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Arsenic trioxide therapy in acute promyelocytic leukemia and beyond: from bench to bedside 总被引:2,自引:0,他引:2
Arsenic trioxide (As2O3) has a long history of use in medicine. However, it was almost forgotten in Western medicine in the recent centuries. Prompted by reports from China about successful treatment of acute promyelocytic leukemia (APL) with As2O3, there was again increasing interest in this drug in the 1990s. This review summarizes the considerable knowledge about the mechanisms of action of As2O3 that was gained during the last 5 - 10 years. It is focused in particular on the effects of As2O3 in non-APL cells. Since As2O3 seems to induce apoptosis and inhibits growth in a large variety of cellular targets, it might become an alternative or adjunct drug to conventional chemotherapy. As2O3 can even be effective in cells resistant to conventional cytostatic agents. Insight into the cellular mechanisms, in particular the impact of the redox state on sensitivity towards As2O3 opens the possibility to enhance As2O3 effects by appropriate combination therapies. 相似文献
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背景与目的:近年来随着新型药物和免疫疗法的成功应用,多发性骨髓瘤(multiple myeloma,MM)患者的缓解率、缓解深度和无病生存率较以往显著提高,然而仍有相当一部分MM患者属于复发/难治性病例。我们的前期研究发现,环腺苷酸(cyclic adenosine monophosphate,cAMP)拟似物和三氧化二砷(arsenic trioxide,As2O3)可以抑制MM细胞增殖并诱导其凋亡,成为MM治疗的新途径。该研究进一步探究As2O3单独和联合环腺苷酸拟似物8-对氯苯硫基环腺苷酸[8-(4-chlorophenylthio) adenosine 3’, 5’-cyclic monophosphate,8-CPT-cAMP]对MM细胞的影响及可能作用机制。方法:以不同浓度As2O3和8-CPT-cAMP单独和联合处理MM细胞系U266细胞,采用细胞计数试剂盒(cell counting kit-8,CCK-8)检测其增殖,应用药物联合指数(combination index,CI)分析两药是否存在协同效应,同时采用流式细胞术检测细胞周期和凋亡率,进一步利用蛋白质印迹法(Western blot)检测细胞凋亡相关蛋白caspase-3和Bcl-2表达的变化。结果:U266细胞经As2O3和8-CPT-cAMP单独或联合处理72和120 h后,联合用药组细胞增殖抑制率分别为(18.01±0.13)%和(28.01±0.14)%,明显高于单独用药组[As2O3组为(11.35±0.01)%和(16.01±0.14)%,8-CPTcAMP组为(12.26±0.30)%和(15.43±0.23)%,P均<0.05];但两药联合处理U266细胞的CI值均大于1。联合用药组72和120 h后U266细胞凋亡率分别达到(22.26±0.13)%和(31.03±0.14)%,显著高于单药组[As2O3组为(10.06±0.01)%和(12.35±0.14)%,8-CPT-cAMP组为(13.26±0.30)%和(18.76±0.23)%,P均<0.05]。同时联合用药组U266细胞内caspase-3蛋白剪切活化和Bcl-2表达下降。结论:As2O3联合8-CPT-cAMP对MM细胞凋亡诱导效应强于单药,但无协同效应。 相似文献
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在急性早幼粒细胞白血病(APL)中,三氧化二砷(As2O3)有效诱导了APL细胞的凋亡,如果能避免早期死亡,多数患者可达到完全缓解和治愈。近几年,人们也研究了它对非APL白血病和多种实体瘤治疗的可能性。同时,越来越多的研究发现,它在体外或体内也抑制非APL白血病和几种实体瘤如肝癌、食管癌和胃癌等细胞的增殖。人们对非APL白血病和实体瘤中As2O3诱导细胞凋亡的机制也进行了研究。并且为取得更满意的疗效和减轻As2O3的细胞毒等副作用,人们对新型As2O3靶向制剂的研发也进行了探索。本文就上述有关研究进展进行综述。 相似文献
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Yoshimasa Nakamura Norihiko Kawamoto Yoshimi Ohto Koji Torikai Akira Murakami Hajime Ohigashi 《Cancer letters》1999,140(1-2):37-45
The inhibitory effects of the diacetylenic spiroketal enol ether epoxide AL-1 from Artemisia lactiflora on a variety of tumor promoter-induced biological responses such as oxidative stress as well as tumor promotion in ICR mouse skin were investigated. AL-1 inhibited TPA-induced intracellular peroxide formation in differentiated HL-60 cells, suggesting that this suppression might be attributable to the inhibition of O2− generation. In a double TPA application system in mouse skin, double pretreatments of AL-1 (810 nmol) significantly suppressed double TPA application-induced H2O2 generation. Pretreatment of AL-1 only before the second TPA treatment was sufficient to inhibit, while only with first treatment was not. From these results we concluded that AL-1 is a specific inhibitor of the activation phase in H2O2 production induced by double TPA treatments. In addition, AL-1 strongly inhibited tumor promoter-induced Epstein–Barr virus (EBV) activation in Raji cells (IC50=0.5 μM), which was comparable to or even stronger than that of curcumin, a well-known antioxidative chemopreventer from turmeric. In a two-stage carcinogenesis experiment with TPA (topical application at 1.6 nmol) and 7,12-dimethylbenz[a]anthracene (DMBA, at 0.19 μmol) in ICR mouse skin, topical application of AL-1 (at 160 nmol) significantly reduced tumor incidence, the numbers of tumors per mouse, and edema formation by 58% (P<0.01 in t-test), 20% (P<0.005 in χ2-test) and 42% (P<0.01), respectively. These results together indicate that an inhibitor of O2− generation is an effective chemopreventer of mouse skin carcinogenesis by their antioxidative property. 相似文献
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目的 探讨维生素C联合三氧化二砷(As2O3)对膀胱癌T-24细胞的影响及其机制。方法 体外培养T-24细胞,分为6组,对照组不做处理,实验组分别加入不同浓度的As2O3 (0.4、4、40 μg/ml)组,维生素C(400 μg/ml)组、维生素C(400 μg/ml)+ As2O3 (0.4 μg/ml)组(联合组),采用细胞增殖曲线检测T-24细胞生长差异情况,用流式细胞术检测细胞周期及凋亡率变化,RT-PCR、Western blot技术检测分析caspase-3、survivin mRNA及蛋白的表达情况。结果 联合组、维生素C(400 μg/ml)组、As2O3 (4 μg/ml)组及As2O3 (40 μg/ml)组均对膀胱癌T-24细胞增殖有显著抑制作用;联合组将细胞阻止在G0/G1期,且凋亡率显著高于其他五组(P<0.05);RT-PCR及Western blot结果显示,维生素C(400 μg/ml)组、联合组的caspase-3 mRNA和蛋白表达升高,survivin mRNA和蛋白表达降低。结论 维生素C联合As2O3 可抑制膀胱癌T-24细胞增殖,促进细胞凋亡,其机制可能与上调caspase-3 mRNA、蛋白,下调survivin mRNA、蛋白表达有关。 相似文献
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Arsenic trioxide (As2O3) has demonstrated effectiveness in treating acute promyelocytic leukemia (APL). Therefore the FDA has approved it to treat APL. In patients with refractory metastatic colorectal carcinoma (CRC), we assessed the efficacy and toxicity of As2O3/AA (ascorbic acid) as the outcome of this trial. Five patients with refractory metastatic CRC who failed all previous standard chemotherapy were enrolled in this study. They were treated with 0.25 mg/kg body weight/day As2O3 and 1000 mg/day of ascorbic acid for 5 days a week for 5 weeks. Each treatment cycle extended for 7 weeks with 5 weeks of treatment and 2 weeks of rest. All the patients developed moderate to severe toxic side effects to arsenic trioxide/AA therapy and therefore the study was discontinued. No CR (complete remission) or PR (partial remission) was observed. CT scans demonstrated stable or progressive disease. Three of the five patients died within 2 to 5 months after cessation of the therapy. None of the deaths could be related to this clinical trial. Two years of follow-up study showed that two patients were alive with stable disease. Under the current treatment regimen all patients developed moderate to severe side effects with no clinically measurable activity. As an alternate, efforts may be made to reduce the dose and arsenic trioxide may be combined with other standard regimen in reversing the chemo resistance. 相似文献
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Strupp C Germing U Aivado M Kündgen A Fenk R Hünerlitürkoglu A Kobbe G Haas R Gattermann N 《Leukemia & lymphoma》2005,46(7):999-1006
Thalidomide is thought to have anti-angiogenic and immunomodulatory properties, including suppression of tumor necrosis factor-alpha, effects on interleukins and interferons, down-regulation of some cell adhesion molecules, and changes in the proportion of lymphocyte subsets. It is unclear whether the clinical response to thalidomide in patients with multiple myeloma (MM), idiopathic myelofibrosis (IM), and myelodysplastic syndromes (MDS) is related to its ability to inhibit angiogenesis or its immunomodulatory effects. We examined the effect of thalidomide on T-lymphocyte subsets in 18 patients with MDS, 6 patients with MM, 4 patients with IM, and 3 patients with angioimmunoblastic lymphoma (AILD). These patients had either a relapse or progressive disease following cytotoxic chemotherapy including high-dose chemotherapy with autologous stem cell support. Thalidomide was first administered at 100 mg/day p.o. and increased to 400 mg/day. T-lymphocyte subsets (CD4 + , CD8 + ) were measured by fluorescence-activated cell sorter (FACS) before and during treatment with thalidomide. Twenty-six of 31 patients responded to thalidomide, most of them achieving partial remission. The median concentration of CD4 + cells was 443/μl, the median of CD8 + cells was 359/μl (CD3 992/μl). In our cohort, no significant changes in absolute numbers or proportions of CD3 + (P = 0.12), CD4 + (P = 0.668), or CD8 + (P = 0.143) cells were observed following the treatment with thalidomide. Although the CD4/CD8 ratio declined from 1.6 to 1.0 during 3 months of thalidomide treatment, this had no statistical significance (P = 0.1). Our findings show that an effect of thalidomide on the T lymphocytes studied is unlikely to be of major importance for the clinical effects. 相似文献
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There are at present disparate published results with regard to the relevance of the Bcl-2 gene family, levels of apoptosis, and cell proliferation in the development and progression of renal cell carcinoma (RCC). The present study analyses the inter-relationship between the expression of representatives of the anti-apoptotic (Bcl-2, Bcl-XL) or pro-apoptotic (Bax) Bcl-2 proteins, incidence of apoptosis, and mitosis in a selected small group of 22 graded RCCs that had paired normal renal tissue, or non-neoplastic tissue in the renal biopsy specimen. The cases were chosen to determine the feasibility of measuring these parameters as potential surrogate markers of progression or treatment failure of the cancers. The results showed that in approximately 50% of the RCCs, where Bcl-2 and/or Bcl-XL expression was high, apoptosis was not detected, and when expression of these proteins was low or not found, increased levels of apoptosis were seen. In most of the remaining 50% of samples, high levels of Bcl-XL but not Bcl-2 were negatively correlated with low levels of apoptosis (Bcl-XL: r=-0.437, P=0.07 and Bcl-2: r=+0.560, P=0.02). For the same group of samples, high Bax expression was found in association with apoptosis (r=+0.578, P=0.02). A novel finding was an association between low expression of Bcl-2 and/or Bcl-XL in normal tissue and the level of expression of these proteins in the RCCs, an intrinsic variation that may be an individual patient factor. The results indicate that, in RCCs with increased expression of Bcl-2 and/or Bcl-XL, levels of apoptosis are minimal and these combined factors may assist in progression of the cancers and resistance to treatments. 相似文献
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The effects of arsenic trioxide (As2O3) on human megakaryocytic leukemia cell lines. With a comparison of its effects on other cell lineages 总被引:1,自引:0,他引:1
Arsenic trioxide (As2O3) has been demonstrated to be effective for the treatment of acute promyelocytic leukemia (APL) and to inhibit proliferation and produce apoptosis in the APL cell line NB4. The effect of this newly utilized chemotherapeutic agent on other lineages is currently under study to evaluate its efficacy for the treatment of other human malignancies and myeloproliferative syndromes. A recent study described the effects of As2O3 upon viability, proliferation, and induction of apoptosis in four different megakaryocytic leukemia cell lines. At pharmacological concentrations (0.5-2 microM) As2O3 selectively inhibits growth and causes apoptosis in the megakaryocytic leukemia cell lines HEL, Meg-01, UT7 and M07e. Pertinently, these concentrations of As2O3 resulted in identical changes in the characteristics of the APL cell line NB4, suggesting that As2O3 could produce its effects in both cellular lineages via a common mechanism of action. Various mechanisms have been proposed for the As2O3-induced changes in NB4 (including modulation of promyelocytic leukemia proteins (PML) and Bcl-2, modification of the glutathione redox system, caspase activation, and cell cycle arrest) and are currently under investigation in the megakaryocytic leukemia cell lines. Recent preliminary results indicate that As2O3 downregulates Bcl-2 expression and induces cell cycle arrest in megakaryocytic cell lines. The use of As2O3 for the treatment of malignant megakaryocytic disorders also has been considered. The in vitro effects of As2O3 on a chronic megakaryocytic proliferative disorder. i.e., Essential Thrombocythemia (ET), have been analyzed and megakaryocyte progenitors have shown an unexpectedly higher resistance to As2O3, in comparison to normal megakaryocyte colony-forming cells. The effects of As2O3 on ET and other megakaryocytic disorders need to be fully examined, in order to determine the clinical efficacy of As2O3 in the treatment of syndromes affecting the megakaryocytic lineage. 相似文献
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Defensins are 20 - 30 amino acid-long, cystine- and arginine-rich peptides that constitute more than 5% of the total cellular proteins in mature granulocytes and at least 30% of proteins in primary granules. Human defensins were reported to have antimicrobial, antifungal, antiviral and tumor lysis activities. Defensin mRNA was isolated using the differential display technique from the well-characterized all-trans retinoic acid (ATRA)-responsive acute promyelocytic leukemia cell line, NB4. The differential display analysis showed an up-regulation of defensin mRNA in NB4 cells after treatment with 10 - 7 M ATRA for 24 h. This expression was not seen in an NB4:R2 cell line, an ATRA-resistant subclone of NB4 cells. In order to investigate further the effects of this gene on our cellular model, we virally infected our cells with full-length defensin cDNA in the sense and antisense directions. Sense defensin induced cell growth arrest and cell death in both cell lines. While NB4 cells died within 48 - 73 h, NB4:R2 cells survived for 96 h before dying in culture. Phenotypic analysis showed high expression of Annexin V in sense-infected cells compared with antisense and uninfected cells in both cell lines. There was not a significant increase in CD11b expression in any of the 2 cell lines used. No cellular response was encountered in antisense-infected cells. Our data suggest that defensin is not only a reliable marker for granulocytic differentiation, but can also be considered a candidate target for molecular therapy in acute promyelocytic leukemia. 相似文献
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三氧化二砷(As2O3)是中药砒霜的主要成分,最初被用于治疗血液系统疾病.近年研究发现,其对多种实体瘤也有良好疗效,其中对胃癌疗效显著.研究证实,As2O3可以抑制胃癌细胞增殖及转移,诱导胃癌细胞凋亡和保护性自噬,抑制胃癌淋巴管和新生血管形成,影响胃癌细胞内端粒相关蛋白的表达. 相似文献
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SP600125 is a specific inhibitor of c-Jun N-terminal kinase (JNK) that is known to strongly induce apoptosis and block cell cycle progression in G2/M phase. In this study, we demonstrated that treatment of U937 cells with SP600125 resulted in significant G2/M cell cycle arrest that was due to decreased cyclin B1 and cdc25c protein levels. Moreover, SP600125 promoted LDH release and DNA fragmentation that was associated with caspase-3 activation and degradation of its substrates. In contrast, overexpression of the antiapoptotic protein Bcl-2 rendered leukemia cells resistant to SP600125-induced apoptosis, but more sensitive to G2/M phase arrest and endoreduplication (>4N DNA). Overexpression of Bcl-2 significantly inhibited SP600125-induced caspase-3 activation and degradation of its substrates, and sustained expression levels of the IAP-2 proteins following SP600125 treatment. The inhibitory effect of Bcl-2 on apoptosis was attenuated by treatment with the small molecule Bcl-2 inhibitor, HA14-1. These data provide important mechanistic insights related to Bcl-2-mediated resistance to SP600125-induced apoptosis, and induction of G2/M phase arrest and endoreduplication. 相似文献
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Pentostatin is a purine nucleoside analog with demonstrated activity in low-grade lymphoid malignancies. The purpose of this study was to determine the dose of pentostatin (dCF) that could be combined with chlorambucil and prednisone to treat chronic lymphocytic leukemia (CLL), evaluate the toxicity of the resulting regimen and to estimate its efficacy. This was a multi-institutional Eastern Cooperative Oncology Group (ECOG) phase I - II study. Individuals with active B-CLL were eligible if they had no prior treatment or were in sensitive first relapse, provided they had normal renal and hepatic function. Pentostatin was evaluated in combination with orally administered chlorambucil 30 mg/m2 and prednisone 80 mg/day, 1 - 5 of each 14-day cycle. The pentostatin dose was 2 mg/m2 IV, day 1 for the first 6 patients; 3 mg/m2 IV, day 1 for the next 6 patients; and 4 mg/m2 IV, day 1 for the last set of 6 patients. Fifty-five patients were entered. Because of increasing toxicity with no apparent improvement in clinical efficacy on escalation of the pentostatin dose, 2 mg/m2 was chosen as the phase II dose, and 43 patients were treated at this level. Thirty-nine of these patients were eligible, of which 38 were evaluable for response, 36 of these 38 had no prior treatment. Complete response (CR) manifested by normal bone marrow morphology, peripheral blood counts and resolution of any lymphadenopathy or hepatosplenomegaly occurred in 17 patients (45%). The overall objective response rate was 87%. The median response duration was 33 months and the median survival 5 years. The median time to treatment failure is 32 months. Severe (Grade 3 + ) infections were seen in 31% of patients and included bacterial pneumonia (n = 4), Pneumocystis pneumonia (n = 1), fungal pneumonia (n = 2), urinary tract infection with sepsis (n = 1) and Herpes Zoster (n = 5). Overall, 11 patients had H. Zoster while on study. Due to toxicity, 33% of patients stopped therapy. Pentostatin, chlorambucil and prednisone is a highly active regimen in CLL but cannot be recommended in present form because of an unacceptable incidence of opportunistic infections. These findings add to other recent reports which suggest combination therapy with pentostatin and alkylators are active in B-CLL. However, these combination chemotherapies will need to be combined with appropriate addition of anti-bacterial and anti-viral prophylaxis to reduce infection risk for B-CLL patients. 相似文献
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The ability of a [111In]bleomycin complex ([111In]BLMC) to kill five cell lines of human lung cancer (small cell lung cancer) was investigated. Cells were exposed to either 0.9% NaC1, [111In]C13, BLM, [111In]BLMC, nonradioactive InC13, or In-BLMC for 60 minutes, plated in soft agarose, and assessed for colony formation. [111In]BLMC (40-200 μ;C) carried by 15-25 μ;g BLM/ml) was more cytotoxic than BLM (15-25 μ;g BLM/ml) by a factor of 1.6-5.3 for five cell lines. The percent survival of N417 cells was 28.4 for [111In]BLMC (40 μ;Ci/15 μ;g BLM/ml) and 54.3 for BLM (15 μ;g/ml); 1.9 for [111In]BLMC (200 μ;Ci/25 μ;g BLM/ml), and 10.0 for BLM (25 μ;g/ml). 111InC13 (200 μ;Ci/ml) and nonradioactive InC13 failed to inhibit colony formation. The new [111In]BLMC may be useful for therapy of some lung cancer patients. 相似文献
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K Kinjo M Kizaki A Muto Y Fukuchi A Umezawa K Yamato T Nishihara J Hata M Ito Y Ueyama Y Ikeda 《Leukemia》2000,14(3):431-438
Recent clinical studies in China and USA showed that arsenic trioxide (As2O3) is an effective treatment of acute promyelocytic leukemia (APL) patients refractory to all-trans retinoic acid (RA). We here investigate the effects of As2O3 on RA-resistant APL in vivo and in vitro using our RA-resistant APL model system. As2O3 can induce inhibition of cellular growth of both RA-sensitive NB4 and RA-resistant UF-1 APL cells via induction of apoptosis in vitro. The expression of BCL-2 protein decreased in a dose- and time-dependent manner in NB4 cells. Interestingly, the levels of BCL-2 protein were not modulated by As2O3, but it did upregulate BAX protein in UF-1 cells. UF-1 cells (1x10(7)) were transplanted into hGM-CSF-producing transgenic SCID mice and successfully formed subcutaneous tumors. After 40 days of implantation, mice were treated with As2O3, all-trans RA and PBS for 21 days. In all-trans RA- and PBS-treated mice, tumors grew rapidly, with a 4.5-fold increase in volume at day 21 compared to the initial size. In marked contrast, tumor size was decreased to half of the initial size by the treatment of As2O3, which resulted in cells with the typical appearance of apoptosis. Interestingly, one of the As2O3-treated mice showed mature granulocytes in the diminished tumor, suggesting that As2O3 had dual effects on RA-resistant APL cells in vivo: both inducing apoptosis and differentiation of the leukemic cells. We conclude that our RA-resistant APL model will be useful for evaluating novel therapeutic approaches to patients with RA-resistant APL, and for further investigation of the metabolism of As2O3 in vivo. 相似文献
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Enhancement of sensitivity by bestatin of acute promyelocytic leukemia NB4 cells to all-trans retinoic acid 总被引:3,自引:0,他引:3
All-trans retinoic acid (ATRA) induces the differentiation of acute promyelocytic leukemia (APL) cells into neutrophils. We found that bestatin, an inhibitor of CD13/aminopeptidase N, enhanced the sensitivity of APL NB4 cells to ATRA at concentrations of 0.1–1000 ng/ml. A structurally different aminopeptidase N inhibitor, actinonin, also increased the effect of ATRA on differentiation, but an inactive stereoisomer of bestatin, (2R,3S)-AHPA-(R)-Leu, did not. Bestatin synergistically enhanced the cytostatic effect of ATRA on NB4 cells. Masking of the cell-surface CD13 by anti-CD13 antibody WM15 blocked the synergistic effect of bestatin and ATRA on differentiation. Thus bestatin, an immunomodulator clinically used for nonlymphocytic leukemia, synergistically increased the ATRA-induced differentiation of NB4 cells by inhibiting CD13/aminopeptidase N on the cell-surface. 相似文献
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