TAC-101, a benzoic acid derivative, inhibits liver metastasis of human gastrointestinal cancer and prolongs the life-span

We examined the anti-tumor effect of a novel benzoic acid derivative, TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid) on models with liver metastasis. Oral administration of TAC-101 significantly inhibited spontaneous liver metastasis of AZ-521 (human gastric cancer ) by orthotopic implan-tation to athymic nude mice. It also inhibited both the liver metastasis of AZ-521 induced by intrasplenic injection and the secondary lung metastasis from the liver. In addition, TAC-101 inhibited the proliferation of Co-3 (human colon adenocarcinoma) that formed a single nodule in the liver of athymic nude mice by intrahepatic implantation. The growth inhibitory effect of TAC-101 on AZ-521 experimental liver metastasis was observed when treatment was started on day 7, 14, or 21 which may correspond to the progressive stage of liver metastasis in clinical settings. Multiple administration of TAC-101 (8 mg/kg/day) significantly prolonged survival time of the animals with liver met astasis by intrasplenic injection of AZ-521 (T/C = 230%) and A549 (human lung adenocarcinoma; T/C = 186%). These effects of TAC-101 were stronger than those of 5-FU, CDDP or ATRA. Furthermore, TAC-101 inhibited the binding of AP-1 to DNA on electrophoretic mobility shift assay using nuclear extract of AZ-521 cells, although ATRA did not inhibit. These findings suggested that TAC-101 may be a candidate for a new class of anti-cancer agents for liver metastasis. © Rapid Science Ltd.     

全反式维甲酸抑制Ets-1介导的肝癌7402细胞离散和侵袭及其分子机制

目的 研究全反式维甲酸(ATRA)对Ets介导的实体瘤细胞侵袭转移性的影响及探讨其分子机制,寻找新的抗癌药物作用靶点。方法 采用基因转染的方法,将Ets-1基因高表达在低侵袭转移的肝癌7402细胞中,使其增殖、离散侵袭能力增强,再经ATRA处理细胞,用细胞生物学方法检测细胞增殖性、肝癌细胞离散性及穿透Transwell聚碳酯膜能力的改变。并用Northern杂交、Western印迹等分子生物学手段检测ATRA的分子作用机制。结果 发现ATRA可抑制7402细胞因Ets-1高表达而增强的增殖、离散、侵袭性,可下调Ets、c-Met基因的表达,使MAPK、PI3K信号途径中两个关键分子 Erk/Akt的磷酸化水平降低。结论ATRA可能通过下调Ets基因的表达,进而使c-Met表达水平降低,导致MAPK、PI3K信号转导减弱而抑制肿瘤细胞增殖和侵袭;Ets基因可以作为抗癌药物作用的靶点来筛选药物或进行药理研究。     

亚砷酸、维甲酸联合小剂量化疗治疗骨髓增生异常综合征的临床疗效

目的分析亚砷酸联合维甲酸(ATRA)及小剂量化疗治疗骨髓增生异常综合征(MDS)的临床疗效。方法收集21例MDS患者，应用亚砷酸联合ATRA及小剂量化疗，观察其有效率及副作用的发生情况。结果治疗后，总有效率达76．2％，长期随访治疗8例，均保持持续缓解状态。未发现严重毒副作用。结论亚砷酸联合ATRA及小剂量化疗治疗MDS安全、有效。     

Respiratory failure during induction chemotherapy for acute myelomonocytic leukaemia (FAB M4Eo) with ara-C and all-trans retinoic acid

We report two cases of acute myeloid leukaemia FAB classification M4Eo with high white cell counts at presentation, who developed acute respiratory failure with pulmonary infiltrates on chest radiograph soon after commencing conventional cytotoxic chemotherapy plus all-trans retinoic acid (ATRA). We suggest that in patients with M4Eo ATRA should be used with caution, perhaps delaying its commencement until the white cell count is < 10 x 109/l.     

Inhibition of growth and induction of apoptosis by all-trans retinoic acid in lymphoid cell lines transfected with the PML/RARα fusion gene

The interaction of an exogenous PML/RARα fusion gene associated with acute promyelocytic leukaemia, with all- trans retinoic acid (ATRA) was examined in two lymphoid cell lines. L1210 and MOLT-4 cells were transfected with PML/RARα cDNA in the expression vector pGD and stable transformants (L1210 PML/RAR α and MOLT-4 PML/RAR α) were selected with G418. ATRA inhibited the growth of these stable transformants, as assessed by [³H]thymidine incorporation, in a dose-dependent manner, but had no effect on the growth of control cells stably transformed with neomycin resistant gene alone. ATRA also induced apoptosis, as assessed by fragmentation of genomic DNA, in L1210 PML/RAR α and MOLT-4 PML/RAR α cells but not in control cells. The exogenous PML/RARα fusion gene therefore probably mediates the effects of ATRA on cell growth and apoptosis in these cell lines.     

ERK is involved in the differentiation and function of dimethyl sulfoxide-induced HL-60 neutrophil-like cells,which mimic inflammatory neutrophils

Reports show that particulate matter (PM) is related to respiratory and cardiovascular diseases. We previously reported the biological effects of PM in vivo and the endocytosis of PM by primary neutrophils from mice. Cell lines can be used to elucidate the mechanism underlying immune responses in detail; however, information is limited regarding the functions of neutrophils after PM exposure. Here, we investigated the immune response of primary neutrophils and dimethyl sulfoxide (DMSO)- and all-trans retinoic acid (ATRA)-differentiated HL-60 (neutrophil-like) cells to PM. We showed that endocytosis by ATRA-HL cells was enhanced compared to that by DMSO-HL cells and that endocytosis in both cells was inhibited by dynamin inhibitors. A MEK inhibitor, but not p38 or JNK inhibitors, inhibited endocytosis. The MEK inhibitor also inhibited the differentiation of ATRA-HL cells to neutrophils. We identified that endocytosis of PM by neutrophils activated the MAPK ERK and p38 pathways. DMSO-HL and ATRA-HL cells both produced TNF-α and IL-8 after lipopolysaccharide (LPS) or PM treatment, whereas non-differentiated HL-60 cells did not. MCP-1 production was enhanced in DMSO-HL cells after LPS or PM treatment, whereas it was high in ATRA-HL cells. Reactive oxygen species (ROS) production was enhanced after PM treatment to DMSO-HL cells. Further, extracellular extracts promoted endocytosis. The MEK inhibitor also reduced the production of TNF-α, IL-8, and MCP-1. Taken together, ERK activation is key for both differentiation and endocytosis, and DMSO-HL cells at day 6 can serve as a model of inflammatory neutrophils, such as bronchus neutrophils, and a good tool to analyze the molecular events involved in immune responses to PM.     

Outcomes of high-risk acute promyelocytic leukemia patients treated with arsenic trioxide (ATO)/all trans retinoic acid (ATRA) based induction and consolidation without maintenance phase: A case Series

Patients with high-risk acute promyelocytic leukemia (APL) have inferior outcomes compared with patients with low-risk APL, predominantly due to higher risk of early mortality related to hemorrhage. The majority of regimens contain prolonged maintenance, but the impact of this phase is not clear in the era of all trans retinoic acid (ATRA) and arsenic trioxide (ATO). We present a retrospective analysis of 10 patients that were treated for high risk APL based on the consolidation treatment phase of APL 0406 study without subsequent maintenance. With a median follow up of 38 months, all patients remain in remission.     

Acute promyelocytic leukaemia with t(11;17)(q23;q12-21) and a good initial response to prolonged ATRA and combination chemotherapy

Acute myeloid leukaemia (AML) of FAB subtype M3 is associated with t(15;17)(q22;q21) and a relatively good prognosis when treated with all- trans retinoic acid (ATRA) and combination chemotherapy. Rarely, alternative balanced translocations have been described in this subtype of AML. The translocation t(11;17)(q23;q21) leading to a PLZF/RARα rearrangement has been described in a very small number of cases and has been associated with a poor response to ATRA and an adverse prognosis. We describe a case of AML FAB type M3 with this translocation who entered morphological and cytogenetic complete remission after concurrent prolonged ATRA and one course of induction chemotherapy and remains in morphological and molecular remission at 10 months after presentation. This diagnosis therefore may not always be associated with a poor initial response to treatment.     

Successful Aortic Valve Replacement Surgery in a Patient with Severe Haemophilia a with Low Titre Inhibitor

Acute leukemia, secondary myelodysplasia and paroxysmal nocturnal hemoglobinuria evolving from severe aplastic anemia (AA) following immunosuppressive therapy are well recognized. However, severe AA occurring after complete remission of acute promyelocytic leukemia (APL) has been documented only once in 2009. We report a case of 30-year-old male diagnosed with APL who achieved complete cytogenetic remission with all-trans retinoic acid based induction regimen and developed severe AA few months later during maintenance therapy.     

Tetraploidy acute promyelocytic leuemia with double t(15;17)/PML-RARA,a case report with review of literature

Acute promyelocytic leukemia (APL) with tetraploidy chromosome harboring t(15;17)(q23;a21) is extremely rare. To date, there are 14 such cases reports that describe this entity, mostly found in Eastern hemisphere. Herein we described a 51-year-old man with a diagnosis of tetraploid acute promyelocytic leukemia with double (15;17) translocations and compare the prototypically clinicopathologic, genetic and molecular findings with those reported in the literature.