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Biomedical subjects

H Mizoguchi

Publications and source records attributed to H Mizoguchi.

At least 145 records · Page 8Linked to original sources
PubMed1998

In vitro and in vivo effects of KT6352, a derivative of indolocarbazole compounds, on murine megakaryocytopoiesis.

We investigated the in vitro and in vivo effects of KT6352, a derivative of indolocarbazole compound, on murine megakaryocytopoiesis. When serum-free megakaryocyte (Meg) colony assay was performed with 100 U/mL of recombinant mouse interleukin-3 (rmIL-3), the addition of 1x10(-11)M to 1x10(-9)M of KT6352 increased the number of Meg colonies. An additional increase of Meg colonies by KT6352 was observed in the serum-free culture containing rmIL-3 plus recombinant mouse interleukin-6 or rmIL-3 plus recombinant mouse stem cell factor. KT6352 did not stimulate Meg colony formation without rmIL-3. When KT6352 was administered intraperitoneally to normal BALB/c male mice at a dose of 10 mg/kg daily for 5 consecutive days, a 2.1-fold increase in the platelet count was observed on day 14, and the prolonged thrombocytopoiesis was detectable from 9 to 27 days after KT6352 administration. A marked increase in the white blood cell count was also observed from 5 to 14 days after KT6352 treatment. Before the gradual increase of platelet counts, 8 days after KT6352 administration, a marked increase in the number of colony-forming units of megakaryocytes (CFU-Megs) in bone marrow and spleen was observed, and a substantial increase in the number of splenic CFU-Megs was observed 14 and 23 days after KT6352 administration. Bone marrow Meg ploidy analysis by two-color flow cytometry showed a shift in the modal ploidy class from 16 to 32 and an increase in the frequency of 64 cells in KT6352-treated mice. These results suggest a possible therapeutic benefit of KT6352 in the management of thrombocytopenia.

Animals↗
PubMed1998

[A phase II study with high-dose cytarabine (NS-075) in adult patients with relapsed and refractory acute leukemia].

A multi-center phase II clinical study with high dose cytarabine (NS-075) was conducted in adult patients with relapsed and/or refractory acute leukemia. 2 g/m2 cytarabine was given 12 times by 3-hour intravenous infusion every 12 hrs. 46 patients were registered, and 44 were evaluable: 35 with acute myeloid leukemia (AML) and 9 with acute lymphoblastic leukemia (ALL). There were 28 males and 16 females, with a median age of 37.5 years (range 15-68), including 6 of more than 60 years. Among 35 patients with AML, there were 16 (45.7%) complete and 2 (5.7%) partial remissions. Among 9 patients with ALL, there were 2 (22.2%) complete and 1 (11.1%) partial remissions. The major non-hematologic toxicities were gastrointestinal symptoms such as nausea/vomiting, anorexia and diarrhea, as well as fever, infection, conjunctivitis, alopecia, hepatic and renal dysfunctions. Central nervous system (CNS) toxicity was mild and reversible. Therapy-related death occurred in 5 patients resulting from prolonged pancytopenia, which suggests the necessity of strict countermeasures for infections as well as good patient care. These results indicate that high-dose cytarabine is a promising therapy for treatment of relapsed and/or refractory acute leukemia.

Adolescent↗
PubMed1997

Development of a novel selective amplifier gene for controllable expansion of transduced hematopoietic cells.

To overcome the low efficiency of gene transfer into hematopoietic cells, we developed a novel system for selective expansion of transduced cells. To this end, we constructed a chimeric cDNA (GCRER) encoding the fusion protein between the granulocyte colony-stimulating factor receptor (G-CSFR) and the hormone-binding domain (HBD) of the estrogen receptor (ER) as a selective amplifier gene. Use of the intracellular signaling pathway of G-CSFR was considered to be appropriate, because G-CSF has the ability not only to stimulate the neutrophil production, but also to expand the hematopoietic stem/progenitor cell pool in vivo. To activate the exogenous G-CSFR signal domain selectively, the estrogen/ER-HBD system was used as a molecular switch in this study. When the GCRER gene was expressed in the interleukin-3 (IL-3)-dependent murine cell line, Ba/F3, the cells showed IL-3-independent growth in response to G-CSF or estrogen. Moreover, the Ba/F3 cells transfected with the Delta(5-195)GCRER, whose product lacks the extracellular G-CSF-binding domain, did not respond to G-CSF, but retained the ability for estrogen-dependent growth. Further, murine bone marrow cells transduced with the GCRER or Delta(5-195)GCRER gene with retroviral vectors formed a significant number of colonies in response to estrogen, as well as G-CSF, whereas estrogen did not stimulate colony formation by untransduced murine bone marrow cells. It is noteworthy that erythroid colonies were apparently formed by the bone marrow cells transduced with the GCRER gene in the presence of estrogen without the addition of erythropoietin, suggesting that the signals from the G-CSFR portion of the chimeric molecules do not preferentially induce neutrophilic differentiation, but just promote the differentiation depending on the nature of the target cells. We speculate that when the selective amplifier genes are expressed in the primitive hematopoietic stem cells, the growth signal predominates and that the population of transduced stem cells expands upon estrogen treatment, even if some of the cells enter the differentiation pathway. The present study suggests that this strategy is applicable to the in vivo selective expansion of transduced hematopoietic stem cells.

Animals↗
PubMed1997

Allelotype analysis in the evolution of chronic myelocytic leukemia.

To elucidate the genetic events that may play important roles in the progression of chronic myelocytic leukemia (CML), we performed allelotype analysis in 30 patients with CML as the disease transformed to accelerated phase or blast crisis (21 myeloid and 9 lymphoid cases). DNAs were extracted from slides of bone marrow smears or from freshly isolated bone marrow mononuclear cells. The DNAs from the same individuals in both chronic phase and either blast crisis or accelerated phase were analyzed at 82 microsatellite markers, which mapped to each of the autosomal arms except the short arms of the acrocentric chromosomes. Loss of heterozygosity (LOH) on at least one locus was observed in 21 of the 30 cases (70%) as the disease progressed. Frequent allelic loss of > or = 20% of the informative cases was observed on chromosome arms 1p (35%), 7p (21%), 19p (20%), and 20q (29%). Allelic losses were also analyzed according to phenotypes. LOH of > or = 20% was detected on 1p (29%), 18p (20%), and 20q (27%) in myeloid blast crisis, and on 1p (50%), 4p (25%), 7p (43%), 9p (29%), 18q (25%), 19p (43%), and 20q (33%) in lymphoid blast crisis. Serial cytogenetic information was available for most of our cases with LOH on these arms, and only one case had loss of both chromosomes 9 and 20. Fractional allelic loss, calculated for each sample as the total number of chromosomal arms lost/total number of arms with information, showed a median value of 0.06 and a mean of 0.098 (range 0 to 0.60). These results suggest that tumor suppressor genes especially on 1p, 7p, 19p, and 20q probably have an important role in the progression to blast crisis of CML.

Adult↗
PubMed1997

Purification, cDNA cloning, and characterization of a new serpin with megakaryocyte maturation activity.

A new member of the serine protease inhibitor (serpin) superfamily with megakaryocyte maturation activity was purified, and its cDNA was cloned and characterized. The predicted amino acid sequence consisting of 380 residues was unique and was 38% identical to the serpin plasminogen activator inhibitor type 2 (PAI-2). The recombinant factor expressed in Chinese hamster ovary cells showed species-specific activity on the induction of megakaryocyte maturation in vitro. When injected into mice, the factor indeed elicited an increase in the number of platelets in plasma. The sequence alignment indicated that the factor possessed a lysine residue at the P1 position, suggesting that it might function as an inhibitor of Lys-specific proteases. Although we could not show any inhibitory activities toward several known Lys-specific proteases, we detected the activity toward protease activity present in the culture supernatant of COLO 201 cells. These results suggested that the protein might influence the maturation of megakaryocytes via action as a serpin.

Amino Acid Sequence↗
PubMed1997

Sequential development of structural and functional alterations in T cells from tumor-bearing mice.

The TCR alpha beta or -gamma delta chains bind the peptide ligand, whereas the associated CD3 delta epsilon gamma and TCR zeta subunits couple the TCR to intracellular signal transduction components. Recently, several groups have described marked alterations in signal transduction elements in T cells from cancer patients or in mice bearing tumor for a few weeks (>26 days). The sequence in which these alterations develop is unknown. The aim of this study was to explore the kinetics of the development of alterations in signal transduction molecules (TCR zeta chain, NF kappaB family proteins, and tyrosine kinase p56(lck)) in mice bearing MC38 colon adenocarcinoma. The results demonstrate that alterations in NF kappaB family proteins, specifically the failure of p65 translocation to the nucleus, occur earlier and more frequently than the decrease in zeta-chain. These defects are paralleled by an impaired ability to produce Th1 cytokines (IL-2 and IFN-gamma). These initial changes are followed by the eventual loss of TCR zeta chain and p56(lck) and a marked decrease in cytotoxic function. An increased rate of lysosomal degradation is one of the mechanisms responsible for the loss of zeta-chain.

Adenocarcinoma↗
PubMed1997

Pure red cell aplasia with thymona: evidence of T-cell clonal disorder.

Pure red cell aplasia (PRCA) sometimes accompanies thymoma. Herein, we report a PRCA patient with thymoma with a clonal disorder of T cells. A 55-year-old man presented with anemia and anterior mediastinum tumor. The laboratory study revealed hemoglobin 8.2 g/dl; leukocytes 15.8 x 10(9)/L with 76.5% neutrophils, 20.0% lymphocytes, and reticulocytes 0.0%. Bone marrow aspirate smears and biopsy sections revealed normal myeloid and megakaryocyte differentiation and contained no erythroid precursors. We made the diagnosis of PRCA. The size of the lymphocytes was small without any granules in the cytoplasm. The surface marker of peripheral blood mononuclear cells demonstrated increased CD2+, CD3+, CD4-, and CD8+ populations. The mediastinal tumor was resected and a thymoma diagnosed. A monoclonal rearrangement of T-cell receptor (TCR)-beta-chain gene was found using Southern blot analysis of the mononuclear cells in both peripheral blood and thymoma. Treatment with prednisolone, thymectomy, and cyclophosphamide exerted no beneficial effect. After initiation of the Cyclosporin A therapy, the patient developed reticulocytosis. This PRCA case seems to present a neoplastic proliferation of CD8+ T cells in peripheral blood and thymus with a monoclonal rearrangement of the TCR-beta-chain gene.

Cell Differentiation↗
PubMed1997

Molecular analysis of the adenomatous polyposis coli gene in sarcomas, hematological malignancies and noncolonic, neoplastic tissues.

Somatic mutations of the adenomatous polyposis coli (APC) gene have been frequently found in sporadic colorectal tumors, and the frequency of such mutations remain constant as tumors progress from benign adenomas to malignant cancers. Thus the mutations of the APC gene may have a major role in the early development of sporadic colorectal tumors. Whether inactivation of the APC gene accounts for other types of primary tumors is still being investigated. We investigated for APC mutations within the mutation cluster region (a 684-bp region containing most of the mutations found in colorectal tumors) in 317 samples from a wide variety of human malignant and premalignant tissues, including 40 lung cancers, 47 renal cell carcinomas, 41 osteosarcomas and 21 other types of sarcomas, 45 acute lymphoid leukemias/lymphomas, 33 acute myeloid leukemias, 27 myelodysplastic syndrome samples, and 20 chronic colitis (ulcerative colitis and Crohn's disease) associated cancers and dysplasias, and 43 human malignant cell lines. We used single-strand conformation polymorphism assay following polymerase chain reaction. Samples with abnormal assay results were reamplified and analyzed by the direct DNA sequencing method. We detected a total of two cases with a base substitution. A silent mutation was detected in a case of myelodysplastic syndrome, and a novel nonsense mutation was discovered in a colorectal cancer cell line, SW837. In summary, we did not detect any functional mutations of the APC gene in a wide variety of tumors except for a colon cancer cell line, suggesting that alterations of the APC gene do not have a major role in the development of lung and renal cancers, various types of sarcomas, or hematological malignancies.

Colonic Neoplasms↗
PubMed1997

Use of antisense oligodeoxynucleotide to delta-opioid receptor mRNA in the study of turnover of delta-opioid receptors in the spinal cord of the mouse.

Pretreatment of male ICR mice with an antisense oligodeoxynucleotide to delta-opioid receptor mRNA (DOR AS oligo, 163 pmol) given intrathecally (i.t.) once a day for 1-3 days produced a time-dependent attenuation of antinociception produced by i.t.-challenged [D-Ala2] deltorphin II (6.4 nmol), a delta-opioid receptor agonist. The attenuation of the [D-Ala2]deltorphin II-induced antinociception caused by pretreatment with DOR AS oligo given i.t. daily was blocked by co-pretreatment with naltriben (14.5 nmol), a delta-opioid receptor antagonist, but was markedly enhanced by concomitant pretreatment with thiorphan (19.7 nmol) or bestatin (14.5 nmol), which inhibits the degradation of endogenously released Met-enkephalin. Concomitant pretreatment with antiserum to Met-enkephalin, but not with antiserum to Leu-enkephalin, beta-endorphin or dynorphin A (1-17), and DOR AS oligo given i.t. daily for 3 days prevented the attenuation of i.t.-challenged [D-Ala2]deltorphin II-induced antinociception caused by the DOR AS oligo pretreatment. Our results support the existence of a turnover of delta-opioid receptors in the mouse spinal cord caused by the release of Met-enkephalin.

Animals↗
PubMed1997

Proliferative effect of postapheresis platelet donor plasma on a megakaryoblastic leukemia cell line.

Platelet donors sometimes show an increased platelet count following apheresis. We analyzed the effect of plasma obtained from such donors, along with thrombopoietin (Tpo), for growth and differentiation-inducing activity on a megakaryoblastic leukemia cell line, Meg-J. Colony formation was stimulated by donor plasma for Meg-J cells in a dose-dependent manner, and the time course of the sampling peaked 1 day after apheresis. Neither the donor plasma nor Tpo induced morphological differentiation. Donor plasma from any sampling time decreased CD41 and CD42b expression by more than 10%, and more than a 10% decrease of CD41 was induced by Tpo. The measurement of plasma Tpo showed no statistically significant increase after platelet donation. Our data suggest that, following apheresis, donor plasma contains factor(s) that: (a) stimulate growth rather than induce differentiation of a megakaryoblastic cell line; (b) are present in increased levels after apheresis; and (c) are different from Tpo.

Blood Donors↗
PubMed1997

[Met5]enkephalin and delta2-opioid receptors in the spinal cord are involved in the cold water swimming-induced antinociception in the mouse.

Mice made cold water swimming (CWS: 4 degrees C, 3 min) produced an opioid-mediated antinociception. Experiments were designed to determine what types of opioid receptors and endogenous opioid peptides in the spinal cord are involved in the CWS-induced antinociception in male ICR mice. Antinociception was measured by the tail-flick test. CWS-induced antinociception was blocked by intrathecal (i.t.) pretreatment with antiserum to [Met5]enkephalin (100 microg, 1 hr), but not by antiserum (100 microg, 1 hr) to [Leu5]enkephalin, beta-endorphin or dynorphin A (1-17). Moreover, i.t. pretreatment with delta2-opioid receptor antagonist naltriben (NTB: 10 microg, 10 min) blocked the antinociception induced by CWS or i.t.-administered [Met5]enkephalin (10 microg). However, the antinociception induced by CWS or i.t.-administered [Met5]enkephalin was not blocked by i.t. pretreatment with delta1-opioid receptor antagonist 7-benzylidene naltrexone (BNTX: 1 microg, 10 min), mu-opioid receptor antagonist D-Phe-Cys-Try-D-Try-Om-Thr-Phe-Thr-NH2 (CTOP: 50 ng, 10 min), or kappa-opioid receptor antagonist norbinaltorphimine (norBNI: 5 microg, 24 hr). These data indicate that [Met5]enkephalin and delta2-opioid receptor in the spinal cord are involved in antinociception induced by CWS.

Animals↗
PubMed1997

Mode of disease progression in primary myelodysplastic syndromes: a Japanese co-operative study. The Refractory Anemia Study Group of The Ministry of Health and Welfare, Japan.

Chronological changes in hematological findings were analyzed in 225 patients with myelodysplastic syndromes (MDS). They were diagnosed between 1990 and 1992. Their hematological findings, i.e. hemoglobin levels, leukocyte and platelet counts, proportions of peripheral blood (PB) blasts and monocytes, and proportion of blasts in bone marrow (BM), were recorded for up to 42 months after diagnosis, when available. BM was examined regularly in only a few patients. Therefore, it was impractical to use the French-American-British Cooperative Group criteria for subtype classification during the disease course. Thus, we used the percentage of PB blasts as the only indicator of stage evolution. We classified the disease into four stages: stage 1, less than 1% PB blasts; stage 2, 1-5% PB blasts; stage 3, 5-30% PB blasts; and stage 4, 30% or more PB blasts. There were 171 patients initially in stage 1, 37 initially in stage 2, and 17 initially in stage 3. Less than half (45%) of the patients initially in stage 1 progressed to stage 2, while 91% of the patients initially in stage 2 and all of the patients initially in stage 3 showed stage evolution. Eight variables, i.e. BM blasts 5% or more, male sex, karyotypic abnormalities, micromegakaryocytes, mononuclear large megakaryocytes, platelet counts 50 x 10(9)/l or higher, abnormal nucleus of granulocytes, and abnormal granules of granulocytes, were found to be significant risk factors for evolution from stage 1 to 2. Evolution from stage 1 to a higher stage within 15 months of diagnosis was associated with impending poor prognosis in most patients. However, of the 67 patients initially in stage 1 who died, 30 did not show stage evolution. Evolution from stage 2 to a higher stage and from stage 3 to stage 4 was also associated with impending poor prognosis. Higher levels of cytopenia were not associated with poorer prognosis in the stage 1 patients. In conclusion, our grading system proved to be useful in evaluating the chronological changes in MDS patients.

Disease Progression↗
PubMed1997

Expression of the MDR1 and MDR3 gene products in acute and chronic leukemias.

We performed immunocytochemistry to detect mdr1 and mdr3 P-glycoproteins (P-gps) in 81 patients with acute and chronic leukemia, using the mdr1 P-gp-specific monoclonal antibody (MoAb) MRK16, and the mdr3 P-gp-specific MDR3M. Immunoreactivity for the mdr1 gene product was positive in 27 out of 81 (33%) patients. Immunoreactivity with the anti-mdr3 P-gp MoAb was positive in 20 out of 81 (25%) patients. Of 54 patients with acute leukemia, 17 (31%) were positive for mdr1 P-gp and 8 (15%) for mdr3 P-gp. A high proportion (60%) of patients with chronic lymphocytic leukemia (CLL) were mdr3 P-gp positive. Of the patients with granular-lymphocyte proliferative disorder (GLPD), a chronic T-cell or natural killer cell leukemia, 8/17 (47%) were positive for mdr1 P-gp and 6/17 (35%) for mdr3 P-gp. Of 23 patients with chronic leukemia (CLL and GLPD), 10 (37%) were positive for mdr1 P-gp and 12 (44%) for mdr3 P-gp. To clarify the function of the mdr3 P-gp, we examined the intracellular rhodamine123 (Rh123) levels of mdr1 P-gp-negative and mdr3 P-gp-positive leukemic cells from patients with acute lymphocytic leukaemia, on the addition of 10 microM cyclosporin A (CyA). The addition of CyA led to significant increases in intracellular Rh123 levels in mdr1 P-gp-negative and mdr3 P-gp-positive leukemic cells. Results of the assay for dye efflux suggested that the mdr3 P-gp has a role in drug resistance, and functional drug-efflux capacity. In 31 acute leukemia patients at initial diagnosis, mdr1 or mdr3 P-gp expression correlated significantly to an outcome of complete remission (CR). In 54 acute leukemia patients, exposure to precytotoxic agents correlated significantly to expression, with a significant higher number of patients mdr1 or mdr3 P-gp positive than negative. In the 54 patients with acute leukemia, mdr1 P-gp expression correlated to mdr3 P-gp expression significantly (p=0.0007). In the 27 patients with chronic leukemia (CLL and GLPD), mdr1 and mdr3 P-gp expression did not correlate to exposure to precytotoxic agents, nor did mdr1 P-gp expression correlate to mdr3 P-gp expression. It may be speculated that precytotoxic agents induced mdr1 and mdr3 P-gp expression in acute leukemia; however, in chronic leukemia, both P-gps were expressed independently of exposure to precytotoxic agents.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1997

Pretreatment with protein kinase C activator phorbol 12,13-dibutyrate attenuates the antinociception induced by mu- but not epsilon-opioid receptor agonist in the mouse.

The effects of pretreatment with a protein kinase C activator, phorbol 12,13-dibutyrate, on antinociception induced by i.c.v.-administered mu-opioid receptor agonist (D-Ala2, NMePhe4, Gly(ol)5) enkephalin (DAMGO) or morphine and epsilon-opioid receptor agonist beta-endorphin were studied in male ICR mice. The tail-flick responses were used for antinociceptive tests. I.c.v. pretreatment with phorbol 12,13-dibutyrate (50 pmol) for 30 or 60 but not 10 min attenuated antinociception induced by i.c.v.-administered DAMGO. I.c.v. pretreatment with phorbol 12,13-dibutyrate (10 and 50 pmol) for 60 min caused a dose-dependent attenuation of DAMGO (19.5 pmol)- or morphine (6.0 nmol)-induced antinociception. The dose-response curve for DAMGO-induced antinociception was shifted to the right by 7.3-fold by i.c.v. pretreatment with phorbol 12,13-dibutyrate (50 pmol) for 60 min. However, the i.c.v.-administered beta-endorphin-induced antinociception was not affected by the same pretreatment with phorbol 12,13-dibutyrate. The attenuation of i.c.v.-administered DAMGO- and morphine-induced antinociception by phorbol 12,13-dibutyrate was reversed by concomitant i.c.v. pretreatment with a selective protein kinase C inhibitor calphostin C. These results suggest that activation of protein kinase C by phorbol 12,13-dibutyrate leads to the desensitization of mu-, but not epsilon-opioid receptor-mediated antinociception. These findings also provide additional evidence for differential intracellular modulation on antinociceptive action of mu- and epsilon-opioid receptor agonists.

Analgesics↗
PubMed1997

Effect of thrombopoietin (c-Mpl ligand) alone and in combination with other hematopoietic growth factors on human megakaryocytopoiesis in serum-free cultures.

The effect of human recombinant (hr) thrombopoietin (TPO) on human megakaryocytopoiesis was studied in a serum-free system. hrTPO induced megakaryocyte colony formation by purified CD 34-positive cells and polyploidization of megakaryocytes by purified CD41a-positive cells. hrTPO gave rise to much smaller colonies which appeared at an earlier time compared to the use of human recombinant interleukin-3 (hrIL-3), suggesting that hrTPO predominantly affects the population of megakaryocyte progenitor cells in the late stage. hrIL-3 additively increased the hrTPO-induced megakaryocyte colony formation by CD34-positive cells. The hrTPO-induced megkaryocyte colony formation was also increased by the presence of hrIL-6, hrIL-11, human recombinant erythropoietin (hrEpo) or human recombinant stem cell factor (hrSCF), none of which stimulated megakaryocyte colony growth when added alone. The combined addition of hrTPO, hrIL-3 and hrSCF to CD34-positive cells markedly stimulated megakaryocyte colony formation and produced large numbers of megakaryocytes. hrTPO stimulated the polyploidization of CD34-positive cell-derived megakaryocytes in liquid culture. However, the addition of hrIL-6, hrIL-11 or hrEpo to hrTPO did not further enhance the hrTPO-induced polyploidization. These findings indicate that at the megakaryocyte progenitor cell level, the effect of hrTPO can be promoted by the presence of various hematopoietic growth factors involved in human megakaryocytopoiesis.

Culture Media, Serum-Free↗
PubMed1997

The effect of pretreatment with a delta 2-opioid receptor antisense oligodeoxynucleotide on the recovery from acute antinociceptive tolerance to delta 2-opioid receptor agonist in the mouse spinal cord.

1. An intrathecal (i.t.) injection of a selective delta 2-opioid receptor agonist, [D-Ala2]deltorphin II, produced an acute antinociceptive tolerance to the antinociceptive effect of a subsequent i.t. challenge of [D-Ala2]deltorphin II. This acute tolerance lasted 3 to 9 h and completely subsided by 12 h. The experiments were designed to examine the effect of pretreatment with an antisense oligodeoxynucleotide to delta 2-opioid receptor mRNA (delta-AS oligo) on the recovery from tolerance to [D-Ala2]deltorphin II-induced antinociception in male ICR mice. 2. Pretreatment with delta-AS oligo (1.63 to 163 pmol, i.t.), but not mismatched oligo (MM oligo) (163 pmol), prevented the recovery from acute tolerance to [D-Ala2]deltorphin II-induced antinociception in a dose-dependent manner. However, treatment with delta-AS oligo (163 pmol) did not prevent the recovery from tolerance to either the mu-opioid receptor agonist [D-Ala2,NMePhe4,Gly(ol)5]enkephalin (DAMGO) or the kappa-opioid receptor agonist U50,488H, indicating subtype specificity in the mechanism by which delta-AS oligo inhibits recovery from delta 2-opioid tolerance. 3. Treatment with [D-Ala2]deltorphin II (i.t.) significantly reduced the binding of [tyrosyl-3,5-(3)H(N)]-Tyr-D-Ser-Gly-Phe-Leu-Thr ([3H]-DSLET), a delta 2-opioid receptor agonist ligand, in the spinal cord 3 h after treatment, but binding returned to control levels by 24 h after treatment. However, [3H]-DSLET binding in the spinal cord remained significantly reduced at 24 h if delta-AS oligo (163 pmol) was coadministered with [D-Ala2]deltorphin II (6.4 nmol). 4. Based on these findings, it is concluded that a single stimulation of spinal cord delta 2-opioid receptors by intrathecally-administered [D-Ala2]deltorphin II induces a long-lasting desensitization of delta 2-opioid receptors to [D-Ala2]deltorphin II. Recovery from delta 2-opioid receptor-mediated antinociceptive tolerance apparently depends on replenishment by newly synthesized delta 2-opioid receptor protein rather than immediate reversal of delta 2-opioid receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1997

Absence of microsatellite instability during the progression of chronic myelocytic leukemia.

Microsatellites are highly polymorphic, short-tandem repeat sequences dispersed throughout the genome. To test the occurrence of genetic instability in the progression of chronic myelocytic leukemia (CML), we studied microsatellite instability (MSI) in 17 patients with CML. The DNAs from both chronic phase and blast crisis were analyzed at 10 loci. No MSI was observed in any of the 17 cases of blast crisis. These results indicate that MSI is rare and is not associated with progression to blast crisis in most cases of CML.

Blast Crisis↗