RESUMEN
PURPOSE: To investigate the efficacy and safety of the novel orally active PI3Kδ inhibitor in relapsed and/or refractory patients with follicular lymphoma (FL) who had received at least two prior systemic treatments. PATIENTS AND METHODS: Histologically confirmed relapsed and/or refractory patients with FL with disease progression after receiving second-line or greater systemic therapy were enrolled. Linperlisib was administered at 80 mg every day, orally in a 28-day cycle until disease progression or intolerable toxicity occurred. The primary outcome for the study was the objective response rate (ORR), with secondary outcomes including the duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate, and drug safety profile. RESULTS: Of 114 screened relapsed and/or refractory patients with FL, 84 were enrolled in the full analysis set (FAS). The ORR of the 84 FAS patients was 79.8% [95% confidence interval (CI), 69.6-87.8, 67 patients], with 13 patients (15.5%) achieving a complete response and 54 patients (64.3%) with a partial response. The median DOR was 12.3 months (95% CI, 9.3-15.9). The median PFS was 13.4 months (95% CI, 11.1-16.7). The 12-month OS rate was 91.4% (95% CI, 82.7-95.8) and a median OS not reached by 42 months. The most frequent (>3%) treatment-related adverse events Grade ≥3 were infectious pneumonia (19.0%), neutropenia (15.5%), decreased lymphocyte count (4.8%), decreased leukocyte count (4.8%), increased lipase (3.6%), decreased platelet count (3.6%), hypertriglyceridemia (3.6%), and interstitial lung disease (3.6%). CONCLUSIONS: Linperlisib demonstrated compelling clinical activity and manageable tolerability for relapsed and/or refractory patients with FL who had received at least two prior systemic therapies.
Asunto(s)
Linfoma Folicular , Humanos , Linfoma Folicular/patología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Progresión de la Enfermedad , Resultado del TratamientoRESUMEN
YY-20394, a highly selective PI3Kδ inhibitor, is under NDA submission for treating follicular lymphoma in China. The absorption, metabolism, and excretion of YY-20394 were evaluated in healthy Chinese male subjects following a single oral dose of 80 mg [14C]YY-20394 (100 µCi).Within 264 h post-dose, 92.1% of the administered dose was recovered, with 58.1% from urine and 34.0% from faeces. YY-20394 was rapidly absorbed in humans, and the peak plasma concentrations occurred at 1.0 h. The absorbed drug fraction was at least 58.1% according to urine recovery.In addition to the parent drug, nine metabolites were identified in plasma, urine, and faeces. Unchanged YY-20394 was the predominant drug-related component in plasma (accounting for 68.4% of the total radioactivity), urine (accounting for 90.0% of the urinary radioactivity) and faeces (accounting for 41.7% of the faecal radioactivity). In humans, the major metabolic sites were the morphine ring and side chains of piperidine rings. The major metabolic pathways involved N-dealkylation, O-dealkylation, glucuronidation and acetylation.Overall, renal elimination played a significant role in the disposition of YY-20394, and the morphine ring and the side chain of the piperidine ring was the predominant metabolic sites.
Asunto(s)
Fosfatidilinositol 3-Quinasas , Inhibidores de Proteínas Quinasas , Administración Oral , Inhibidores de la Angiogénesis , Radioisótopos de Carbono/análisis , Heces/química , Humanos , Masculino , Derivados de la Morfina/análisis , Inhibidores de las Quinasa Fosfoinosítidos-3 , PiperidinasRESUMEN
YY-20394, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, was investigated in a first-in-human study of patients with relapsed or refractory B-cell malignancies. During dose escalation, 25 patients received 20-200 mg of YY-20394 daily. The primary outcome measures were tolerability and dose-limiting toxicity (DLT). The secondary outcomes were pharmacokinetic parameters, progression-free survival (PFS) and the objective response rate (ORR). Since no patients experienced DLT, the maximum tolerated dose (MTD) was not reached. The majority (≥ 5%) of drug-related adverse events were ≥ grade III, being neutropenia (44.0%), pneumonia (16.0%), hyperuricemia (12.0%), lymphocythemia (8.0%), leukopenia (8.0%) and pneumonitis (8.0%). The overall ORR was 64.0% (95% confidence interval (CI): 45.2, 82.8%) including 5 patients with complete remission (CR), 11 with partial remission (PR), 2 with stable disease (SD) and 7 with progressive disease (PD), while the disease control rate (DCR) was 72.0% (95% CI: 54.4, 89.6%). The ORR of 10 patients with follicular lymphoma was 90%. The median PFS time was 255 days. One PR patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received 40 mg q.d. had a durable response of around 36 months. The median PFS time of 10 patients with follicular lymphoma was 300 days. A recommended phase 2 dose of 80 mg q.d. was established. Considering that YY-20394 was well-tolerated with promising preliminary efficacy, further development is warranted.Trial registration clinicaltrials.gov, NCT03757000, retrospectively registered, November 28, 2018, https://clinicaltrials.gov/ct2/show/NCT03757000?term=NCT03757000&draw=2&rank=1 .
Asunto(s)
Linfoma de Células B/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B , Inhibidores de las Quinasa Fosfoinosítidos-3/efectos adversos , Resultado del TratamientoRESUMEN
Clinical trials of immunotherapy in mantle cell lymphoma have not yet delivered desirable results, partly because of the inhibitory machinery of the tumor and its microenvironment. Here we investigated the role of B7-H1, a member of the B7 family of co-stimulatory/co-inhibitory ligands, in mantle cell lymphoma-mediated immunosuppression. Allogeneic CD3(+), CD4(+) and CD8(+) T cells were purified and co-cultured with irradiated mantle cell lymphoma cells. Mantle cell lymphoma-reactive T-cell lines from HLA-A*0201(+) healthy blood donors were generated after in vitro restimulation, and were subjected to functional tests. We found that B7-H1 expressed on mantle cell lymphoma cells was able to inhibit T-cell proliferation induced by the tumor cells, impair the generation of antigen-specific T-cell responses, and render mantle cell lymphoma cells resistant to T-cell-mediated cytolysis. Blocking or knocking down B7-H1 on mantle cell lymphoma cells enhanced T-cell responses and restored tumor-cell sensitivity to T-cell-mediated killing in vitro and in vivo. Knocking down B7-H1 on mantle cell lymphoma cells primed more CD4(+) or CD8(+) memory effector T cells. Our study demonstrates for the first time that lymphoma cell-expressed B7-H1 may lead to the suppression of host anti-tumor immune responses in mantle cell lymphoma and targeting tumor cell B7-H1 may represent a novel approach to improve the efficacy of immunotherapy in patients with mantle cell lymphoma.
Asunto(s)
Antígeno B7-H1/biosíntesis , Regulación Neoplásica de la Expresión Génica , Tolerancia Inmunológica/fisiología , Linfoma de Células del Manto/metabolismo , Linfocitos T/metabolismo , Escape del Tumor/fisiología , Animales , Antígeno B7-H1/inmunología , Proliferación Celular , Técnicas de Cocultivo , Humanos , Linfoma de Células del Manto/inmunología , Ratones , Ratones SCID , Linfocitos T/inmunologíaRESUMEN
Graft-versus-host disease (GVHD) is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 (TLR4), which is a major receptor for bacterial lipopolysaccharides (LPS), in the development of acute GVHD, we used a TLR4-knockout (TLR4(-/-)) mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4(-/-) mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type (TLR4(+/+)) mice. In addition, histopathological analyses revealed that in TLR4(-/-)âBALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4(+/+), TLR4(-/-) mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4(-/-) mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 (Th1) development was obviously attenuated compared with TLR4(+/+) mice dendritic cells, and the levels of interferon-γ (IFN-γ) and IL-10, Th2-cell specific cytokines, were significantly higher in the serum of TLR4(-/-)âBALB/c than in TLR4(+/+)âBALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Receptor Toll-Like 4/deficiencia , Receptor Toll-Like 4/genética , Animales , Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Bazo/citología , Bazo/inmunología , Bazo/trasplante , Receptor Toll-Like 4/fisiología , Trasplante Homólogo/efectos adversosRESUMEN
Celastrol is a natural compound extracted from the traditional Chinese medicinal herb, Tripterygium wilfordii Hook. It has attracted interests for its potential anti-inflammatory and antitumor effects. However, the molecular mechanisms of celastrol-induced apoptosis in cancer cells remain unclear. In this study, we investigated the effects of celastrol on the human non-small-cell lung cancer (NSCLC) cell line A549 in vitro. Celastrol caused a dose- and time-dependent growth inhibition of A549 cells with an IC(50) of 2.12 µM at 48 h treatment. Celastrol induced A549 cells apoptosis as confirmed by annexin V/propidium iodide staining and DNA fragmentation. Celastrol-induced apoptosis was characterized by cleavage of caspase-9, caspase-8, caspase-3, and PARP protein, increased Fas and FasL expression, and a reduction in the mitochondrial membrane potential. Furthermore, celastrol induced the release of cytochrome c. Celastrol also up-regulated the expression of pro-apoptotic Bax, down-regulated anti-apoptotic Bcl-2, and inhibited Akt phosphorylation. These results demonstrate that celastrol can induce apoptosis of human NSCLC A549 cells through activation of both mitochondria- and FasL-mediated pathways.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Proteína Ligando Fas/genética , Mitocondrias/efectos de los fármacos , Triterpenos/farmacología , Receptor fas/genética , Anexina A5/análisis , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Caspasa 3/genética , Caspasa 3/metabolismo , Caspasa 8/genética , Caspasa 8/metabolismo , Caspasa 9/genética , Caspasa 9/metabolismo , Línea Celular Tumoral , Citocromos c/metabolismo , Fragmentación del ADN/efectos de los fármacos , Regulación hacia Abajo , Proteína Ligando Fas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Concentración 50 Inhibidora , Medicina Tradicional China , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/enzimología , Triterpenos Pentacíclicos , Propidio/análisis , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal , Regulación hacia Arriba , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo , Receptor fas/metabolismoRESUMEN
Multiple myeloma (MM) is an incurable B-cell malignancy characterized by accumulation of malignant plasma cells in the bone marrow and by recurrent or persistent infections. Toll-like receptors (TLRs) are essential in the host defense against infections. The aim of this study was to investigate TLR initiated responses in MM cells including proliferation, anti-apoptosis and immune escape. Myeloma cell lines gene transcription, cell cycle and protein expression were detected by RT-PCR, real-time PCR, western blot, ELISA and flow cytometry analysis. 3H-thymidine was used for measuring cell proliferation, and Annexin V-PI flow cytometry for the detection of cell apoptosis. We show that human myeloma cell lines expressed TLRsï¼and LPS induced the proliferation and partially protected MM.1S and ARP-1 cells from adriamycin-induced apoptosis. LPS appears to induce proliferation via MyD88 and MAPKs signaling. In addition, LPS treatment upregulated myeloma cell secretion of cytokine IL-18 and expression of immunoregulatory factors B7-H1, B7-H2 and CD40 mRNA and helped myeloma cells to escape immune surveillance. Our results show that TLRs are functional on myeloma tumor cells, and the ligands to these TLRs have a functional role in affecting myeloma cell proliferation, survival, and response to chemotherapy and immune attacks.
Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Receptor Toll-Like 4/inmunología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Dendríticas/inmunología , Humanos , Lipopolisacáridos/farmacología , Sistema de Señalización de MAP Quinasas , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Receptor Toll-Like 4/metabolismoRESUMEN
OBJECTIVE: To investigate the TLR4 signaling in multiple myeloma cell proliferation and apoptosis. METHODS: TLR4 gene transcription and protein expression were detected by RT-PCR and PE flow cytometry staining; the cells proliferation were detected by MTT assay; doxorubicin-induced apoptosis of cells was detected by AnnexinV-PI double staining flow cytometry. RESULT: TLR4 gene transcription and protein expression was detected in the myeloma cell lines. Under the lipopolysaccharides (LPS) stimulation, MM1-s cells TLR4 positive proliferation significantly increased (P<0.05), but not found in U266 cells TLR4 negative; MM1-s cells showed the resistance to doxorubisin-induced apoptosis, but LPS did not protect doxorubicin-induced U266 cell apoptosis. CONCLUSION: TLR4 signaling may play an important role both in multiple myeloma proliferation and survival.
Asunto(s)
Apoptosis/fisiología , Proliferación Celular , Mieloma Múltiple/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Línea Celular Tumoral , Humanos , Mieloma Múltiple/inmunología , Mieloma Múltiple/patologíaRESUMEN
PURPOSE: To evaluate the efficacy and toxicity of leucovorin (LV) plus 5-fluorouracil (5-FU) combined with oxaliplatin every 2 weeks on previously untreated advanced colorectal cancer patients in Chinese population. PATIENTS AND METHODS: Forty-nine patients were enrolled to receive, entirely as inpatients, 2-weekly cycles of oxaliplatin 85 mg/m2 i.v. over 2 hours on Day 1, together with leucovorin 200 mg/m2 over 2 hours, 5-FU 400 mg/m2, bolus, followed by a 22-hours infusion of 5-FU at 600 mg/m2 Days 1-2 (FOLFOX4) every 2 weeks. Treatment was given until progression or unmanageable toxicity. In all, 49 patients received ≥ 1 oxaliplatin dose and a median of 7 treatment cycles (range 1â¼27 cycles). RESULTS: Of the 45 eligible patients, 1 complete response (CR) and 18 partial responses (PRs) were observed for an overall response rate of 42.2 percent (95 percent confidence interval 26â¼56 percent). Median progression-free survival was 7.2 months (6.4â¼8.0) and median overall survival was 14.8 months (13.1â¼16.5). Six patients (12.2 percent) reported Grade 3â¼4 neutropenia. Thirty-one patients (62.3 percent) experienced Grade 1â¼3 neurotoxicity and only 5 patients (10.2 percent) experienced Grade 3 neurotoxicity. CONCLUSION: In our experience, FOLFOX4 regimen is active and well tolerated in patients with previously untreated advanced colorectal cancer in Chinese population.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , China , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , OxaliplatinoRESUMEN
OBJECTIVE: To assess the polymorphism of UGT1A gene in Chinese, and to investigate the correlation between UGT1A polymorphism and irinotecan toxicity in colorectal cancer patients. METHODS: 70 patients with advanced colorectal cancer were treated with irinotecan and 5-fluorouracil. Polymorphism analysis was performed in all those patients and 100 healthy subjects. Genomic DNA was extracted from peripheral blood and genotyped using polymerase chain reaction and direct sequencing. RESULTS: 14 patients exhibiting grade 3 - 4 neutropenia (20.0%), 16 patients experienced grade 2 - 4 diarrhea (22.9%), including only 4 patients with grade 3 - 4 diarrhea (5.7%). Compared with TA6/7 and TA7/7, UGT1 A1 * 28 wild genotype TA6/6 was significantly associated with reduced toxicity (42.1% vs. 15.7%, P = 0.027). There was no significant difference in the distribution of UGT1A genotypes between colorectal cancer patients and healthy subjects. CONCLUSION: Chinese patients exhibit less irinotecan-related diarrhea due to higher frequence of UGT1A A1 * 28 wild genotype TA6/6.
Asunto(s)
Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/análogos & derivados , Neoplasias Colorrectales/genética , Diarrea/inducido químicamente , Glucuronosiltransferasa/genética , Adulto , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pueblo Asiatico/genética , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Estudios de Casos y Controles , China , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Predisposición Genética a la Enfermedad , Genotipo , Glucuronosiltransferasa/metabolismo , Humanos , Irinotecán , Neutropenia/inducido químicamente , Polimorfismo Genético , Adulto JovenRESUMEN
OBJECTIVE: To investigate the expression of survivin mRNA in hematological malignancy cells and its correlation with HHT-induced cell apoptosis. METHODS: Hematological malignancy cell lines MUTZ-1, K562, Jurkat, RPMI and HL60 were treated with HHT in vitro. Cell apoptosis was observed by flow cytometry (FCM) and the expression of surviving and XIAP mRNA was evaluated with semi-quantitative RT-PCR. RESULT: The expression of survivin mRNA on cell lines was negatively correlated to HHT-induced cell apoptotic rate (r=-0.980, P=0.003). There were no significant differences in XIAP expression among these 5 cell lines. CONCLUSION: Survivin could be used as a new marker for drug-sensitivity and a new target for treatment of hematological malignancies.
Asunto(s)
Apoptosis/efectos de los fármacos , Harringtoninas/farmacología , Proteínas Asociadas a Microtúbulos/biosíntesis , Síndromes Mielodisplásicos/patología , Proteínas de Neoplasias/biosíntesis , Células HL-60 , Humanos , Proteínas Inhibidoras de la Apoptosis , Células K562 , Proteínas Asociadas a Microtúbulos/genética , Síndromes Mielodisplásicos/metabolismo , Proteínas de Neoplasias/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Survivin , Células Tumorales CultivadasRESUMEN
BACKGROUND: The inhibitor of apoptosis (IAP) gene family is involved in the suppression of apoptotic cell death as well as an increasing number of seemingly unrelated cellular functions. It is not known, however, whether IAP expression in malignant hematopoietic cells is affected by chemotherapeutic agents such as homoharringtonine (HHT). In this study, we investigated mRNA expression levels of IAPs, especially survivin, in various hematopoietic cell lines in relation with apoptosis induced by HHT. METHODS: Semiquantitative reverse transcriptase polymerase chain reaction was used to determine survivin mRNA levels. Cell apoptosis was examined by flow cytometry. Cell viability and proliferation assay was evaluated by MTT. The experiments were performed on the malignant hematopoietic cell lines MUTZ-1, K562, Jurkat, RMPI and HL60, with or without survivin antisense-oligodeoxynucleotides (AS-ODN) and HHT. RESULTS: The expression levels of survivin mRNA were variable in the cell lines and negatively correlated to HHT induced cell apoptosis. Survivin AS-ODN significantly decreased mRNA level of survivin, but not those of bax and bcl-2. Survivin also inhibited MUTZ-1 cell growth and induced apoptosis in a dose dependent manner. AS-ODN and HHT showed synergistic effect on MUTZ-1 cell growth. CONCLUSION: The apoptotic effect of HHT on the hematopoietic cell lines is associated with decreased level of survivin expression. Survivin could be a new marker for drug sensitivity and a new target for cancer treatment.
Asunto(s)
Anemia Refractaria con Exceso de Blastos/patología , Apoptosis/efectos de los fármacos , Harringtoninas/farmacología , Leucemia/patología , Proteínas Asociadas a Microtúbulos/genética , Anemia Refractaria con Exceso de Blastos/metabolismo , Ciclo Celular , Línea Celular , Homoharringtonina , Humanos , Proteínas Inhibidoras de la Apoptosis , Leucemia/metabolismo , Proteínas de Neoplasias , Oligonucleótidos Antisentido/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/genética , ARN Mensajero/análisis , Survivin , Proteína X Asociada a bcl-2RESUMEN
OBJECTIVE: To investigate the expression of apoptotic protein inhibitors, survivin and XIAP, in patients with myelodysplastic syndromes (MDS) and in the cell line MUTZ-1, as well as to explore the possible mechanisms of homoharringtonine (HHT) in the treatment of MDS. METHODS: Bone marrow samples from 47 patients with de novo MDS at diagnosis were examined and bone marrow samples from 15 normal donors were used as control. A MDS-RAEB cell line MUTZ-1 was used as in vitro model. Detection of apoptotic cells and cell cycle analysis were performed with flow cytometry (FACS). The expression of apoptotic protein inhibitor survivin and XIAP in the MDS cells were detected by RT-PCR technique. MUTZ-1 were treated with antisense oligodeoxynucleotide (AS-ODNs) of survivin and or HHT, the effects were evaluated by cell viability and cell apoptosis. RESULTS: Survivin mRNA positive rate in MDS were significantly higher than that in normal controls (38.3% and 0, respectively, P < 0.01), and the positive rate in high risk group (RAEB, RAEBT and CMML) was significantly higher than that in RA/RAS group (53.6% and 16.7%, respectively, P < 0.05). XIAP was expressed in all untreated MDS and healthy controls. XIAP mRNA expression in high risk group was significantly higher than that in RA/RAS subtypes and healthy controls (1.55 +/- 0.34, 0.74 +/- 0.24, and 1.01 +/- 0.28, respectively, P < 0.01). However, XIAP mRNA expression was significantly lower in RA/RAS subtypes than in healthy control (0.74 +/- 0.24 and 1.01 +/- 0.28, P < 0.054). Apoptosis peak detected by FACS analysis and positive Annexin V FITC staining on cell membrane indicated that HHT could induce MUTZ-1 cell undergoing apoptosis in dose- and time-dependent manners. Treatment of MUTZ-1 cells with HHT revealed that HHT could significantly down-regulate survivinexpression but had no significant effect on XIAP expression in the cells. AS-ODNs of survivin could inhibit MUTZ-1 cells growth, induce them to apoptosis and sensitize them to HHT. CONCLUSION: The expression levels of survivin; Institute of Hematology, Oncology and Tumor Immunology, Robert Roessle Clinic, Humboldt University, Berlin, Germany (Wolf Dieter Ludwig, Christian Wuchter) and XIAP vary in different subtypes of MDS patients, suggesting that the proteins may play an important role in the pathogenesis of the disease. Down-regulation of survivin in MUTZ-1 cells may be one of the mechanisms that HHT induces apoptosis of MDS cells.