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Biomedical subjects

H Tsutani

Publications and source records attributed to H Tsutani.

64 records · Page 4Linked to original sources
PubMed1986

Pharmacokinetics of aclarubicin and its metabolites in humans and their disposition in blood cells.

The pharmacokinetics of aclarubicin, a new anthracycline antibiotic, was studied in five patients with acute leukemia or in L1210 cell suspension. Aclarubicin disappeared very rapidly from plasma and whole blood after administration at a dose of 20 mg per patient by iv bolus injection. The concentration of active metabolite M1, on the other hand, increased for up to 2 or 4 hrs after administration and exceeded that of aclarubicin, and then remained at much higher concentrations than aclarubicin for up to 24 hrs after administration. In addition, the levels of aclarubicin and its metabolites in whole blood were much higher than the corresponding plasma levels in four of the patients. The drug concentrations in blood cells of 11 patients determined 4 hrs after administration showed a significant positive correlation with leukocyte counts. Moreover, the concentration of aclarubicin and its metabolites was found to be much higher in the leukocyte fraction than in the erythrocyte fraction in vivo and in vitro. These findings indicate that aclarubicin and its metabolites in blood cells were mainly accumulated in leukocytes. In the study of intracellular drug distribution in L1210 cells, the largest amount of aclarubicin was incorporated into the nuclear fraction. This suggests a close relationship between the pronounced drug accumulation in leukocytes and the high affinity of aclarubicin for DNA.

Aclarubicin↗
PubMedDate not supplied

A novel Philadelphia chromosome-positive cell line with multipotential properties.

A novel Philadelphia chromosome-positive cell line was established from the peripheral blood of a patient with chronic myelogenous leukemia in megakaryoblastic crisis. This cell line, designated TN922 showed the positive phenotypes for myeloid, monocyte-macrophage, erythroid and megakaryocytic markers. The stimulation with phorbol 12-myristate 13-acetate (PMA) increased the expression of megakaryocytic markers including the platelet peroxidase activity, dimethylsulfoxide or transforming growth factor-beta promoted up-regulation of the erythroid markers. Stimulation with PMA, tumor necrosis factor-alpha or interleukin-6 also brought about the expression of monocytoid markers. These findings indicated that TN922 cell line has the property of acting as multipotential progenitor cells. TN922 cells showed gradual growth in the absence of growth factors but the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) promoted cell growth. The message of GM-CSF was detected in TN922 cells and the neutralizing antibody against GM-CSF receptor alpha-subunit suppressed cell growth. These results indicated that TN922 cell line proliferates in an autocrine secretion of GM-CSF.

Aged↗
PubMedDate not supplied

Molecular remission induced by fractionated dose-escalating donor leukocyte infusion without graft-versus-host disease in a patient with chronic myelogenous leukemia relapsed after allogeneic bone marrow transplantation.

A 39-year-old male with CML who relapsed 5 years and 8 months after allogeneic bone marrow transplantation achieved complete molecular remission following fractionated dose-escalating donor leukocyte infusions. Acute or chronic graft-versus-host disease (GVHD) did not occur and the patient remained asymptomatic throughout treatment. Since no prophylaxis against GVHD was administered, this case indicated that the graft-versus-leukemia effect is entirely separate from GVHD in certain conditions.

Adult↗
PubMedDate not supplied

DNA-binding characteristics of aclarubicin as compared with daunorubicin and doxorubicin.

The effect of ionic strength on aclarubicin - DNA complexes was studied in comparison with its effect on daunorubicin - or doxorubicin - DNA complexes, using the spectrophotometric method. The hypochromic shift of aclarubicin, induced by its binding to native DNA, decreased to a lesser extent by the addition of Na+ than those of daunorubicin and doxorubicin, which suggests that aclarubicin-native DNA complexes are the most stable at high ionic strength. Similar examinations were made with heat-denatured DNA and polyvinyl sulfate (PVS). Aclarubicin-denatured DNA complexes showed a greater decrease in the hypochromic shift by the addition of Na+ than the corresponding complexes with native DNA. However, for daunorubicin and doxorubicin, there were no significant differences between the complexes of anthracyclines with native and denatured DNAs. In addition, the hypochromic shift of aclarubicin-PVS complexes decreased more prominently by the addition of Na+ than those of daunorubicin - and doxorubicin - PVS complexes. These results suggest that the electrostatic interaction of aclarubicin with DNA is more labile than that of daunorubicin and doxorubicin, since anthracyclines bind to single-stranded DNA and polyelectrolytes primarily by electrostatic interaction. Therefore, the other types of interaction, which may be stronger than that of daunorubicin and doxorubicin, seem to be associated with the higher stability of aclarubicin-native DNA complexes at high ionic strength. The structural differences between aclarubicin and daunorubicin or doxorubicin are considered to contribute to the differences in DNA-binding characteristics observed in this study.

Aclarubicin↗
PubMedDate not supplied

Reverse effect of guanine on the inhibitory action of mycophenolic acid during nucleic acid synthesis.

Mycophenolic acid (MPA) was demonstrated to inhibit DNA and RNA synthesis in L1210 cells strongly; however these effects were remarkably reduced by guanine. The presence of MPA in the medium decreased the guanine nucleotide contents (GMP, GDP, GTP) of the cells, but the addition of guanine reversed this effect. We have reported previously that MPA had no inhibitory effect on hypoxanthine guanine phosphoribosyltransferase (HGPRTase) activity. Together these findings suggest that the decrease of guanine nucleotides induced by MPA is restored by GMP, which is formed from guanine by HGPRTase in the cells. It is speculated that a suppressor of HGPRTase activity, such as 6-mercaptopurine, may protect the antitumor activity of MPA by preventing the conversion of guanine to GMP.

Animals↗
PubMedDate not supplied

Pharmacokinetic and clinical pilot study of high-dose intermittent ubenimex treatment in patients with myelodysplastic syndrome.

Ubenimex is an orally active aminopeptidase inhibitor with an immunomodulating action. A pharmacokinetic and clinical pilot study of high-dose intermittent ubenimex was performed in patients with myelodysplastic syndrome. Ubenimex (150 mg/body) was administered orally, twice per day (at a 3 hr interval), twice a week, for at least 8 weeks. The concentrations of ubenimex and p-OH ubenimex, another active metabolite, increased gradually up to 7.1 +/- 4.7 micrograms/ml (mean +/- SD) at 5 hr and 0.25 +/- 0.15 mu/ml at 6 hr. The low percentage (4.2%) of the AUC ratio (p-OH ubenimex/ubenimex) suggested minimal metabolism. The plasma half-life of ubenimex was 2.1 +/- 0.7 hr and the total urinary recovery of both was 71.4% in 48 hr. Among 8 patients clinically studied, one achieved good response and another achieved minor response. These findings suggested good bioavailability, and a certain effectiveness of ubenimex in this administration method, which was worth trying, at least in restricted cases, such as cases with refractory disease or with a poor performance status.

Adult↗