homoharringtonine and Cell-Transformation--Neoplastic

A total of 32 patients (25 with advanced MDS and 7 with t-AML) were enrolled in this study to evaluate the efficacy and toxicity of the low-dose cytarabine and homoharringtonine in combination with granulocyte colony-stimulating factor (G-CSF) (CHG protocol) in patients with advanced myelodysplastic syndromes (MDS) or MDS-transformed acute myeloid leukemia (t-AML). All the patients were administered the CHG regimen comprising low-dose cytarabine (25 mg/day, intravenous continuous infusion, days 1-14), homoharringtonine (1 mg/day, intravenous continuous infusion, days 1-14), and G-CSF (300 microg/day, subcutaneous injection, days 0-14, interrupted when the peripheral white blood cell count reached >20 x 10(9)/L). The overall response rate was 71.9% after the administration of one course of the CHG regimen. Of the 32 patients, 15 (46.9%) achieved complete remission (CR) and 8 (25%) achieved partial remission (PR). This regimen was followed by a post-remission therapy that included conventional chemotherapy, when CR was achieved. Of the patients with CR who just received post-remission regimens as homoharringtonine and cytarabine (HA) and daunorubicin and cytarabine (DA) 6 relapsed rapidly and just had a mean 6.1 months of CR. Otherwise, the other 8 out of 14 patients with CR alternatively received subsequent chemotherapy, which combined mitoxantrone, idarubicin, pirarubicin, or aclarubicin with cytarabine. The mean CR duration of the 8 patients had reached 10.6 months, and 5 of the 8 still kept a continuous CR. The median overall survival (OS) was 18.2 months. There were no statistically significant differences for CR, PR, and OS when the patients were grouped by age, blasts in bone marrow, and karyotypes, respectively. No treatment-related deaths were observed. Myelosuppression was mild to moderate, and no severe non-hematological toxicity was observed. Thus, a CHG priming regimen as an induction therapy was well tolerated and effective in patients with advanced MDS or t-AML. Stronger and alternative subsequent chemotherapy is necessary for patients with CR to maintain longer CR and better OS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cell Transformation, Neoplastic; Cytarabine; Disease Progression; Dose-Response Relationship, Drug; Female; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Neoadjuvant Therapy; Treatment Outcome; Young Adult

Sarcomas are difficult to treat and the therapy, even when effective, is associated with long-term and life-threatening side effects. In addition, the treatment regimens for many sarcomas, including Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma, are relatively unchanged over the past two decades, indicating a critical lack of progress. Although differentiation-based therapies are used for the treatment of some cancers, the application of this approach to sarcomas has proven challenging. Here, using a CRISPR-mediated gene knockout approach, we show that Inhibitor of DNA Binding 2 (ID2) is a critical regulator of developmental-related genes and tumor growth in vitro and in vivo in Ewing sarcoma tumors. We also identified that homoharringtonine, which is an inhibitor of protein translation and FDA-approved for the treatment of leukemia, decreases the level of the ID2 protein and significantly reduces tumor growth and prolongs mouse survival in an Ewing sarcoma xenograft model. Furthermore, in addition to targeting ID2, homoharringtonine also reduces the protein levels of ID1 and ID3, which are additional members of the ID family of proteins with well-described roles in tumorigenesis, in multiple types of cancer. Overall, these results provide insight into developmental regulation in Ewing sarcoma tumors and identify a novel, therapeutic approach to target the ID family of proteins using an FDA-approved drug.

Topics: Animals; Carcinogenesis; Cell Transformation, Neoplastic; Genes, Developmental; Homoharringtonine; Humans; Inhibitor of Differentiation Protein 2; Mice; Proteins; Sarcoma, Ewing

Ribosomal protein (RP) L23 has been suggested to be a negative regulator of cell apoptosis. In the present study, we analyzed RPL23 expression in 169 patients with myelodysplastic syndrome (MDS) by using real-time PCR. The apoptosis of CD34(+) marrow cells was examined by flow cytometry, and the correlation between RPL23 expression levels and apoptosis in CD34(+) cells was assessed. We then analyzed the clinical significance of RPL23 expression for predicting disease progression and patient survival as well as therapeutic response in patients administered with a cytarabine, homoharringtonine, and G-CSF (CHG) regimen or decitabine therapy. Increased RPL23 expression was found in patients with higher-risk MDS than in patients with lower-risk disease (p = 0.004). RPL23 expression levels were found being inversely correlated with decreased apoptotic ratio of CD34(+) cells in higher-risk patients (r = -0.672, p < 0.001). Compared to patients with normal RPL23 expression levels, those with increased RPL23 expression presented higher rates of transformation to acute myeloid leukemia (p = 0.005) and reduced 2-year survival rates (p = 0.012). Multivariate regression analysis showed that RPL23 expression level was an independent predictor of prognosis, regardless of patient age, IPSS score, or hemoglobin level. Moreover, patients with RPL23 over-expression appeared to have lower response rates to CHG chemotherapy (p = 0.027) but similar response rates to decitabine treatment. In conclusion, the over-expression of RPL23 might confer apoptosis resistance in CD34(+) cells, which may lead to disease progression and adverse prognosis in MDS. Increased RPL23 expression was an inverse indicator for CHG regimen, but not for decitabine treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Azacitidine; Cell Transformation, Neoplastic; Cytarabine; Decitabine; Female; Gene Expression Regulation, Neoplastic; Granulocyte Colony-Stimulating Factor; Harringtonines; Homoharringtonine; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Predictive Value of Tests; Prognosis; Ribosomal Proteins; Risk Factors; Treatment Outcome; Young Adult