TI: Elevated levels of dolichol in the brains of mucopolysaccharidosis and related disorders.

AU: Sakakihara-Y; Imabayashi-T; Suzuki-Y; Kamoshita-S

SO: Mol-Chem-Neuropathol. 1994 Jun; 22(2): 97-103

AB: The contents of total dolichol were measured in the cerebral cortex of various patients with lysosomal storage disorders, including mucopolysaccharidosis. Strikingly high levels of dolichol were demonstrated in GM1-gangliosides, Sanfilippo B syndrome, and a severe type of Hunter syndrome as well as neuronal ceroid-lipofuscinosis. An increased level of dolichol in cerebral cortex in neuronal ceroid-lipofuscinosis (NCL) was once regarded as pathognomonic for NCL. Our data, however, suggest that an increased level of dolichol in cerebral cortex is a nonspecific phenomenon related to some lysosomal dysfunction secondary to various neurodegenerative disorders.

TI: A rapid microassay for dichloroacetate in serum by gel-permeation chromatography.

AU: Sakakihara-Y; Nakamura-G; Tokoeda-Y; Abe-T; Kamoshita-S

SO: Eur-J-Clin-Chem-Clin-Biochem. 1994 Feb; 32(2): 79-83

AB: We have developed a novel, rapid microassay for dichloroacetate in the serum. The serum sample is directly injected into a gel-permeation high-performance liquid chromatography apparatus. The peak of dichloroacetate appears after a giant protein peak. The method requires a very small amount of serum (10 microliters), and the analysis time is short (20 min). Using this micro method, we measured the serum concentrations of dichloroacetate in healthy adult volunteers and paediatric patients with congenital lactic acidosis. Although the effect of dichloroacetate on the neurological manifestations of congenital lactic acidosis has not been proved to be beneficial, the potential usefulness of dichloroacetate in refractory lactic acidosis in cardiac and respiratory failure has been recognized, and human as well as animal studies have been undertaken in many laboratories. To prevent possible side effects of dichloroacetate, it has been recommended that the minimal effective dose be used. Our microassay method is useful for both human and animal experiments, even after administration of minimal doses.

TI: Treatment of Philadelphia-chromosome-positive human leukemia in SCID mouse model with herbimycin A, bcr-abl tyrosine kinase activity inhibitor.

AU: Honma-Y; Matsuo-Y; Hayashi-Y; Omura-S

SO: Int-J-Cancer. 1995 Mar 3; 60(5): 685-8

1994

AB: The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr-abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin a, which effectively reduced intracellular phosphorylation by bcr-abl tyrosine kinase, preferentially inhibited the growth of Ph1-positive leukemia cell lines. Injection of Ph1-positive and -negative leukemia cell lines into mice with severe combined immunodeficiency (SCID) resulted in the death of all mice due to leukemia, although the severity of illness varied according to the cell lines used. Administration of herbimycin A significantly enhanced the survival of mice inoculated with the Ph1-positive leukemia cell lines tested but barely affected the survival of mice inoculated with the Ph1-negative leukemia cell lines tested. These results suggest that herbimycin A and related compounds may be useful for the treatment of Ph1-positive leukemia. The disease that developed using the Ph1-positive leukemia cell line NALM-20 resembled human Ph1-positive acute lymphoid leukemia. There was an inverse relationship between the survival time of mice and the number of cells inoculated. The SCID mouse-NALM-20 human leukemia chimera would be a good experimental model for screening tyrosine kinase inhibitors as therapeutic agents against Ph1-positive leukemia.

TI: Plasma cell leukemia with myelofibrosis.

AU: Murayama-T; Matsui-T; Hayashi-Y; Taniguchi-T; Ito-M; Natazuka-T; Imoto-S; Iwata-N; Isobe-T; Ito-H; et-al

SO: Cancer-Res. 1994 Jun 1; 54(11): 2865-8

1994

AB: The t(16;21)(p11;q22) translocation is a recurrent chromosomal abnormality found in several types of myeloid leukemia. We have previously demonstrated that the breakpoints of this translocation are clustered in a specific intron of the ERG gene on chromosome 21, which has recently been reported to be involved in Ewing's sarcoma. We show here that the TLS/FUS gene on chromosome 16 is fused with the ERG gene to produce the TLS/FUS-ERG chimeric transcript by this translocation. The TLS/FUS gene has been identified as a translocated gene in myxoid liposarcoma by the t(12;16)(q13;p11) translocation and encodes an RNA-binding protein that is highly homologous to the product of the EWS gene involved in Ewing's sarcoma. Thus, the TLS/FUS-ERG gene fusion in t(16;21) leukemia is predicted to produce a protein that is very similar to the EWS-ERG chimeric protein responsible for Ewing's sarcoma.

TI: Liver function studies in children with acute lymphocytic leukemia after cessation of therapy.

AU: Bessho-F; Kinumaki-H; Yokota-S; Hayashi-Y; Kobayashi-M; Kamoshita-S

SO: Med-Pediatr-Oncol. 1994; 23(2): 111-5

1994

AB: We investigated liver function in 27 children with acute lymphocytic leukemia (ALL) after cessation of therapy. Induction therapy consisted of prednisolone+vincristine (VP regimen) alone (16 patients) or with addition of daunorubicin (4 patients) or L-asparaginase (7 patients). Patients treated with VP regimen received short courses of VP regimen every 12 weeks for the first year of maintenance. Twenty-five patients remained in first complete remission and had completed 3-year maintenance therapy with methotrexate (MTX) and 6-mercaptopurine (6-MP) 1-7 years prior to this study. Twenty-three patients had received transfusions of packed red blood cells or fresh whole blood (1-11 units; median: 2 units) but none had evidence of either hepatitis B or hepatitis C. Alanine aminotransferase (ALT), which was measured every 3 months during maintenance therapy, had values more than three times the upper limit of the normal range in 25% of the measurements in more than half of the patients. However, by 3 months after the completion of maintenance therapy, ALT had normalized in all patients and remained normal in all but two patients until the time of this study. Serum bilirubin, serum albumin, and prothrombin time were all within normal limits. Fasting and 2-hour postprandial total serum bile acids were high in 5 of 13 patients and in 6 of 13 patients, respectively. The ratio of cholic acids+deoxycholic acids to chenodeoxycholic acids+lithocholic acids was below 1 in all but two patients, whereas this ratio was above 1 in all controls. Our bile acid profile results indicate the necessity of careful long-term follow-up of survivors of ALL treated with hepatotoxic chemotherapy during childhood.

TI: An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation.

AU: Ichikawa-H; Shimizu-K; Hayashi-Y; Ohki-M

SO: Cancer-Res. 1994 Jun 1; 54(11): 2865-8

1994

TI: Effects of herbimycin A and its derivatives on growth and differentiation of Ph1-positive acute lymphoid leukemia cell lines.

AU: Sato-S; Honma-Y; Hozumi-M; Hayashi-Y; Matsuo-Y; Shibata-K; Omura-S; Hino-K; Tomoyasu-S; Tsuruoka-N

SO: Leuk-Res. 1994 Mar; 18(3): 221-8

1994

AB: The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr/abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin A, an inhibitor of tyrosine kinase, preferentially inhibited the growth of Ph1-positive acute lymphoid leukemia (ALL) cell lines, as well as Ph1-positive chronic myeloid leukemia (CML) cell lines. Although noncytotoxic concentrations of herbimycin A induced erythroid differentiation of two CML-derived cell lines, K562 and KU812, in a previous study, the differentiation-inducing effect of herbimycin A on Ph1-positive ALL cell lines was less strong. Herbimycin A enhanced some differentiation-associated properties of one Ph1-positive ALL cell line, L2, but the effect of herbimycin A on the other Ph1-positive ALL cell lines was cytotoxic rather than cytostatic (differentiation-inducing). Several derivatives of herbimycin A were synthesized and their effects on the cell proliferation of Ph1-positive CML and ALL cell lines were examined. The sensitivities of the Ph1-positive cell lines to herbimycin A derivatives were different from the data on the rat kidney cell line infected with Rous sarcoma virus (v-src) derived from a previous study, suggesting bcr/abl kinase may differ in sensitivity from other tyrosine kinases. Moreover, the sensitivities of the ALL cell lines were not the same as those of the CML cell lines. These results suggest that a specific inhibitor of bcr/abl kinase could be an effective antileukemic agent against Ph1-positive CML or ALL.

TI: [A study of E2A gene in childhood acute lymphoblastic leukemia]

AU: Hayashi-Y; Kikuchi-A; Kobayashi-S; Shikano-T; Hanada-R; Yamamoto-K; Sotomatsu-M; Ishimoto-K; Sako-M; Yamamori-S; et-al

SO: Rinsho-Ketsueki. 1994 Jan; 35(1): 9-13

1994

AB: E2A gene rearrangements and E2A-PBX1 chimeric mRNA produced by t(1;19) were examined in 50 cases with acute lymphoblastic leukemia (ALL). Nine of 10 ALL cases with t(1;19) showed the rearrangement by Southern blotting using the E2A gene probe when digested with Xba I, Bgl II, and Eco RI, and the remaining one having hyperdiploidy which was considered to be a sign of good prognosis, lacked E2A rearrangement. Six of 7 ALL cases with t(1;19) that were tested showed the predicted 164 bps band of E2A-PBX1 chimeric mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR), while a case having t(1;19) without E2A rearrangement and 10 cases lacking t(1;19) did not. Three ALL cases tested did not have E2A-PBX1 mRNA at the time complete remission 4 months after diagnosis. Forty ALL cases lacking t(1;19), including 4 cases with t(11;19), did not reveal rearrangement of E2A. We conclude that t(1;19)-ALL can be molecularly diagnosed, and minimal residual disease could be detected by the RT-PCR method.

Edited by Toshio Hishi