CAG regimen for refractory or relapsed adult T-cell acute lymphoblastic leukemia: A retrospective, multicenter, cohort study.

Adult patients with relapsed or refractory T-cell acute lymphoblastic leukemia (R/R-T-ALL) have extremely poor prognosis, representing an urgent unmet medical need. Finding an optimal salvage regimen to bridge transplantation is a priority. The CAG (cytarabine, aclarubicin, and G-CSF) regimen was initially used by one group in China, showing unexpectedly promising results in 11 R/R-T-ALL patients. Here, we report the multicenter results of 41 patients who received the CAG regimen as salvage therapy. After one cycle of the CAG regimen, complete remission and partial remission were achieved in 33 (80.5%) and two (4.9%) patients, respectively. Failure to respond was observed in six patients (14.6%). Early T-cell precursor (ETP) (n = 26) and non-ETP (n = 15) patients had a similar CR rate (80.8% vs 80.0%, P = .95). Among 41 patients, allo-HSCT was successfully performed in 27 (66%) patients (22 in CR and 5 in non-CR). With a median follow-up time of 12 months, the estimated 2-year overall survival and event-free survival were 68.8% (95% CI, 47.3%-83.0%) and 56.5% (95% CI, 37.1%-71.9%), respectively. The CAG regimen was well-tolerated, and no early death occurred. Our multicenter results show that the CAG regimen is highly effective and safe, representing a novel choice for adult patients with R/R-T-ALL and providing a better bridge to transplantation.

[Prognostic significance of EBMT score system for hematological malignancies with allogeneic hematopoietic stem cell transplantation].

OBJECTIVE: To evaluate the impact of EBMT score system in patients with hematological malignancies received allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 144 consecutive patients were analyzed retrospectively. According to the EBMT score system, including age, disease status before transplantation, interval between diagnoses to transplantation, donor/recipient sex match and donor type, patients were divided into 3 risk groups: low risk (score 0-1), intermediate risk (score 2-3) and high risk (score 4-7). RESULTS: The median follow-up duration were 413 (10-1827) days for all patients and 837 (166-1827) days for alive patients. The estimated 4-year overall survival (OS), transplant-related mortality (TRM) and relapse rate (RR) were (57.5±4.6)%, (21.6±3.7)% and (42.7±6.1)%, respectively. The 4-year OS, TRM and RR were (72.2±9.0)%, (8.1±4.5)% and (27.3±8.7)% in the low-risk group, significantly superior to both intermediate-risk group [(57.7±6.0)%, (23.1±5.1)% and (44.9±8.3)%] and high-risk group [(36.9±10.2)%, (33.5±9.2)% and (51.5±11.8)%] (P<0.01, 0.02 and 0.009 for OS, TRM and RR respectively). CONCLUSION: The EBMT score system provides prognostic significance for OS, TRM and RR in patients with hematological malignancies received allo-HSCT.

Targeting poly (ADP-ribose) polymerase partially contributes to bufalin-induced cell death in multiple myeloma cells.

Despite recent pharmaceutical advancements in therapeutic drugs, multiple myeloma (MM) remains an incurable disease. Recently, ploy(ADP-ribose) polymerase 1 (PARP1) has been shown as a potentially promising target for MM therapy. A previous report suggested bufalin, a component of traditional Chinese medicine ("Chan Su"), might target PARP1. However, this hypothesis has not been verified. We here showed that bufalin could inhibit PARP1 activity in vitro and reduce DNA-damage-induced poly(ADP-ribosyl)ation in MM cells. Molecular docking analysis revealed that the active site of bufalin interaction is within the catalytic domain of PAPR1. Thus, PARP1 is a putative target of bufalin. Furthermore, we showed, for the first time that the proliferation of MM cell lines (NCI-H929, U266, RPMI8226 and MM.1S) and primary CD138(+) MM cells could be inhibited by bufalin, mainly via apoptosis and G2-M phase cell cycle arrest. MM cell apoptosis was confirmed by apoptotic cell morphology, Annexin-V positive cells, and the caspase3 activation. We further evaluated the role of PARP1 in bufalin-induced apoptosis, discovering that PARP1 overexpression partially suppressed bufalin-induced cell death. Moreover, bufalin can act as chemosensitizer to enhance the cell growth-inhibitory effects of topotecan, camptothecin, etoposide and vorinostat in MM cells. Collectively, our data suggest that bufalin is a novel PARP1 inhibitor and a potentially promising therapeutic agent against MM alone or in combination with other drugs.

[Allogeneic peripheral blood stem cell transplantation from sibling donors for 10 patients with multiple myeloma].

OBJECTIVE: To evaluate the efficacy of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from sibling donors for treatment of multiple myeloma (MM). METHODS: Ten patients with MM received allo-PBSCT with conditioning consisting of fludarabine plus melphalan and cyclophosphamide mostly.CsA plus mycophenolate mofetil (MMF) and short-term MTX were applied to prevent graft versus host disease (GVHD) in 8 patients, FK506 plus short-term MTX in other 2 patients. RESULTS: All patients engrafted successfully, the median time for ANC > 0.5 × 10(9)/L was 16 (12 - 24) days, and for BPC > 20 × 10(9)/L 23 (16 - 102) days. Five patients developed acute GVHD, and only one III-IV aGVHD. Of 9 patients, 7 developed chronic GVHD. The transplant-related mortality (TRM) at 100 days was 10% (1/10), mainly from heart and renal failure and severe infection. The 1-year expected overall survival (OS), 1-year disease-free survival (DFS) and relapse rate were 67.5%, 55.56% and 11.11% respectively. Up to now, 6 patients were still alive, of them 1 patient have survived over 99 months after allo-PBSCT. CONCLUSION: Young MM patients having HLA-identical sibling donors well tolerated allo-PBSCT based on fludarabine to prolong their OS by reducing TRM, though further work is warranted.

[Treatment options and prognosis in newly diagnosed multiple myeloma patients].

OBJECTIVE: To explore the effect of treatment option on the response and outcomes in multiple myeloma (MM) patients suitable for autologous hematopoietic stem cell transplantation (auto-HSCT). METHODS: A total of 71 newly-diagnosed MM patients less than 65 years admitted to RuiJin Hospital from June 2005 to December 2009 were analyzed retrospectively. Among them, 21 received auto-HSCT (HSCT group) with standard conditioning of melphalan 200 mg/m(2), 30 received conventional chemotherapy (conventional group) and 20 received Bortezomib-based therapy (Bortezomib group). The responses and outcomes of different treatments were analyzed. RESULTS: The median follow-up duration for all patients was 18 (1 - 58) months with estimated 3-year overall survival (3-yr OS) of (79.8 ± 6.3)% and progression-free survival (3-yr PFS) of (54.8 ± 9.0)%. Thirty-four patients achieved complete remission (CR) or very good partial remission (VGPR) on induction therapy, which were 80% for the Bortezomib group, 33.3% for the conventional group and 38.3% for the HSCT group. After auto-HSCT the CR + VGPR rate was increased to 76.1% for the HSCT group. Overall, the 3-yr PFS was (26.3 ± 13.8)% (median 21 months), (40.5 ± 20.1)% (median 25 months) and (93.8 ± 6.1)%(median not reached, P = 0.025) for conventional, Bortezomib and HSCT groups respectively. Univariate analysis demonstrated that CR/VGPR after induction (P = 0.020), best response of CR/VGPR (P < 0.01), autoHSCT (P = 0.002) and maintenance therapy after CR/VGPR (P = 0.0005) were associated with improved PFS and that CR/VGPR after induction (P = 0.009), best response with CR/VGPR (P < 0.01), maintenance therapy for any patients (P = 0.035) and maintenance therapy for patients with CR/VGPR (P = 0.031) were associated with OS. In multivariate analysis, only auto-HSCT (P = 0.039) and best response of CR/VGPR (P = 0.009) were independent prognostic factors for PFS and the best response of CR/VGPR was the only independent prognostic factor for OS (P = 0.005). The estimated 3-yr OS was (62.4 ± 13.7)%, (94.1 ± 5.7)% and (87.9 ± 8.3)% respectively for 3 groups. CONCLUSIONS: For newly-diagnosed MM younger than 65 are suitable for auto-HSCT, the best response of CR/VGPR was associated with OS and PFS. Auto-HSCT is also important prognostic factor for PFS. Induction therapy with Bortezomib can achieve rapid CR/VGPR while auto-HSCT as a crucial consolidation therapy and maintenance therapy maybe also important for improvement of long-term outcome.

Intravenous busulfan-cyclophosphamide as a preparative regimen before allogeneic hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia.

The use of i.v. busulfan (BU) instead of the oral formulation can improve outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) by reducing toxicity and transplantation-related mortality (TRM). There are limited reports of i.v. BU used to treat patients with acute lymphoblastic leukemia (ALL). The present study was performed to evaluate the efficacy and toxicity of i.v. BU/cyclophosphamide (CY) conditioning in adult ALL. We retrospectively analyzed 42 consecutive patients who underwent allo-HSCT with BU/CY conditioning between January 2007 and October 2010 with an HLA-matched donor (sibling, n = 18; unrelated, n = 24). Thirty-three patients were in first complete remission (CR1), 2 were in second complete remission (CR2), and 7 were in a more advanced stage. Median patient age was 28 years (range, 17∼55 years). The median follow-up was 15 months (range, 1∼48 months). Overall, 13 patients died, for a 30-month overall survival of 56.5% ± 10.6% (65.7% ± 12.5% for patients in CR1 vs 25.4% ± 15.5% for those in CR2 or beyond; P < .001). Eleven patients experienced relapse between 2 and 26 months after allo-HSCT, with a 30-month relapse rate (RR) of 40% ± 10.9% (32.0% ± 12.7% for patients in CR1 vs 71.4% ± 17.1% for those in CR2 or beyond; P = .001). The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 39.2% ± 8.8%, and that of grade III-IV acute GVHD was 7.4% ± 4.1%. The incidence of chronic GVHD was 63.9% ± 11.7%, and that of extensive chronic GVHD was 19.3% ± 7.9%. Only 2 cases of clinically diagnosed veno-occlusive disease (VOD) were documented (4.7%), and 1 of these patients died of severe VOD. Other BU/CY conditioning-associated toxicities were diffuse alveolar hemorrhage in 1 patient and hemorrhagic cystitis in 8 patients. Four patients died due to TRM, for a 30-month TRM of 9.7% ± 4.6%. This study demonstrates that i.v. BU/CY can be considered a feasible conditioning regimen for adult ALL, with low incidences of VOD and TRM.

[The impact of autologous stem cell transplantation on the prognosis in multiple myeloma].

OBJECTIVE: To evaluate the efficacy of autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) and its impact on the prognosis of MM. METHODS: Retrospective analysis was performed in 28 patients with MM (group A) treated with ASCT in our hospital from October 1998 to February 2007, compared with those not received ASCT in the same time period including 23 patients with near complete response (nCR) or better (group B) and 25 patients with partial response (PR) (group C). The duration of response (DOR), time to progression (TTP) and overall survival (OS) were compared by Kaplan-Meier method in the 3 groups. RESULTS: Eight patients without nCR or better (7 in PR and 1 in MR) after ASCT achieved CR (2 cases) and nCR (5 cases). Complete response (CR) rate was 10.7% (3 cases) and 42.9% (12 cases) before and after ASCT respectively in group A. DOR was 33 months for group A, 17 months for group B and 18 months for group C, and TTP was 45, 43 and 28 months respectively. After a median follow-up of 30 months, patients in group A and in group B had a trenel of longer OS than in group C although there was no statistically significant difference. CONCLUSIONS: ASCT can further enhance the response, prolong the DOR and TTP and probably OS, and therefore improve the quality of life in MM. MM patients not achieved good response by non-ASCT therapy may benefit from ASCT.

[Detection of serum free light chain and its clinical significance in nonsecretory multiple myeloma].

OBJECTIVE: To explore the clinical significance of serum free light chain (sFLC) levels in nonsecretory multiple myeloma (NSMM). METHODS: Nine NSMM patients were hospitalized in our department from Feb 2002 to Sep 2006 and no M-components was found in their serum and urine by immunofixation electrophoresis (IFE). sFLC was assayed by immuno-nephelometry. The clonality of sFLC was estimated by serum kappa:lambda sFLC ratio. Meanwhile, serum immunoglobulin, total kappa and lambda light chain level were also determined in these patients. RESULTS: Increased serum concentrations of either kappa or lambda sFLC (and abnormal kappa/lambda ratios) were detected in 6 of 9 patients with NSMM although their serum immunoglobulin levels were not elevated and total kappa:lambda light chain ratios (1.32 - 2.20) were in the reference range. All the 9 patients had clonal IgH gene rearrangements. CONCLUSION: Quantification of sFLC by immuno-nephelometry is more sensitive than that of serum total light chain measurement and is helpful in estimating the clonality of the light chain in patients with NSMM.

[Bortezomib-based combination therapy for relapsed or refractory multiple myeloma].

OBJECTIVES: To investigate the efficacy and toxicity of bortezomib based combination therapy for Chinese patients with relapsed or refractory multiple myeloma (MM), and to determine the combination regimen, dosage and cycles in application of bortezomib for MM therapy. METHODS: Forty-six patients with refractory or relapsed myeloma were treated with bortezomib (1.3 mg/m2) as an intravenous bolus twice weekly for 2 weeks on day 1, 4, 8, and 11 in a 3-4 week cycle, in combination with dexamethasone, dexamethasone plus thalidomide, CD (C-cytoxan, D-dexamethasone), MD (M-mitoxsnteone), DCEP (E-etoposide, P-platinol), and DT-PACE regimens (T-thalidomide, A-adriamycin). Response to bortezomib was evaluated according to the criteria of the International Myeloma Working Group (IMWG) before initiation of each cycle. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0. Forty-nine matched patients with relapsed and refractory MM who received thalidomide based combination therapy were used as a historical control group. RESULTS: Among 43 of the 46 patients whom could be evaluated, the overall response rate was 72.1% (the control group was 51.0%, P < 0. 05), including complete response in 5 patients (11.6%), very good partial response in 12 patients (27.9%), and partial response in 14 patients (32.6%). The overall response rate after one and two cycles was 30.2% and 58.1% (P < 0.05), respectively. The frequent adverse events were thrombocytopenia (62.8%), fatigue (55.8%), nausea (51.2%) and peripheral neuropathy (30.2%); all of the events could be tolerated. The most common adverse event in the control group was constipation( 69.4%), followed by fatigue (59.2%) and dizziness (46.9%). CONCLUSIONS: Bortezomib based combination therapy is a new effective therapy in relapsed or refractory myeloma patients with a higher response rate and different toxicities as compared with thalidomide based combinations.

[Efficacy of thalidomide combined dexamethasone on newly diagnosed multiple myeloma].

BACKGROUND & OBJECTIVE: Thalidomide is effective in treating refractory and relapsed multiple myeloma (MM). However, the efficacy of thalidomide in induction therapy for newly diagnosed MM remains unknown. This study was to evaluate the efficacy of thalidomide combined dexamethasone (TD induction regimen) on previously untreated MM, and observe the adverse events. METHODS: Thirty-nine patients with newly diagnosed MM received oral administration of thalidomide at a dose of 100-300 mg/day continuously and dexamethasone at a dose of 20-40 mg/day on Days 1-4, 9-12, 17-20 in odd months and on Days 1-4 in even months. TD regimen was repeated every 28 days. Thirty-six MM patients who received VAD regimen (vindesine, adriamycin, and dexamethasone) was regarded as a historical matched controls. The efficacy, survival time and adverse events were compared between the two groups. RESULTS: The overall response rates were 71.8% in TD group and 61.1% in VAD group (P>0.05). The median progression-free survival was 14 months in TD group and 9 months in VAD group (P>0.05). Within a median follow-up of 13 months (range, 1-30 months), median overall survival (OS) was not reached in TD group, and was 29 months in VAD group. The most common adverse events (always not higher than grade 2) were constipation, fatigue, dizziness and somnolence in TD group. More grade 3-4 adverse events, included leucopenia and thrombocytopenia, and higher infection rate were observed in VAD group as compared with those in TD group (P<0.05). CONCLUSIONS: The combination of thalidomide and dexamethasone is an effective induction regimen for newly diagnosed MM. It may be considered as a replacement of VAD regimen.

Prognostic factors and staging systems of multiple myeloma:.

BACKGROUND: Previous studies found a range of prognostic factors but no consensus about the proper staging system for multiple myeloma has been achieved. This study explored the prognostic factors to find a staging system for multiple myeloma most suitable for Chinese patients. METHODS: Between February 1990 to August 2004, 206 patients (138 men and 68 women, mean aged (59 +/- 11) years) who were initially diagnosed as multiple myeloma in Changzheng Hospital (Shanghai, China) and had followup records were enrolled in this study. Potential prognostic factors were evaluated by univariate and multivariate analyses. Four staging systems were applied to compare their suitability for the patients. RESULTS: The median survival time of the patients was 33 months. The 1-, 3- and 5-year survival rates were 80.18%, 48.08% and 33.7% respectively. Factors identified as adversely affecting survival were older age, severe bone lesions, low haemoglobin, low platelet, low serum calcium, low serum albumin, high proportion of plasma cells in marrow, high serum creatinine, high serum beta(2) microglobulin and high C-reactive protein. Among these, only C-reactive protein, beta(2) microglobulin, albumin and age were the independent prognostic factors. There were statistically significant survival differences among the three groups in Durie Salmon staging system and Bataille staging system, but not in British Medical Research Council staging system or International Staging System. CONCLUSIONS: High beta(2) microglobulin, high C-reactive protein, low albumin and old age are independent prognostic factors of multiple myeloma. Bataille staging system appears to be optimal for Chinese multiple myeloma patients.

[Clinical features of multiple myeloma patients with extramedullary disease: a report of 40 cases from a single center].

OBJECTIVE: To analyze the clinical and laboratory features and risk factors of multiple myeloma (MM) with extramedullary disease (EM) and its extraosseous localizations at diagnosis and during the course of MM. METHODS: The clinical features, survival rate and prognostic factors were retrospectively analyzed in 40 patients having EM from a total of 418 MM patients hospitalized in Changzheng Hospital from 1993 to 2006. RESULTS: Among the 40 patients, the first three localizations of EM involved soft tissue, pleura or peritoneum and central nervous system (CNS). Median duration of follow-up was 30 months. The median overall survival (OS) was 28 months. Twenty-five patients (6%) were found to have EM at diagnosis (group A), and their median OS was 16 months and 15 patients (3.6%) developed EM during the course of the disease (group B), and their expected median OS was 72 months. There was a significant difference between group A and B (P = 0.0045) for OS. Compared with those in group A, patients in group B had a higher percentage of plasmacytes (P = 0.022) and plasmablasts (P = 0.029) in bone marrow, and less advanced stage for international staging system (ISS) (P = 0.027). Log-rank univariate analysis showed that higher CRP level, higher serum LDH, Stage II and III for ISS, Hb < 110 g/L at diagnosis were poor prognostic factors. However, multivariate analysis with COX model showed none of them were statistically significant. CONCLUSION: EM tumors are not a rare manifestation of MM. Soft tissue in the commonest area involved. Higher serum CRP and LDH level, more advanced stage for ISS, anemia and having EM are poor prognostic factors of MM.

[Prognostic analysis and assessment on the clinical staging systems of multiple myeloma--a report of 206 cases].

BACKGROUND & OBJECTIVE: Multiple myeloma (MM) is a heterogeneous disease of plasma cell tumor with poor prognosis. This study was to explore the prognostic factors of MM in China, and find the most suitable clinical staging systems. METHODS: Univariate and multivariate analyses were carried out on 18 clinical and laboratory indexes from 206 MM patients. These MM patients were classified according to 4 staging systems to compare their survival status. RESULTS: Of the 206 patients, 138 were men and 68 were women, with median age of 59 years (ranged 27-90 years) and median survival time of 33 months. The 2-and 5-year survival rates were 64.7% and 33.7%. Univariate analysis identified 10 prognostic factors: age, the amount of bone marrow plasma cells, hemoglobin, platelet count, adjusted serum calcium, albumin, creatinine, beta2 microglobulin, C-reactive protein, and skeletal disease stage. Multivariate analysis showed that C-reactive protein, beta2 microglobulin, albumin, age were independent prognostic factors. Significant differences of survival period existed among the 3 groups classified according to Durie Salmon staging system and Bataille staging system as well as between group I and group II of International staging system. However, no significant difference was found among the 3 groups classified according to British Medical Research Council staging system and between group II and group III of International staging system. CONCLUSIONS: High level of C-reactive protein, high level of beta2 microglobulin, low level of albumin and old age are correlated to poor prognosis. Durie Salmon staging system and Bataille staging system are suitable for Chinese MM patients.

[Bortezomib in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma].

OBJECTIVE: To investigate the efficacy and toxicity of bortezomib in combination with dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma(MM). METHODS: Sixteen patients(9 males, 7 females, mean age 57. 5 yrs) with refractory or relapsed MM were treated with bortezomib (1. 3 mg/m(2) ) by intravenous bolus twice a week for 2 weeks, or 3. 5 mg once a week in a 21-day cycle, followed by an intravenous injection of dexamethasone 30 - 40 mg. The patients had received one to four courses at least. Response to bortezomib was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT) before initiation of each bortezomib chemotherapy course. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3. 0. RESULTS: The median follow-up duration from the beginning of bortezomib treatment was 6 months. Clinical response was observed in 14 patients (87.5%), including near complete response in 6, partial response in 5, minimal response in 3 and no response in 2. The most common adverse events were gastrointestinal symptoms (nausea and vomiting in 12, constipation in 3, severe diarrhea in 3 patients), thrombocytopenia (8 patients) and fatigue(3 patients). The adverse events were subsided on routine supportive care. CONCLUSIONS: Bortezomib in combination with dexamethasone is an effective therapy with a high response rate and manageable toxicities for patients with relapsed or refractory myeloma.

[The effect of cyclin D2 shRNA on the proliferation and apoptosis of LP-1 cell].

OBJECTIVE: To construct cyclin D2 (CCND2) short hairpin RNA ( shRNA) plasmid for repressing the expression of CCND2 in human myeloma cell line LP-1,and to detect its effect on the proliferation and apoptosis of LP-1 cell. METHODS: A CCND2 shRNA model was constructed and cloned into plasmid pGensil-2, then the plasmid was transfected into LP-1 cell in vitro. The CCND2 expression cell proliferation, cell cycle and cell apoptosis of the transfected LP-1 cells were studied by RT-PCR, trypanosome staining, flow cytometry and annexin V assay. RESULTS: The transfection efficiency of LP-1 cell was 34. 2%. In the transfected LP-1 cell CCND2 mRNA expression was reduced significantly, the cell growth was inhibited significantly and the cell cycle was partly arrested in G, phase. The apoptosis rate of the transfected LP-1 cell after 72 h was (25.7+/-4.8)%. CONCLUSION: The inhibition of CCND2 in LP-1 cells could inhibit the cell growth and induce cell apoptosis. CCND2 maybe a new therapeutic target.

[Detection of IgH-MMSET fusion gene in multiple myeloma patients and its significance].

OBJECTIVE: To detect the IgH-MMSET fusion gene resulted from t (4;14) translocation in multiple myeloma and illuminate its significance. METHODS: IgH-MMSET fusion gene was detected in bone marrow specimens of 25 multiple myeloma (MM) patients and MM cell line NCI-H929 using reverse-transcription PCR (RT-PCR) assay followed by nested PCR to increase the sensitivity. The purified PCR products were cloned into pGEM-T vector and then sequenced using M13 forward primers. The fragment sequences were compared with that in GenBank to find matched sequences. RESULTS: Only a 438 base pair long fragment was obtained after RT-PCR assay and was confirmed by sequencing to be a fusion gene product of IgH gene and MMSET gene in MM cell line NCI-H929. The breakpoints were located within the C micro region of IgH gene on chromosome 14 and intron 3 of MMSET gene on chromosome 4. IgH-MMSET hybrid transcripts were detected in 3 of 25 MM patients through nested PCR assay. The amplified fragments of the 3 patients were 237 base pairs (bp), 239 bp and 239 bp in length, respectively. The breakpoints on chromosome 4 were identical to that of NCI-H929 cell. CONCLUSIONS: The formation of IgH-MMSET fusion gene is resulted from t (4;14) translocation in MM. The incidence rate is 12.0%. The presence of IgH-MMSET fusion gene may predict poor prognosis.

[Mechanism of arsenic trioxide-induced cytotoxicity on multiple myeloma cells].

BACKGROUND & OBJECTIVE: Multiple myeloma (MM), a plasma cell tumor, is difficult to cure by now. Previous study showed that As2O3 could inhibit the proliferation and induce the apoptosis of myeloma cell in vitro. The aim of this study was to explore the possible mechanism of arsenic trioxide (As2O3) on multiple myeloma cells. METHODS: The cytotoxic effects of As2O3 on five myeloma cell lines U266, SKO-007, LP-1, HS-Sultan, and KM3 were examined using MTT bioassay, and the concentration of 50% growth inhibition (IC(50)) was calculated. The synergistic or antagonistic effects of menadione (VK(3)), N-acetyl-cysteine (NAC), and reduced glutathione (GSH) combined with As2O3 were also examined. The cellular GSH levels in five MM cell lines and its changes in U266 cells after treated with As2O3, VK(3), NAC, and exogenous GSH were determined by colorimetric assay, and the relationship between IC(50) and cellular GSH levels was analyzed. RESULTS: As2O3 inhibited the proliferation of all five myeloma cells, but with different sensitivity. GSH contents in five MM cells were correlated with its IC(50) significantly (r=0.87,P< 0.05). Oxidant VK(3) had significant synergistic effect with As2O3, and antioxidants NAC and GSH partly blocked the growth inhibition of As2O3. Both As2O3 and VK(3) decreased the GSH contents, NAC and GSH increased them contrarily. CONCLUSION: One of the mechanisms of effect of As2O3 on myeloma cells may be through decreasing the cellular GSH levels and inducing myeloma cell apoptosis.

[Effects of arsenic trioxide on cell cycle and expression of cyclin dependent kinase inhibitors of multiple myeloma cells].

OBJECTIVE: To study the effects of arsenic trioxide (As(2)O(3)) on cell cycle and expression of cyclin dependent kinase inhibitors (CDKIs) in multiple myeloma (MM) cells, and explore its pharmacological mechanism. METHODS: The DNA content of MM cells line HS-Sultan was analyzed by flow cytometry after exposure to As(2)O(3), the effects on expression of CDKI P15, P16 AND P21 were studied by reverse transcriptase PCR. RESULTS: DNA flow cytometric analysis showed that As(2)O(3) induced most of HS-Sultan cells, arrest at G(0)/G(1) phase and a small fraction at G(2)/M phase and apoptosis occurred mainly in S phase. There was no expression of P15 and P16 mRNA in untreated HS-Sultan cells and 1.0 micromol/L As(2)O(3) could make them expressed after exposed 24 or 48 hours respectively. Expression of P12 mRNA was obviously elevated by As(2)O(3) comparing with that of control. CONCLUSION: One of the pharmacological mechanisms of As(2)O(3) is to activate the expression of CDKI P15, P16 and P21, and consequently affect cell proliferation cycle.