[Show abstract][Hide abstract] ABSTRACT: The effects of all-trans retinoic acid (ATRA) and valproic acid (VPA), alone and in combination, on the human acute promyelocytic leukemia (APL) cell line NB4 were investigated in view of differentiation induction and growth inhibition. After 48 h of treatment, not only ATRA but also VPA induced differentiation in NB4 cells, and their combination further augmented the differentiation activity. Furthermore, the upregulation of transcription factors including CCAAT/enhancer-binding proteins (CEBPα, β, ε) and PU.1, which are known to be critical factors for normal myelopoiesis, granulocytic maturation and being repressed in APL, concurred with the differentiation induction. A significant cell growth inhibition was observed after the treatment with VPA, which was further strengthened by the addition of ATRA. Given the importance of C/EBPs and PU.1 in myeloid development, these results, thus, suggest that restoration of the normal function of the myeloid cell transcriptional machinery is a major molecular mechanism underlying the differentiation induction in NB4. Therefore, these results may provide novel insights into a possible combinational therapeutic approach for APL patients.
International Journal of Oncology 12/2013; · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A close correlation between the cytocidal effects of arsenic trioxide (ATO) and aquaporin-9 (AQP9) expression levels has been proposed, yet detailed studies are still needed to confirm this association. Thus, in the present study, the correlation between the expression levels of AQP9 and sensitivity to ATO was investigated using two acute promyelocytic leukemia (APL) cell lines, NB4 and HT93A, as well as primary APL cells from newly diagnosed and relapsed APL patients. A substantially higher sensitivity to ATO-mediated induction of apoptosis was observed in the NB4 cells when compared to that in the HT93A cells. In addition, markedly higher expression levels of AQP9, as assessed using flow cytometry, along with more intracellular arsenic accumulation, were observed in the NB4 cells. More importantly, similar to APL cell lines, the trend of expression levels of AQP9 correlated closely with the differential sensitivity to ATO-mediated induction of apoptosis in primary APL cells. In contrast, no correlation was observed between ATO sensitivity associated with AQP9 expression levels and the expression profiles of cell surface markers as well as chromosomal alterations. These results provide direct evidence that the expression levels of AQP9, rather than other biomarkers such as cell surface markers and chromosomal alterations, correlate closely with the sensitivity to ATO in both APL cell lines and primary blasts. These findings suggest that the AQP9 expression status of APL patients is a predictive marker for the successful outcome of ATO treatment, since AQP9 plays a pivotal role in various arsenite-mediated biological effects on normal and cancer cells. Moreover, flow cytometry may be a new convenient and valuable tool for analyzing the AQP9 status of APL patients compared to current methods such as western blotting.
[Show abstract][Hide abstract] ABSTRACT: The effects of arsenic trioxide (ATO), all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF), alone or in combination, were investigated by focusing on differentiation, growth inhibition and arsenic uptake in the acute promyelocytic leukemia (APL) cell line HT93A. ATO induced differentiation at low concentrations (0.125 µM) and apoptosis at high concentrations (1-2 µM). Furthermore, ATRA induced greater differentiation than ATO. No synergistic effect of ATRA and ATO was found on differentiation. G-CSF promoted differentiation-inducing activities of both ATO and ATRA. The combination of ATRA and G-CSF showed maximum differentiation and ATO addition was not beneficial. Addition of 1 µM ATRA and/or 50 ng/ml G-CSF to ATO did not affect apoptosis compared to ATO treatment alone. ATRA induced expression of aquaporin-9 (AQP9), a transmembrane transporter recognized as a major pathway of arsenic uptake, in a time- and dose-dependent manner. However, treatment with 1 µM ATRA decreased arsenic uptake by 43.7% compared to control subject. Although G-CSF addition did not enhance AQP9 expression in the cells, the reduced arsenic uptake was recovered to the same level as that in controls. ATRA decreased cell viability and addition of 50 ng/ml G-CSF to ATRA significantly increased the number of viable cells compared with that in ATRA alone treated cells. G-CSF not only promotes differentiation-inducing activities of both ATRA and ATO, but also makes APL cells vulnerable to increased arsenic uptake. These observations provide new insights into combination therapy using these three agents for the treatment of APL.
[Show abstract][Hide abstract] ABSTRACT: This book looks at the latest research studies on apoptosis in medicine. It is divided into three sections for convenient and easy reading. The first section which comprises two chapters is an introduction of the subject of apoptosis to the uninitiated. The second section which comprises a single solitary chapter looks at apoptosis in normal physiology during bone resorption under mechanical stress. The third and the final section reviews apoptosis in a number of pathological conditions with an emphasis on cancer.
edited by Tobias M. Ntuli, 08/2012; IntechOpen., ISBN: 978-953-51-0701-9
[Show abstract][Hide abstract] ABSTRACT: Speciation of arsenic trioxide (ATO) metabolites in clinical samples such as peripheral blood (PB) from acute promyelocytic leukemia (APL) patients has been conducted. However, speciation of arsenicals in bone marrow (BM) has not yet been performed. Profiles of arsenic speciation in plasma of BM were thus investigated and compared with those of PB plasma from a relapsed APL patient. The total arsenic concentrations in high molecular weight fraction (HMW-F) of BM and PB plasma were also determined.
Response assessment was evaluated by BM aspirate examination and fluorescence in situ hybridization analysis. The analyses of total arsenic concentrations and speciation were preformed by inductively coupled plasma mass spectrometry (ICP-MS), and high-performance liquid chromatography (HPLC)/ICP-MS, respectively.
Response assessment showed that the patient achieved complete remission. The total arsenic concentrations in BM plasma increased with time during the consecutive administration. The PB plasma concentrations of methylated arsenic metabolites substantially increased after the start of administration, while those of inorganic arsenic were still kept at a low level, followed by substantially increase from day-14 after administration. The arsenic speciation profiles of PB plasma were very similar to those of BM plasma. Furthermore, the total arsenic concentrations of HMW-F in BM plasma were much higher than those in PB plasma.
The behaviors of arsenic speciation suggested for the first time that arsenic speciation analysis of PB plasma could be predicative for BM speciation, and showed relatively higher efficiency of drug metabolism in the patient. These results may further provide not only significance of clinical application of ATO, but also a new insight into host defense mechanisms in APL patients undergoing ATO treatment, since HMW proteins-bound arsenic complex could be thought to protect BM from the attack of free arsenic species.
[Show abstract][Hide abstract] ABSTRACT: Arsenic trioxide (arsenite, As(III)) has shown a remarkable clinical efficacy, whereas its side effects are still a serious concern. Therefore, it is critical to understand the effects of As(III) on human-derived normal cells for revealing the mechanisms underlying these side effects. We examined the effects of As(III) on primary cultured chorion (C) and amnion (A) cells prepared from human fetal membranes. A significant dose-dependent As(III)-mediated cytotoxicity was observed in the C-cells accompanied with an increase of lactate dehydrogenase (LDH) release. Higher concentrations of As(III) were required for the A-cells to show cytotoxicity and LDH release, suggesting that the C-cells were more sensitive to As(III) than the A-cells. The expression levels of aquaporin 9 (AQP9) were approximately 2 times higher in the C-cells than those in the A-cells. Both intracellular arsenic accumulation and its cytotoxicity in the C-cells were significantly abrogated by sorbitol, a competitive AQP9 inhibitor, in a dose-dependent manner. The protein expression levels of multidrug resistance-associated protein (MRP) 2 were downregulated by As(III) in the C-cells, but not in the A-cells. No significant differences in the expression levels of MRP1 were observed between C- and A-cells. The protein expression of P-glycoprotein (P-gp) was hardly detected in both cells, although a detectable amount of its mRNA was observed. Cyclosporine A, a broad-spectrum inhibitor for ABC transporters, and MK571, a MRP inhibitor, but not PGP-4008, a P-gp specific inhibitor, potently sensitized both cells to As(III)-mediated cytotoxicity. These results suggest that AQP9 and MRP2 are involved in controlling arsenic accumulation in these normal cells, which then contribute to differential sensitivity to As(III) cytotoxicity between these cells.
Toxicology and Applied Pharmacology 09/2011; 257(2):198-208. · 3.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 56-year-old man presented to our hospital with a pelvic mass. The tumor was diagnosed to occur from right seminal vesicle and to be a benign solitary fibrous tumor by transrectal tumor biopsy. The tumor enlarged during follow up, and he under-went resection of the tumor.
[Show abstract][Hide abstract] ABSTRACT: Introduction: We retrospectively reviewed and compared the operation records and long-term results of patients with metastatic renal cell carcinoma (mRCC) who underwent laparoscopic cytoreductive nephrectomy and those who underwent open procedure.Methods: A total of 75 patients with mRCC who underwent cytoreductive nephrectomy between 1997 and 2007 were studied: 23 patients in the laparoscopy group (LCN group) and 52 in the open group (OCN group). Most patients received interferon-based cytokine therapy after surgery. Patients with tumor thrombus in the inferior vena cava were excluded from this study.Results: Operating time in the LCN group was significantly longer than in the OCN group (320.3 min vs 269.6 min, P=0.049). Blood loss was less in the LCN group (527.8 ml) than in the OCN group (1372.3 ml, P=0.072). Convalescence was shorter in the LCN group (18.1 d) than in the OCN group (32.9 d, P<0.0001). Median follow-up periods were 15 months (range 2–110 months) and 17 months (range 1–103 months) in the LCN group and OCN group, respectively. There was no statistically significant difference between the two groups with regard to disease-specific patient survival and progression-free survival.Conclusions: Laparoscopic cytoreductive nephrectomy is a feasible alternative for patients with mRCC because its benefits include less blood loss and shorter convalescence. In addition, the long-term oncological results of laparoscopic cytoreductive nephrectomy are comparable to those of the open procedure.
Asian Journal of Endoscopic Surgery 01/2010; 3(3):140-144.
[Show abstract][Hide abstract] ABSTRACT: We assessed concentrations of arsenic trioxide (As(2)O(3)) and its metabolites in the plasma and cerebrospinal fluid in acute promyelocytic leukemia patients who achieved complete remission with intravenous As(2)O(3). Arsenic trioxide exists as high molecular mass proteins and low molecular mass proteins in the plasma, and metabolites seem to be able to penetrate blood-brain barrier. Methylarsonic acid (MA) in the cerebrospinal fluid is stably detected and its level was higher than that in plasma after As(2)O(3) treatment. Trivalent arsenic (AS(III)) and dimethylarsinic acid (DMA) became detectable after As(2)O(3) infusion, though the levels of arsenic metabolites in the cerebrospinal fluid was lower than plasma levels. Results suggest that a combinatory treatment of As(2)O(3) with other chemotherapeutics could be effective for APL patients with CNS involvement.
Leukemia research 10/2009; 34(3):403-5. · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 42-year-old female presented with right back pain. The CT scan revealed a 72-mm space-occupying lesion in the middle portion of the right kidney. No metastasis was proven. She underwent laparoscopic radical nephrectomy and lymph node disection. The histopathological examination revealed a high-grade primitive small round tumor the cells of which were strongly positive for CD99 and vimentin. Fluorescence in situ hybridization analysis using a DNA probe for the Ewing sarcoma breakpoint region 1 (EWSR 1) on chromosome 22g12 revealed a rearrangement of the EWSR 1 locus. The diagnosis was Ewing's sarcoma / primitive neuroectodermal tumor of the kidney. She underwent 13 cycles of chemotherapy, and has no evidence of recurrence 19 months after surgery.
[Show abstract][Hide abstract] ABSTRACT: Arsenic trioxide (As(2)O(3)) has been widely accepted as the second-best choice for the treatment of relapsed and refractory acute promyelocytic leukemia (APL) patients. However, a few studies have been conducted on a detailed speciation of As(2)O(3) metabolites in blood samples of patients. To clarify the speciation of arsenic, the blood samples were collected at various time points from a patient with APL after remission induction therapy and during consolidation therapy. The total amounts of arsenic in blood cells and plasma, and the plasma concentrations of inorganic arsenic and methylated metabolites were determined by inductively coupled plasma mass spectrometry (ICP-MS) and high-performance liquid chromatography/ICP-MS, respectively. The total amounts of arsenic in the blood cells were 4-10 times higher than those in plasma. Among all arsenic metabolites, the pentavalent arsenate (As(V)) in plasma was more readily eliminated. During the drug-withdrawal period, the initial plasma concentrations of trivalent arsenic (As(III)) declined more rapidly than those of methylarsonic acid and dimethlyarsinic acid, which are known as the major methylated metabolites of As(III). On the other hand, during the consecutive administration in the consolidation therapy period, the plasma concentrations of total arsenic and arsenic metabolites increased with time. In conclusion, these results may support the idea that methylated metabolites of As(2)O(3) contribute to the efficacy of arsenic in APL patients. These results also suggest that detailed studies on the pharmacokinetics as well as the pharmacodynamics of As(2)O(3) in the blood cells from APL patients should be carried out to provide an effective treatment protocol.
Analytical and Bioanalytical Chemistry 12/2008; 393(2):689-97. · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study was made to present our experience and results with transperitoneal laparoscopic-assisted renal biopsy (LARB) in Nagoya University Hospital as a good alternative for open renal biopsy.
21 patients (14 male, 7 female, mean age 58 years, range 21-83 years) were unsuitable for percutaneous renal biopsy. Therefore, they underwent laparoscopic-assisted renal biopsy. The kidney was approached transperitoneally via three ports, cortical tissue was obtained using a 16-gauge gun-mounted semiautomatic biopsy needle. Hemostasis was obtained by applying pressure on the renal puncture using gauze until bleeding had been stopped (range 5-20 min).
Adequate cortical tissue and accurate diagnoses were obtained in all patients. Mean operative time was 83 min (range 65-120 min) and mean estimated blood loss was 5.5 ml (range 1-10 ml). There were no intraoperative complications: no open conversion, blood transfusions or gross hematuria. All patients walked about freely and could tolerate regular food on the first postoperative day. The only postoperative complication was a hernia formation at the place of trocar insertion 3 months after the operation in one patient who previously underwent multiple surgery for 3 arterial grafts and appendicitis.
LARB is a safe and accurate procedure for obtaining cortical biopsies with minimal blood loss. Although LARB remains a surgical procedure which requires general anesthesia, LARB to date may be considered as a good alternative to open renal biopsy for patients in whom a closed percutaneous approach is either a relative or absolute contraindication.