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Acute myeloid leukemia (AML) has a poor prognosis and requires new approaches for treatment. We have reported that a combination of vitamin D‐based cell differentiation agents (doxercalciferol/carnosic acid [D2/CA]) added following the cytotoxic drug arabinocytosine (AraC) increases AML cell death (CD), a model for improved therapy of this disease. Because AraC‐induced CD is known to involve reactive oxygen species (ROS) generation, here we investigated if the modulation of cellular REDOX status plays a role in the enhancement of cell death (ECD) by D2/CA. Using thiol antioxidants, such as N‐acetyl cysteine (NAC), we found a significant inhibition of ECD, yet this occurred in the absence of any detectable change in cellular ROS levels. In contrast, NAC reduced the vitamin D receptor (VDR) abundance and its signaling of ECD. Importantly, VDR knockdown and NAC similarly inhibited ECD without producing an additive effect. Thus, the proposed post‐AraC therapy may be compromised by agents that reduce VDR levels in AML blasts. [ABSTRACT FROM AUTHOR]

Despite progress in understanding the biology of acute myeloid leukemia (AML), and despite advances in treatment, the majority of patients with AML die from the disease. The observation that Vitamin D can induce AML blast cells in vitro to differentiate along the monocytic lineage was made 30 years ago; however, it remains to translate this into a clinically meaningful strategy. This is a review of published clinical experience regarding the use of Vitamin D and its analogs, either alone or in combination with other agents, to treat AML. In many of these reports, investigators included patients with myelodysplasia (MDS) as well as AML patients in their treatment cohorts; therefore reports of Vitamin D and its analogs in treating MDS are included. This review documents heterogeneity in selection criteria for patients treated in these studies, the spectrum of Vitamin D analogs used in various studies, and the differing dosing strategies employed by investigators. Despite examples of occasional clinical efficacy, barriers remain to the successful application of Vitamin D in the treatment of MDS and AML. These include the lack of definition of a particularly sensitive target population, and the as yet unknown optimal choice of Vitamin D analog and dosing schedule. [ABSTRACT FROM AUTHOR]

Induction of terminal differentiation is a conceptually attractive approach for the therapy of neoplastic diseases. Although vitamin D derivatives (deltanoids) can induce differentiation of AML cells in vitro, so far deltanoids have not been successfully brought to the clinic, due to the likelihood of life-threatening hypercalcemia. Here, we incubated freshly obtained blood cells from patients with AML with a plant antioxidant (PAOx), silibinin (SIL), alone or together with a deltanoid. Twenty patients with AML (all subtypes except M3) were available for this study, and in 14 (70%), SIL (60 µM) either induced differentiation ex vivo, or enhanced differentiation induced by deltanoids, or both. Interestingly, SIL acting alone induced differentiation only in cases in which chromosome aberrations could not be detected. In eleven samples sufficient material was available for a limited analysis of the underlying events. Quantitative RT-PCR showed that differentiation markers were upregulated at the mRNA level by both SIL and deltanoids, suggesting that intracellular signaling pathways upstream of transcription factors (TFs) were activated by these agents. Western analysis for proteins which function as TFs in deltanoid-induced monocytic differentiation, such as members of Jun and C/EBP families, surprisingly demonstrated that SIL upregulated all these TFs in the cases tested. This suggests that although the presence of SIL may not always be sufficient to induce differentiation, it can serve as a differentiation enabling factor for blasts obtained from a large proportion of patients with AML. Thus, SIL/deltanoid combinations warrant further consideration as preventive/therapeutic regimens in human leukaemia. [ABSTRACT FROM AUTHOR]

The article presents the author's views on the facts related to treatment of glioma. The author says that the cases of primary central nervous system malignant neoplasms diagnosed constitute about two percent of the cancers in the United States. These malignancies derive from neuroglial cells, the connective tissue matrix cells, which provide architectural support for neurons and respond to brain injury. The author further adds that in recent years, there have been advances in the understanding of the pathobiology of gliomas, including the identification of some of the molecular changes.