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慢性関節リウマチ (RA) に対してmethotrexate (MTX) 低用量パルス療法を施行し, 早期に汎血球減少症となった維持透析患者の2症例を経験した. 症例1:46歳, 女性, 血液透析歴16年. RAの治療にMTX 5.0mg/週で2回投与した後, 突然大量の性器出血をきたし, 緊急入院となった. 入院時の白血球数200/μl, Hb 3.8g/dl, 血小板数3.5万/μlと汎血球減少症をきたしていた. MTXによる骨髄抑制と考え, granulocyte colony stimulating factor (G-CSF) 製剤, 赤血球, 血小板輸血, 抗生剤の投与を行った. 第12病日に白血球数3,600/μlと正常化した. 症例2:49歳, 女性. 血液透析歴9か月. RAの治療目的にて入院した. Prednisolone, NSAIDs投与にても関節痛が改善しないため, MTX低用量パルス療法を施行した. MTXを2.5mg/週で2回投与した後に白血球数300/μl, Hb 5.8g/dl, 血小板数1.3万/μlと汎血球減少症をきたした. MTXによる骨髄抑制と考え, G-CSF製剤, 赤血球, 血小板輸血, 抗生剤, leucovorinの投与を行い, 第19病日に白血球数6,700/μlと正常化した. MTXは腎不全症例では排泄遅延のため, 副作用が強くでる可能性がある. MTXの50-60%がアルブミンと結合するため, 通常の血液透析ではMTXの除去は不十分で血中濃度が高値となりやすい. また, 本症例のごとくMTX少量投与で短期間のうちにアレルギー反応と思われる副作用が発現しているため, 透析患者においても副作用の出現のリスクが高く, MTXは少量投与であっても使用しないほうが望ましいと思われる.

The pharmacokinetics of retinol palmitate were studied, and a therapeutic trial was performed in patients with ANLL. In the pharmacokinetics study, retinol was the only metabolite that was detected in plasma, and the peak concentration was 332 μg/dl (about 1.2 × 10 −5 M) 2.1 h after administration of retinol palmitate. Five patients with ANLL (4 with ANLL-M3 and one with ANLL-M2) were treated with retinol palmitate. In all patients with ANLL-M3, bone marrow suspension culture studies revealed that retinol induced both morphological and functional differentiation of immature leukemic cells. During the course of the treatment with retinol palmitate, morphological differentiation of bone marrow immature leukemic cells was observed in all patients with ANLL-M3 within 3–4 days after initiation of the therapy. In three of the four patients who underwent conventional chemotherapy, the sequential treatment with retinol palmitate resulted in a complete remission: controlling residual bone marrow leukemic cells. None of the patients showed any signs of aggravation of DIC in the coagulation parameters. These findings suggest the possibility that retinol palmitate functions as salvage therapy by inducing maturation and slowing proliferation, there by clearing out the residual leukemic cells following conventional chemotherapy.

Scabies was first found in a 71-year-old female who had been diagnosed as having leukemic transformation of primary myelofibrosis and had undergone treatment for the disease. She was admitted to the hospital in December 1986, because of abdominal fullness and a generalized subcutaneous tumor that proved to be myeloblastoma. For treatment of the underlying disease, the regimen of the combination of vindesine, cyclophosphamide, 6-mercaptopurine, and prednisolone was selected. She developed cardiac failure and fell into a coma one month after starting the anticancer therapy. She was put on artificial respiration and on additional steroid therapy as well. Dexamethasone was administrated at 16 mg/day. Since the myeloblastomas found on admission regressed, the steroid therapy was continued. She was in coma for a few days before her skin lesions turned red and formed a grayish crust in the lower abdominal region. Several days later, the doctor responsible for the treatment of this patient developed pruritus and exanthema on both arms, and soon many nurses in the same hospital-ward developed similar symptoms. At approximately the same time, the patient with myelofibrosis was diagnosed as having Norwegian scabies: the crusted skin lesions revealing many Sarcoptes scabiei mites. Two doctors (2/18), 17 nurses (17/19) and 3 other patients (3/51) were found to have contracted scabies, and we recognized the hospital spread of the infection. The first patient was isolated in a private room, and we avoided direct contact with her. The persons with scabies were treated with crotamiton liniment. The first scabies patient died of cardiac failure 1 month after falling into a coma.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of tsutsugamushi disease (scrub typhus) with atypical lymphocytes with a multilobated nucleus is reported. Although this type of atypical lymphocyte has been reported in patients with viral infections such as adult T-cell leukemia, infectious mononucleosis, human immunodeficiency virus (HIV) infection, this is the first reported case of atypical lymphocyte with a multilobated nucleus in a patient with rickettsial infection. This type of atypical lymphocyte seems to exist in a broad spectrum of infectious diseases.

Recent progress in chemotherapy for acute myeloid leukemia (AML) has achieved a favorable outcome; however, treatment for patients who do not respond to conventional chemotherapy and who develop multiple drug resistance has yet to be established [1]. Differentiation induction therapy with retinoid, a family of molecules comprising both natural and synthetic analogues of retinol, seems to open the way for an alternative approach to the treatment of AML, especially acute promyelocytic leukemia (APL)[2,3]. Because karyotypic hallmark of APL, a reciprocal translocation between the long arms of chromosomes 15 and 17, includes the breakpoint region of the retinoic acid receptor α gene [4]. In order to clarify the appropriate combination therapy between conventional anti-metabolites and cell-differentiation agents, we describe here the dynamics of the activation pathway of 6-mercaptopurine (6-MP) in fresh leukemic promyelocytes and promyelocytic cell line HL-60 cells during retinoid-induced cell differentiation in vivo and in vitro.

A 67-year-old woman with acute promyelocytic leukemia (APL) showed a marked decrease in leukemic promyelocytes with concomitant maturation of leukemic cells during treatment with retinol palmitate. A culture study in vitro revealed that retinol, which is the main metabolite of retinol palmitate detected in plasma, induced morphological and functional maturation of leukemic promyelocytes. These findings may indicate that retinol palmitate induces cell differentiation and slows proliferation of leukemic cells in vivo, and that the reduction in cell growth is the key phenomenon in the clearing of leukemic cells, rather than the maturation phenomenon itself.

A number of human myeloid leukemia cell lines have been established which can not only be maintained as immature blast cells in continuous, self-renewing culture but also be induced to undergo maturation toward either the myeloid or monocytic phenotype1). Such cell lines have attracted considerable attention in these days because they provide experimentally accessible model systems with which to define basic mechanisms involved in the regulation of myeloid progenitor cell proliferation and differentiation. The HL60 cell line, originally isolated from a patient with acute promyelocytic leukemia, can be lead to myeloid morphological, functional, and biochemical changes have been observed during DMSO-induced differentiation2). In differentiated HL60 cells, purine nucleotide synthesis decreases3), but there have been some reports demonstrating a drastic change in purine nucleotides pool during differentiation4–6). This seem to the presence of a complicated mechanism involved in differentiation. We used DMSO-treated HL60 cells to investigate the role of salvage and de novo pathway for intracellular purine nucleotide metabolism during proliferation and differentiation.

The pharmacokinetics of oral N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (PLAC), a lipophilic and deaminase-resistant derivative of 1-beta-D-arabinofuranosylcytosine (ara-C), were determined in patients with hematologic malignancies. The concentration of ara-C and 1-beta-D-arabinofuranosyluracil (ara-U), metabolites of PLAC, were measured by radioimmunoassay and gas chromatography-mass spectrometry-mass fragmentography, respectively. The concentration of PLAC was determined by measuring ara-C, which was derived from PLAC by hydrolyzation. In six patients given an oral bolus of PLAC (300 mg/m2), the plasma-disappearance curve of PLAC corresponded to a one-compartment open model, including first-order absorption. The peak plasma level was 22.9 +/- 6.4 ng/ml, and the predicted time to reach the peak level was 2.5 +/- 1.0 h. The elimination half-life was 3.8 +/- 2.7 h. The plasma ara-C level increased slowly to 6.9 ng/ml during the 1st 2-3 h after administration and remained over 1.0 ng/ml for 12 h. Plasma ara-U was detectable for at least 24 h, with a peak concentration of 376 ng/ml at 6 h. Urinary PLAC excretion was below the limit of detection (5 ng/ml) in all cases. Prolonged urinary ara-C and ara-U excretion was detected, but the total recovery rate was low (6.7% in 24 h) and varied between patients. In spite of the lipophilic nature of the drug, the PLAC concentration in the cerebrospinal fluid, measured at 3 or 6 h, was below the limit of detection in all four patients with no meningeal involvement. This study showed low but persistent levels of PLAC in plasma and tissues, with a continuous release of small amounts of ara-C, which demonstrated antitumor activity in patients with hematologic malignancies.

Transport and intracellular metabolism of the three fluorinated pyrimidines, FU, FUR and FUdR in normal human RBCs, L-1210, HL-60, CCRF-CEM and Hela cells were studied. The cells were suspended in HB 101 medium and incubated at 37°C in the presence of each labelled compound. At the desingated time, the cell suspension was put onto silicone oil layer (specific gravity:1.034) and centrifuged at 12,000xg in 7 sec. The radioactivity of cell pellet obtained was counted following lysis with NCS tissue solubilyzer. The acid-soluble fraction from cell pellet was applied onto silica gel TLC plate and chromatographed. The plate was cut into 0.5cm strips and their radioactivities were counted. All three compounds showed the same velocity of transport by RBCs. FUR transport velocity was, however, markedly high in case of L-1210, HL-60, CCRF-CEM cells and not in Hela cells. FU and FUdR transports remained at low level. These results showed that intracellular phosphorylation of the compound resulted in the acumulation in cells since FUR was preferentially converted to nucleotide form, while FU and FUdR were not in all cells studied. The chromatogram of FUdR treated CCRF-CEM and Hela cells revealed that the main radioactive peak coinsided with FU. It was concluded that FUR acumulated as its nucleotide form, while FUdR was mainly converted to FU in these cells.

Changes of PRPP-related enzyme activities and incorporation rates of glycine, Hx and Ad into acid soluble fraction (ASF) of HL60 cells were studied during terminal differentiation induced by incubation with 1.6% DMSO for 43 hours. Activities of HPRT, APRT, and PRPP synthetase were determined in homogenate treated with activated chacoal. H(A)PRT activities were measured based on the determination of conversion of 14C-labeled Hx (Ad) to IMP (AMP). PRPP synthetase activities were measured as follows; PRPP, which was formed by interaction of R-5-P, ATP and enzyme solution, was measured by HPRT assay system. Incorporation rates of Ad, Hx, and glycine into purine nucleotides were measured after incubation at 37 °C for 20 min in the presence of the respective 14C-labeled compound in HB101 medium. ASFs of cell pelletes, which were obtained by silicon oil procedure, were chromatographed. Radioactivities of all purine nucleotides were counted. HPRT and APRT activities increased 3.3 folds (4.69 to 15.70 nmol/min/106cells) and 1.5 folds (4.20 to 6.26) higher, respectively, but no increase in PRPP synthetase activities was shown. The incorporation of glycine decreased 2.2 folds (215 to 99 pmol/min/106 cells) lower in rate, but those of Ad and Hx showed no remarkable changes. It was concluded that the decreased rate of de novo synthesis was a major change during terminal differntiation.