tretinoin and tetraarsenic-tetrasulfide

This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of an oral tetra-arsenic tetra-sulfide (As4S4) -containing formula named the Realgar-Indigo naturalis formula (RIF) compared with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed acute promyelocytic leukemia (APL).. In all, 242 patients with APL were randomly assigned (1:1) to oral RIF (60 mg/kg) or ATO (0.16 mg/kg) combined with all-trans retinoic acid (ATRA; 25 mg/m(2)) during induction therapy. After achieving complete remission (CR), all patients received three courses of consolidation chemotherapy and maintenance treatment with sequential ATRA followed by either RIF or ATO for 2 years. The primary end point was the rate of disease-free survival (DFS) at 2 years, which was assessed for noninferiority with a 10% noninferiority margin.. The median follow-up time was 39 months. DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6% (95% CI, -3.0% to 8.0%). The lower limit of the 95% CI of DFS difference was greater than the -10% noninferiority margin, confirming noninferiority (P < .001). No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P = .62) or the overall survival at 3 years (99.1% v 96.6%; P = .18). The rates of adverse events were similar in the two groups.. Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Drugs, Chinese Herbal; Female; Fever; Follow-Up Studies; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Liver; Maintenance Chemotherapy; Male; Middle Aged; Oxides; Remission Induction; Sulfides; Treatment Outcome; Tretinoin; Young Adult

To compare the efficacy of all-trans retinoic acid (ATRA) combining chemotherapy and As4S4 with ATRA combining chemotherapy for the maintenance treatment of patients with acute promyelocytic leukemia (APL).. Sixty patients with APL induced to complete remission by ATRA and consolidated by chemotherapy were randomly divided into two groups. Thirty patients as As4S4 group received ATRA + As4S4 + chemotherapy, and another thirty patients as non-As4S4 group were treated only with ATRA + chemotherapy as maintenance therapy. The therapeutic effects, side effects and PML-RARalpha gene expression were analyzed.. The three-year continuous complete remission (CCR) rate was 90.0% for As4S4 group and 61.1% for non-As4S4 group, the difference being statistically significant. Significant difference was also found in the positive rate of PML-RARalpha fusion gene between the two groups. The side effects were mild.. APL patients in maintenance therapy with ATRA + 6-MP + MTX + As4S4 can obtain a higher CCR.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Sulfides; Treatment Outcome; Tretinoin

Tetra-arsenic tetra-sulfide (As4S4) is an arsenic compound with antitumor activity, especially in acute promyelocytic leukemia (APL) that are resistant to retinoic acid (RA). Although recent studies have revealed that the therapeutic action of As4S4 is closely associated with the induction of cellular apoptosis, the exact molecular mechanism underlying this action in RA-resistant APL remains to be clarified. In this study, we found that As4S4-induced apoptosis was accompanied by reduced mRNA and protein expression of SET gene in RA-resistant NB4-R1 cells. Moreover, RNAi knockdown of SET gene further promoted As4S4-induced apoptosis, while SET overexpression recovered the cell viability, suggesting that As4S4 induces apoptosis through the reduction of SET protein in NB4-R1 cells. We also observed that the knockdown of SET gene resulted in the upregulation of protein phosphatase 2 (PP2A) expression and the downregulation of promyelocytic leukemia and retinoic acid receptor α fusion gene (PML-RARα) expression, which were enhanced by As4S4 treatments. By contrast, overexpression of SET gene resulted in PP2A downregulation and PML-RARα upregulation, which were abolished by As4S4 pretreatment. Since PP2A is a proapoptotic factor and PML-RARα is an antiapoptotic factor, our results suggest that As4S4-induced apoptosis in RA-resistant NB4-R1 cells is through the downregulation of SET protein expression, which, in turn, increases PP2A and reduces PML-RARα expressions to lead to cell apoptosis.

Topics: Apoptosis; Arsenicals; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Drug Resistance, Neoplasm; Histone Chaperones; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; RNA, Messenger; Sulfides; Transcription Factors; Tretinoin

Tetra-arsenic tetra-sulfide (As(4)S(4)), with improved toxicity profiles relative to arsenic trioxide, is the essential component of the new oral arsenic formulation which is highly effective and safe in the treatment of both newly diagnosed acute promyelocytic leukemia (APL) and more importantly relapsed/refractory APL. Although it is investigated that the therapeutic action of As(4)S(4) is closely associated with its induced cells apoptosis, the definitive systematic molecular mechanism of action of As(4)S(4) in APL therapy is still remained unknown. In this study, a serial of assays in vitro about the cytotoxicity of As(4)S(4) and cellular apoptotic evidences were done, then a proteomic investigation with the high-resolution two-dimensional electrophoresis system and mass spectrometry were performed to obtain for the first time systematic identification and characterization of the global proteome of apoptosis induced by As(4)S(4) in retinoic acid (RA)-resistant cells. Among them, expressional and functional regulations of target proteins SET, RPP2 and PHB might be the potential novel effective therapeutic strategies for RA-resistant APL. This study will not only facilitate to understand the signal transduction of apoptosis of RA-resistant APL cells induced by As(4)S(4) as a whole, but also is important to screen for drug targets as a new therapeutic strategy for hematopoietic malignant tumors.

Topics: Apoptosis; Arsenicals; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Prohibitins; Proteomics; Signal Transduction; Sulfides; Tretinoin