Artemisinin-type drugs for the treatment of hematological malignancies.

Qinghaosu, known as artemisinin (ARS), has been for over two millennia, one of the most common herbs prescribed in traditional Chinese medicine (TCM). ARS was developed as an antimalarial drug and currently belongs to the established standard treatments of malaria as a combination therapy worldwide. In addition to the antimalarial bioactivity of ARS, anticancer activities have been shown both in vitro and in vivo. Like other natural products, ARS acts in a multi-specific manner also against hematological malignancies. The chemical structure of ARS is a sesquiterpene lactone, which contains an endoperoxide bridge essential for activity. The main mechanism of action of ARS and its derivatives (artesunate, dihydroartemisinin, artemether) toward leukemia, multiple myeloma, and lymphoma cells comprises oxidative stress response, inhibition of proliferation, induction of various types of cell death as apoptosis, autophagy, ferroptosis, inhibition of angiogenesis, and signal transducers, as NF-κB, MYC, amongst others. Therefore, new pharmaceutically active compounds, dimers, trimers, and hybrid molecules, could enhance the existing therapeutic alternatives in combating hematologic malignancies. Owing to the high potency and good tolerance without side effects of ARS-type drugs, combination therapies with standard chemotherapies could be applied in the future after further clinical trials in hematological malignancies.

Umbilical cord blood CD34(+) stem cells and other mononuclear cell subtypes processed up to 96 h from collection and stored at room temperature maintain a satisfactory functionality for cell therapy.

BACKGROUND AND OBJECTIVES: Umbilical cord blood (UCB) is a good stem cell source for cell therapy. We recently demonstrated that cord blood mononuclear cell (MNCs) subtypes were viable and functional until 96 h after collection, even stored at room temperature. Now, we analyzed the viability and functionality of the cells before and after cryopreservation. MATERIALS AND METHODS: Twenty UCB units were analyzed at 24 and 96 h after collection, frozen for 6 months, thawed and re-evaluated. MNCs were analyzed by flow cytometry, viability by 7-AAD and clonogenic assays (CFU) were performed. RESULTS: After 96 h of storage, no substantial loss of MNC was found (median 7.320 × 10(6 ) × 6.05 × 10(6) ). Percentage and viability CD34(+) cells, B-cell precursors and mesenchymal stem cells were not affected. However, mature B and T lymphocytes as well as granulocytes had a substantial loss. CFU growth was observed in all samples. Prefreezing storage of 96 h was associated with a relative loss of colony formation (median 12%). Postthaw, this loss had a median of 49% (24 h samples) to 56% (96 h samples). CONCLUSION: The delay of 96 h before UCB processing is possible, without a prohibitive impairment of CD34(+) loss in number and functionality.

Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms.

We hypothesized that specific molecular mutations are important biomarkers for response to DNA methyltransferase inhibitors (DNMT inhibitors) and may have prognostic value in patients with myelodysplastic syndromes (MDS). Mutational analysis was performed in 92 patients with MDS and related disorders who received 5-azacytidine (n=55), decitabine (n=26) or both (n=11). Mutational status was correlated with overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analysis. Risk stratification models were created. TET2, DNMT3A, IDH1/IDH2, ASXL1, CBL, RAS and SF3B1 mutations were found in 18, 9, 8, 26, 3, 2 and 13% of patients, respectively. In multivariate analysis, TET2(MUT) and/or DNMT3A(MUT) (P=0.03), platelets > or = 100 × 10(9)/l (P=0.007) and WBC<3.0 × 10(9)/l (P=0.03) were independent predictors of better response. TET2(MUT) and/or DNMT3A(MUT) (P=0.04) status was also independently prognostic for improved PFS, as were good or intermediate cytogenetic risk (P<0.0001), age<60 (P=0.0001), treatment with both 5-azacytidine and decitabine (P=0.02) and hemoglobin > or = 10 g/dl (P=0.01). Better OS was associated with ASXL1(WT) (P=0.008) and SF3B1(MUT) (P=0.01), and, similar to PFS, cytogenetic risk (P=0.0002), age (P=0.02) and hemoglobin (P=0.04). These data support the role of molecular mutations as predictive biomarkers for response and survival in MDS patients treated with DNMT inhibitors.

Lack of association between MDM2 SNP309 and TP53 Arg72Pro polymorphisms with clinical outcomes in myelodysplastic syndrome.

MDM2/p53 pathway plays an important role in the control of apoptotic and proliferation mechanisms, and alterations in this pathway have been described in myelodysplastic syndromes (MDS). We investigated the frequency of MDM2 SNP309, TP53 Arg72Pro polymorphisms in de novo MDS and the association of these polymorphisms with clinical characteristics. Our results showed that the frequencies of genotypes for MDM2 SNP309 and TP53 Arg72Pro did not differ between MDS and healthy controls and that these polymorphisms were not associated with clinical and laboratory parameters, disease progression and overall survival, suggesting that MDM2 and TP53 polymorphisms are not involved in risk for MDS, or in the clinical and laboratory characteristics of the disease.