The Novel Agent CAHB Effect On The Myelodysplastic Syndrome(MDS) In Vivo And In Vitro

Myelodysplastic syndrome (MDS) is a group of highly heterogeneous disorders characterized by cytopenia, myeloid cell dysplasia, and frequent transformation to acute myeloid leukemia. It occurs at a high incidence in the elderly population. The molecular pathogenesis of the disease is poorly understood and its prognosis is poor.The diagnosis and classification of MDS are mainly based on the morphological features of blood and bone marrow cells in conjunction with other ancillary studies. The World Health Organization (WHO) working group has proposed a classification system that takes into account the clinical, etiological, and cytogenetic data. The International Scoring System for Evaluating Prognosis (IPSS), which has proven to be highly useful for this purpose, is a risk-based classification system for MDS based on cytogenetic abnormalities and can be used to guide therapeutic choice. For MDS patients with low IPSS scores (low-risk), appropriate treatment includes supportive care, hematopoietic growth factors, and immunomodulatory drugs. For those with high IPSS scores, chemotherapy is appropriate at low or intense doses. Until recently, the vast majority of MDS patients were treated with supportive therapy alone, such as transfusions. Allogeneic stem cell transplantation (SCT) has the potential for cure,although its role has been limited due to the age and comorbidity of MDS patients. Response to most therapies occurs slowly and sometimes months elapse before a response can be observed. The response rate for most drugs remains less than 20%. In the last few years, new agents such as 5-azacytidine, decitabine, thalidomide, lenalidomide, and infliximab have shown promising efficacy and tolerability in clinical trials. It can be challenging for a clinician to choose the most appropriate treatment for an individual patient.Here we discuss a new agent, CAHB, for MDS treatment. CAHB is a differentiation inducer and showed a good response in phase I clinical trail. We used it to treat 3 high risk MDS patients for two courses and the results were encouraging. Though the peripheral blood cells of the three patients were not improved, all of them had a decrease in bone marrow blasts without severe side effect, the fall. percentage were 48.1 %, 58.7% and 81.2% respectively.In order to analyze the inhibitory effect of CAHB on the growth of human MDS-RAEB cell line MUTZ-1 and to explore the possible cellular and molecular mechanism, we used MTT assay, flow cytometry, and RT-PCR methods. MTT assay showed treatment with CAHB remarkably inhibited the growth of MUTZ-1 cells in a dose-dependent and time-dependent manner. The IC₅₀ at 24 h, 48 h, and 72 h were 16.08±3.13mmol/L,5.60±0.21mmol/L, and 3.83 ±0.22mmol/L, respectively. Flow cytometry proved MUTZ-1 cells had a significant dose-dependent apoptosis after cultured with CAHB (0, 2.5, 5, 10mmol/L) for 24 h, . After treatment with CAHB (0, 1.25, 2.5, 5mmol/L), the mRNA expression of survivin gene was decreased (survivin/GADPH ratio:0.95±0.02, 0.87±0.01, 0.79±0.03, 0.72± 0.01) as the CAHB dose (0, 1.25, 2.5, 5mmol/L) rising by RT-PCR Therefore, CAHB could inhibit MUTZ-1 cell growth and survivin gene may play a role in the apoptosis of MUTZ-1 cells induced by CAHB.We conclude that CAHB may serve as a novel agent for high risk MDS, although the underlying mechanism needs long term studies with a larger number of cases.