used. No correlation was found between D10 Ara-C values measured in suspension or in methylcellulose. However, a significant association with outcome was found between D10 Ara-C in suspension and response to treatment with a regimen in which Ara-C was the only chemotherapeutic agent used. No such association was detected when the D10 values obtained with the clonogenic assay were compared with outcome for the same group of 15 patients. Finally, a feasibility experiment was performed in which blast cells were exposed to Ara-C repeatedly during exponential growth over 238 days. A dose-related inhibition of growth was observed; no evidence was seen of emerging drug-resistant cells. Nor did the morphology of the cells change as a result of drug exposure. We conclude that drug sensitivities of AML blast cells in culture are dependent on measurement methods, even when techniques affecting cell proliferation are compared. Measurements of drug sensitivity in culture may best be interpreted when the bases of the assay systems are understood.

Adult↗
PubMed1986

Effects of recombinant GM-CSF on the blast cells of acute myeloblastic leukemia.

The effects of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) were compared to those of media conditioned by the continuous bladder carcinoma line, HTB9 (HTB9-CM), using three criteria. First, both GM-CSF and HTB9-CM stimulated blast colony formation in methylcellulose cultures, patient-to-patient variations were seen in the dose-response curves, and GM-CSF was effective, but less so that HTB9-CM. Second, GM-CSF also enhanced growth of blast progenitors in suspension culture, indicating its capacity to support self-renewal. GM-CSF was as effective as HTB9-CM in the production of adherent cells during the growth of blast cells in suspension, a finding that is interpreted to mean that GM-CSF also supports postdeterministic events in blast differentiation. Finally, colonies growing in the presence of GM-CSF were not phenotypically different than those stimulated by HTB9-CM.

Cells, Cultured↗