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Biomedical subjects

S Sakamaki

Publications and source records attributed to S Sakamaki.

At least 55 records · Page 3Linked to original sources
PubMed1998

Retroperitoneal extrarenal angiomyolipoma with early gastric carcinoma.

We present a very rare case of a retroperitoneal extrarenal angiomyolipoma accompanied by early gastric cancer. A 41-year-old Japanese man, who had undergone surgery for a type IIc early gastric cancer 2 years earlier, was admitted to hospital presenting with back pain and abdominal fullness. Computed tomographic scanning and magnetic resonance imaging of the abdomen disclosed a massive fatty tumor extending from the hepatic hilus to the retroperitoneum. A large retroperitoneal tumor mass with no sign of involvement in the kidney was totally resected by radical surgery. Histologically, the tumor was classified as an angiomyolipoma.

Adenocarcinoma↗
PubMed1998

Treatment for advanced testicular cancer with high-dose chemotherapy and autologous blood stem cell transplantation.

BACKGROUND: This study was carried out to investigate the efficacy and safety of high-dose chemotherapy (HDC) for the treatment of patients with advanced testicular cancer. METHODS: Seven patients were treated with high-dose carboplatin, etoposide, and ifosfamide followed by autologous blood stem cell transplantation. One patient received 1 cycle, 4 patients received 2 cycles, and 2 patients received 3 cycles of HDC. We performed a total of 15 autologous blood stem cell transplantations: 8 with autologous bone marrow; 6 with peripheral blood stem cells; and 1 with peripheral blood stem cells in addition to autologous bone marrow. RESULTS: Four of the 7 patients achieved a pathologic complete response via early use of HDC and additional salvage surgery. All 4 patients are still alive without evidence of disease at 12, 30, 33, and 54 months, respectively. One patient is alive with active disease at 35 months. Two patients refractory to conventional chemotherapy died of progressive disease at 5 and 27 months, respectively. The hematologic recovery after HDC was rapid, and peripheral blood stem cells tended to have shorter hematologic recovery compared with those from autologous bone marrow, although the difference was not significant. Nonhematologic toxicity was usually mild and manageable. CONCLUSION: High-dose chemotherapy, followed by autologous blood stem cell transplantation, may be safe and effective for patients with advanced testicular cancer, particularly when early use of HDC is conducted for chemotherapy-sensitive patients. A further large, long-term, follow-up study will be needed to define the role of HDC.

Adolescent↗
PubMed1997

Fibronectin fragment-facilitated retroviral transfer of the glutathione-S-transferase pi gene into CD34+ cells to protect them against alkylating agents.

To protect bone marrow cells from the toxicity of chemotherapy, a multidrug resistant gene or a dihydrofolate reductase gene has been introduced into stem cells. These genes, however, are not capable of conferring refractoriness to alkylating agents (AA), which are some of the most commonly used agents in chemotherapy regimens. In the present study, an attempt was made to endow human stem cell (CD34+ cells) with resistance to cyclophosphamide, a well-known AA, and adriamycin (ADM) by transducing the glutathione-S-transferase pi (GST-pi) gene whose product is thought to detoxify AA by conjugating them with glutathione and to remove a toxic peroxide formed by ADM. The gene transduction was carried out retrovirally with a virus titer of 1 x 10(5) FFU/ml, employing a recombinant fibronectin fragment; transduction efficiency was extremely low without the fragment. Incubation with interleukin-6 and stem cell factor enhanced the expression of fibronectin ligands VLA4 and VLA5 on CD34+ cells. This enhanced expression of VLA4 and VLA5 was considered to facilitate a close contact of the CD34+ cell to the retroviral vector via fibronectin fragments and the subsequent transduction process. The GST-pi gene-transduced CD34+ cells formed almost 3- and 2.5-fold more CFU-GM than neo gene-transduced CD34+ cells in the presence of 2.5 microg/ml of 4-hydroperoxycyclophosphamide (4-HC), an active form of cyclophosphamide, and 30 ng/ml ADM, respectively. The transfectants formed an appreciable number of colonies, even at higher concentrations of these drugs (5.0 microg/ml of 4-HC, 50 ng/ml of ADM) whereas neo gene-transduced or nontransduced CD34+ cells formed no colonies at all, indicating the possibility of selecting out the transfectants by exposing them to these anticancer drugs. Thus, we were able to demonstrate that transduction of the GST-pi gene confers resistance to cyclophosphamide as well as to ADM, and therefore this approach can be applied clinically for high-dose chemotherapy.

Alkylating Agents↗
PubMed1997

Suppression of intracellular Cu-Zn SOD results in enhanced motility and metastasis of Meth A sarcoma cells.

We have previously described an inverse relationship between Cu-Zn superoxide dismutase (SOD) activity and invasiveness of a clone of human tongue cancer cells. In these cells, suppression of Cu-Zn SOD activity by transfection with anti-sense cDNA enhanced motility in vitro. The present studies were undertaken to determine whether the inverse relationship between intracellular Cu-Zn SOD activity and motility is a general property of other tumor cells and whether this enzyme indeed defines in vivo metastatic potential. Murine Meth A sarcoma-derived ML-01 cells, which have low metastatic activity, were transfected with anti-sense Cu-Zn SOD cDNA. Two clones with very different SOD activities--ML-AS2, with the most suppressed, and ML-AS5, with the least suppressed activity-were analyzed for their motility and metastatic capability. Compared to the mocktransfectant ML-neo, the metastatic potential and motility of the ML-AS2 and ML-AS5 were increased 4.5- and 2.1-fold, respectively. Superoxide treatment enhanced the motility of the AS clones but not that of the ML-neo cells. Our results clearly show that there is an inverse relationship between the intracellular level of Cu-Zn SOD, cell motility and in vivo metastatic potential.

Animals↗
PubMed1997

Intra-mesenteric artery steroid administration relieved severe refractory gastro-intestinal graft-vs.-host disease in an allogeneic bone marrow transplantation patient.

We report a case of severe gastro-intestinal (G-I) graft-vs.-host disease (GVHD) successfully treated with intra-mesenteric artery steroid administration. A 29-year-old man with severe aplastic anemia (SAA) was submitted to HLA-identical unrelated allogeneic bone marrow transplantation (BMT) and was found to be suffering from grade IV G-I GVHD. Although cyclosporine, steroid pulse therapy, and FK506 proved ineffective, 30 mg of water-soluble prednisolone as administered into each the superior and inferior mesenteric artery with remarkable effects. This treatment was repeated two times, and the symptoms of G-I GVHD disappeared completely.

Adult↗
PubMed1997

Acute exacerbation of hepatitis due to reactivation of hepatitis B virus with mutations in the core region after chemotherapy for malignant lymphoma.

A 43-year-old Japanese man who was positive for hepatitis B surface (HBs) antigen and HB e antibody, underwent chemotherapy for non-Hodgkin's lymphoma. After the chemotherapy he suffered from acute exacerbation of hepatitis because of reactivation of HBV. Recovery was achieved with interferon-alpha, glucagon-insulin therapy, and plasma exchange. Mutations were detected in codons 97, 100, 129, and 131 of the core region of HBV. The peptide encoded from the core region including such mutations possibly had greater antigenicity to induce cytotoxic T cell activity in the host. Core region mutations may be a crucial cause of the acute exacerbation of hepatitis B seen after chemotherapy.

Acute Disease↗
PubMed1997

Long-term survival and differentiation of human peripheral blood CD34+ cells in SCID mice.

Human peripheral blood progenitor cells (PBPC) are currently used as a source of hematopoietic reconstitution by autologous transplantation after myeloabrative chemotherapy for malignancies. PBPC would also be useful for allogeneic transplantation since the collection of PBPC is much safer than that of bone marrow stem cells (BM). For allogeneic transplantation, it is imperative to confirm that PBPC contains self-renewable stem cells that can sustain a long lasting hematopoiesis. In the present study, we examined the reconstitution of human hematopoiesis in severe combined immunodeficiency (SCID) mice by transplanting peripheral blood CD34+ cells in which the neo gene was transduced as a marker. In 2 of 4 mice receiving PB-CD34+ cell transplantation, the neo gene appeared as early as 4 weeks and lasted as long as 24 weeks in all DNA preparations of bone marrow, peripheral blood and spleen cells from the SCID mice, while in 2 of 4 mice receiving BM-CD34+ cell transplantation, although the neo gene also lasted as late as 24 weeks, it did not appear as early as in the mice receiving PB-CD34+ cell transplantation. A similar observation was noted in clinical trials, i.e. the white blood cell and platelet recovered earlier by transplantation of PBPC than of BM. In mice who had the neo gene, we were also able to demonstrate by FACS the presence of human lineage specific antigen in the cells as late as 24 weeks after transplantation with PB-CD34+ cells, and the presence of human IgG in the sera 10 weeks after transplantation. These findings indicate that PB-CD34+ cells contain long-term repopulating stem cells which undergo differentiation in SCID mice.

Animals↗
PubMed1997

[Successful high-dose chemotherapy combined with autologous bone marrow transplantation in a case of refractory follicular lymphoma].

A 34-year-old patient with follicular lymphoma who was treated with CHOP followed by COPP for 3 years, became resistant to treatment in December 1993. Histological findings and surface markers of cervical lymph node cells revealed no change from previous findings. Tumor cell involvement of bone marrow was also observed by molecular analysis of DNA fragments with bcl-2 oncogene and J-H gene probes. Following 2 courses of salvage chemotherapy with NOAC-M regimen (novantrone, cytarabine and methylprednisolone), There was an 88% reduction of tumor mass on computed tomographic findings. Through the use of polymerase chain reaction analysis of residual cells with the bcl-2 translocation, we confirmed the in vivo purging of tumor cells from bone marrow and we harvested marrow cells for autologous transplantation. After high-dose chemotherapy (HDC) with ranimustine, cisplatin, etoposide and cyclophosphamide followed by bone marrow transplantation (BMT), complete remission was achieved. The patient has survived for 16 months and remains disease free. The standard chemotherapy regimen for advanced low grade non-Hodgkin's lymphoma has not yet been defined. Although we must follow this patient carefully to determine the effect of HDC with BMT for a long time, this seems to be an effective complementary treatment for patients responding to conventional salvage regimens.

Adult↗
PubMed1997

[A case of pure red cell aplasia accompanied with granular lymphocytic leukemia the tumor cells of which suppressed colony formation of BFU-E, and which was successfully treated by cyclophosphamide and cyclosporin A].

A 69-year-old woman with pure red cell aplasia and granular lymphocytic leukemia was reported. Because her granular lymphocyte count was in the normal range at the time of admission, we diagnosed the patient as primary pure red cell aplasia (PRCA). The granular lymphocyte count increased slowly, and we find monoclonal T cell receptor rearrangement, the case was diagnosed as granular lymphocytic leukemia accompanied with PRCA. Although single administration of cyclosporin or cyclophosphamide induced severe side effects obtained combined administration of low doses of these agents obtained good Hb increase. This case was granular lymphocytic leukemia with normal granular lymphocytic count at the time of diagnosis, the tumor cell suppressed BFU-E colony formation, and combined administration of low dose CPM and CyA yielded good effects.

Aged↗
PubMed1996

Hepatic iron deprivation prevents spontaneous development of fulminant hepatitis and liver cancer in Long-Evans Cinnamon rats.

Several clinical studies have suggested that excess hepatic iron accumulation is a progressive factor in some liver diseases including chronic viral hepatitis and hemochromatosis. However, it is not known whether iron-induced hepatotoxicity may be directly involved in hepatitis, cirrhosis, and liver cancer. The Long-Evans Cinnamon (LEC) rat, which accumulates excess copper in the liver as in patients with Wilson's disease, is of a mutant strain displaying spontaneous hemolysis, hepatitis, and liver cancer. We found previously that LEC rats harbored an additional abnormality: accumulation of as much iron as copper in the liver. In the present study, we compared the occurrence of hepatitis and liver cancer in LEC rats fed an iron-deficient diet (ID) with those in rats fed a regular diet (RD). The RD group showed rapid increments of hepatic iron concentrations as the result of hemolysis, characteristics of fulminant hepatitis showing apoptosis, and a 53% mortality rate. However, no rats in the ID group died of fulminant hepatitis. Hepatic iron, especially "free" iron concentration and the extent of hepatic fibrosis in the ID group were far less than those of the RD group. At week 65, all rats in the RD group developed liver cancer, whereas none did in the ID group. These results suggest that the accumulation of iron, possibly by virtue of synergistic radical formation with copper, plays an essential role in the development of fulminant hepatitis, hepatic fibrosis, and subsequent hepatocarcinogenesis in LEC rats.

Animals↗
PubMed1996

Transfection of glutathione S-transferase (GST)-pi antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan, and etoposide.

The goal of this study was to demonstrate that glutathione S-transferase (GST)-pi is directly involved in the intrinsic and acquired resistance of cancer cells to anticancer drugs. To this end, GST-pi antisense cDNA was transfected into the cultured human colon cancer cell line M7609, which expresses an innately high level of GST-pi and shows intrinsic drug resistance, and into an M7609 strain with acquired resistance to Adriamycin (ADR;i.e., M7609/ADR cells). The changes in the sensitivity of these transfectants to various anticancer drugs were investigated. The intracellular concentrations of GST-pi in M7609/anti-1 cells and M7609/anti-2 cells, two clones that were established by transfection of GST-pi antisense cDNA into M7609 cells, were decreased to approximately half of those detected in the parent cells (M7609) and in the control cells transfected with vector alone (M7609/pLJ). The sensitivities of the antisense transfectants in relation to ADR, cisplatin, melphalan, and etoposide were increased -3.3-fold, 2.3-fold, 2.2-fold, and 2.1-fold, respectively, compared with those of M7609 and M7609/pLJ. On the other hand, the sensitivities of the antisense transfectants to Taxol, vincristine, 5-fluorouracil, and mitomycin C were not significantly changed. Similarly, the transfection of antisense cDNA into M7609/ADR cells resulted in the reduction of intracellular GST-pi concentration (by about half) and an increased sensitivity to ADR (4.4-fold), but no increase in 5-fluorouracil sensitivity. Thus, GST-pi is considered to be a multidrug resistance factor that is responsible for both the intrinsic and acquired resistance of cancer cells to anticancer drugs such as ADR, cisplatin, melphalan, and etoposide.

Antineoplastic Agents↗
PubMed1996

[Gene therapy for cancer].

The strategies of gene therapy for cancer can be classified as: 1. regulation of oncogenes and anti-oncogenes, 2. immunogenetherapy, 3. support of chemotherapy, 4. suicide gene therapy, and 5. gene marking. The first one is the strategy to inhibit the expression of oncogenes by their antisenses or rhybozymes, or to introduce anti-oncogenes into those tumor cells with the inactivate effector cells (lymphocytes) by transducing cytokine genes, etc., followed by retransfering the gene-modified effector cells to patients (adoptive immunotherapy). The other one is to augment antigenicity of tumor cells. The immunogenetherapy method has been widely used for 70% of gene therapy of human cancer, because cells can be transduced ex vivo. The anti-tumor effects of human gene therapy using a GM-CSF gene by Muligan et al. or an IL-2 gene by Tahara and Lotze are expected. The third is the strategy to protect bone marrows from large dose of anti-cancer drug by transducing a multidrug resistance gene into those bone marrow cells or periphen blood stem cells, overcoming dose limiting of the drug. The fourth strategy is to transduce the herpes simplex virus thymidine kinase (KSV-TK) gene for activating the cytocydal prodrug (ganciclovir: GCV) into tumor cells in order to kill the tumor cells themselves following administration of GCV. At present, vectors most widely used for gene transduction are retroviruses and adenoviruses. However, the transduction using these vectors are primarily conducted ex vivo. The direct in vivo gene delivery method to target tumor cells are required.

Cytokines↗
PubMed1996

[CD7, HLA-DR, CD38 positive acute undifferentiated leukemia with subcutaneous tumor and thymoma].

A case of acute undifferentiated leukemia (AUL), accompanied by subcutaneous tumor and thymoma is reported. The analysis of immunophenotype showed that the leukemic blasts were positive for CD7, HLA-DR, CD38 and CD34 in 17.5% but negative results were obtained for other lymphoid and myeloid antigens. The leukemic blasts had a rearranged immunoglobulin heavy chain (IgH) gene and T cell receptor delta (TCR-delta) chain gene chromosomal abnormality, 47, XY, +8, t(13; 17) (q12; q21), -17, +M was observed. In general, the CR rate is low and prognosis is poor in patients with AUL. In our case, CR was not achieved by the therapy with JALSG-ALL87 protocol, but was achieved by subsequent treatment with high dose ara-C therapy and combination chemotherapy including intermediate-dose ara-C, mitoxantrone, etoposide and prednisolone.

ADP-ribosyl Cyclase↗
PubMed1995

Efficacy of TNF-alpha gene-transduced tumor cells in treatment of established in vivo tumor.

The therapeutic effect of TNF gene-transduced mouse fibrosarcoma cells (Meth-A: C5) on pre-inoculated parental cells (Meth-A: M0) was studied. Subcutaneous (s.c.) transplantation of M0 cells into one flank of syngeneic BALB/c mice was followed by s.c. injection of irradiated MO or C5 into the opposite flank 1 week later. The initial M0 tumor (T-MO) completely regressed in C5-vaccinated mice, whereas in M0-vaccinated mice continuous growth of T-M0 was observed. When a similar experiment was carried out in SCID mice, no regression of T-MO was observed, suggesting that the tumor regression in BALB/c mice was not due to direct anti-tumor activity of TNF secreted from C5, but to systemic immunity. Regression of the rechallenged M0 tumor was observed in mice which had shown T-MO regression by C5 vaccination, but rechallenged Colon 26 cells (syngeneic to BALB/c mice) continued to grow, indicating a specific immunity to Meth-A cells). The systemic immunity evoked in C5-vaccinated mice was directly demonstrated by enhanced killer activities of LAK and CTL with a proliferation of T-cell population in their splenocytes. Abrogation of the therapeutic effect of C5 vaccination with anti-Thy 1 and anti-Lyt 2 also demonstrates the involvement of cellular immunity in tumor regression.

Animals↗
PubMed1995

Combination therapy with recombinant human granulocyte colony-stimulating factor and erythropoietin in aplastic anemia.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) and erythropoietin (rhEPO) were used to treat patients with aplastic anemia (AA). In terms of effects on erythrocyte recovery, the combined use of rhG-CSF and rhEPO showed a favorable response in 6 of 14 (42.9%) patients with moderate AA following 10 weeks treatment and in 3 of 14 (21.4%) patients thereafter. However, the response was poor in patients with severe AA (3/13). A favorable response in severe AA was observed in 1 of 13 (7.7%) patients following 10 weeks treatment and in 2 of 13 (15.4%) patients thereafter. The overall effect on erythrocytes was observed in 44.4% patients. A dose of 400 micrograms/m2 G-CSF was sufficient to cause an increase in neutrophil count and 100 IU/kg rhEPO appeared to be sufficient to cause an increase in erythrocyte count. In 6 of 27 (22.2%) patients, a trilineage response was observed. Interestingly, a delayed and long-lasting effect was obtained in 5 of 27 (18.5%) patients. These results suggest that rhG-CSF can synergize with rhEPO in erythrocyte response, especially in patients with moderate AA.

Adult↗