[Clinical study on chemotherapy for multiple myeloma: Part IV: Prognostic factors related to long survival].
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Biomedical subjects
Publications and source records attributed to T Tsubota.
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Chromosome analysis was performed on 1 patient with diffuse lymphoma of mixed type by histologic diagnosis and on 7 patients with the acute type of adult T-cell leukemia (ATL). Specific abnormalities in chromosome 14 at break band q11 with the assigned locus of the alpha-chain gene of the T-cell antigen receptor were identified in 6 of 8 patients. Inv(14) (q11q32) was found in 2 patients and translocation of chromosome 14 at break band q11 was observed in 4. Donor chromosomes involved in translocation of the 14q11 varied, i.e., chromosomes 3, 7 or X, with the exception of one patient whose donor chromosome origin could not be determined. The breakpoint in chromosome 3 was in band p25, a region reported to include the locus of the c-raf-I oncogene. In chromosome 7, it was in band p11, a region reported to include the locus of the c-erb-B oncogene, and in the sex chromosome X, it was in band q11. One patient also had a chromosome 14 aberration at break band q32. Of the 2 remaining patients, one had lost chromosome 14 and the other had an isochromosome 14q. Our observation and other reported findings suggest that the rearrangement of chromosome 14 at break band q11 is specific for lymphoma-type or acute-type ATL patients, and aberrations of proto-oncogene expression or the coding sequence by recombination involving a T-cell antigen receptor gene due to chromosome inversion or chromosome translocation may play an important role in T-cell neoplasia including ATL.
Chromosome aberrations and clinical features of three patients with adult T cell leukemia-lymphoma (ATL) not associated with human T cell leukemia virus type I (HTLV-I) are described. From their clinical features, two patients were diagnosed as acute type and one patient was diagnosed as chronic type, which later converted to acute crisis. Clonal and many chromosomal abnormalities were observed before therapy in the two acute type cases and at relapse in the chronic type case. Karyotype aberrations, including trisomy 3, trisomy 7, trisomy 21, del(6)(q21), del(10)(p13), 14q11 translocation, and loss of X chromosome, all of which are frequently found in HTLV-I associated ATL, were also seen in these cases of HTLV-I-negative ATL.
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The presence of antibodies against adult T cell leukemia antigen (ATLA) was studied in 59 patients with chronic respiratory diseases. Of 13 patients with diffuse panbronchiolitis, 3, who developed adult T cell leukemia, had the anti-ATLA antibody and 8 had the related, anti-ATLA-like antibody. Of 13 cases of idiopathic interstitial pneumonia, 8 had the anti-ATLA-like antibody. Except for only one case, these antibodies were not detected in 33 patients with bronchial asthma or sarcoidosis and 20 healthy adults examined. These results suggested that the test of these antibodies would be useful for the diagnosis of diffuse panbronchiolitis and idiopathic interstitial pneumonia which frequently develop lung cancers.
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Fatty acids of plasma and erythrocyte membrane sphingomyelin were determined by gas chromatography-mass spectrometry in adrenoleukodystrophy (ALD) without adrenal insufficiency. Mass chromatogram tracing with the ion at m/z 143 [(CH2)6COOH3]+ showed increases of saturated very long chain fatty acids in plasma and erythrocyte membrane sphingomyelin in ALD. The C26:0/C22:0 ratios in plasma were 0.121, 0.057 and 0.007 in cases 1 and 2, and a control subject, respectively. The C26:0/C22:0 ratios in erythrocyte membrane sphingomyelin were 0.386, 0.211 and 0.093 in cases 1 and 2 and the control subject, respectively. The demyelinating process of ALD was clearly observed in both the inversion recovery 2100/500 and spin echo 2100/80 scans on magnetic resonance imaging. The magnetic resonance image in case 1 revealed widespread demyelinated lesions, involving almost the entire cerebrum and cerebellum, at 4 years after the onset, while that in case 2 revealed demyelinated lesions mainly limited to parieto-occipital areas at 1 year after the onset.
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Macromomycin (MCR), an unique membrane-reactive anticancer antibiotic, was incubated with murine monoclonal anti-HLA IgG1 antibody (H-1) in the presence of carbodiimide. The resulting mixture was fractionated with a Sephadex G-200 column. The first and second fractions were shown to contain MCR-(H-1) conjugate by the elution profile, as well as by the Sarcina lutea growth inhibition assay and Ouchterlony double-diffusion method. A membrane immunofluorescence test with anti-MCR and anti-mouse IgG antibodies demonstrated specific localization of MCR-(H-1) on the surface of HLA-bearing NALL -1 cells. MCR-(H-1) inhibited the growth of HLA-lacking NS-1 cells statistically less effectively than MCR alone (p less than 0.01). On the other hand, the conjugate and free MCR equally inhibited the growth and 3H-TdR incorporation of HLA-bearing NALL -1 cells. These results indicate that the antibody-bound MCR retained both MCR and antibody activities, and thus exerted antibody-targeting MCR cytotoxicity in vitro.
Methotrexate (MTX), a folate antagonist and anticancer agent, was linked covalently to murine monoclonal anti-HLA IgG1 antibody (H-1) with the use of dextran T-40 as a multivalent carrier. As determined spectrophotometrically, the conjugate was composed of 9.20 mol MTX per 1 mol antibody. Of the substituted MTX, 46.3% (4.30 mol MTX per 1 mol antibody) exhibited inhibitory activity on dihydrofolate reductase. The MTX conjugated to H-1 [MTX-(H-l)] showed significantly stronger cytotoxicity against HLA-bearing cells than cells lacking HLA (p less than 0.001) in cultivation after a 2-hour exposure to the drugs. In the same experiment, free MTX showed equivalent cytotoxicity to cells both bearing and lacking HLA. When cells were cultivated for 3 days with the drugs, MTX-(H-l) also showed significantly stronger cytotoxicity than free MTX or MTX-control IgG conjugate against HLA-bearing cells (p less than 0.001), and the MTX-(H-l), MTX-control IgG, and free MTX showed equivalent cytotoxicity to cells lacking HLA. Our results indicate that the MTX-(H-l) conjugate binds to the cell surface antigen by its antibody action and exerts greater MTX cytotoxicity than free MTX in vitro.
Bleomycin (BLM), a potent anticancer glycopeptide antibiotic, was linked covalently to murine monoclonal anti-HLA IgG1 antibody (H-1) with the use of dextran T-40. As determined spectrophotometrically, the conjugate was composed of 57.5 moles BLM per mole antibody. Of the substituted BLM, 18.4% (10.6 moles BLM per mole antibody) exhibited antimicrobial activity. The BLM-(H-1) conjugate showed stronger cytotoxicity than BLM alone against HLA-bearing cells in cultivation after a 30-min exposure to the drugs. In the same experiment, the conjugate was less toxic than BLM against cells lacking HLA.
The in vivo antitumor activity of NCS-immune immunoglobulin G (IgG) [Neocarzinostatin (NCS) conjugated with rabbit IgG antibody against a human leukemia cell line (NALL-1)] was evaluated in immunosuppressed newborn Syrian hamsters into which a transplantable human leukemia cell line, BALL-1 was implanted. After intraperitoneal (i.p.) injection of the conjugate, hamsters preinoculated i.p. with BALL-1 cells survived longer than hamsters treated with control solutions (p less than 0.01). The control solutions were NCS, immune IgG, a mixture of NCS and immune IgG, NCS-normal IgG conjugate and physiological saline. There was no change in body weight in the NCS-immune IgG-treated hamsters. The growth of subcutaneously (s.c.) implanted BALL-1 tumors was also inhibited by i.p. administration of NCS-immune IgG; however, the degree of inhibition was not significantly different from that obtained by administration of NCS alone, a mixture of NCS and immune IgG or NCS-normal IgG conjugate. These results indicate that NCS-immune IgG was effective against i.p. BALL-1 tumors, but was less effective against s.c. implanted tumors.
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