Speciation of arsenic trioxide metabolites in peripheral blood and bone marrow from an acute promyelocytic leukemia patient

Abstract

BackgroundSpeciation of arsenic trioxide (ATO) metabolites in clinical samples such as peripheral blood (PB) from acute promyelocytic leukemia (APL) patients has been conducted. However, speciation of arsenicals in bone marrow (BM) has not yet been performed. Profiles of arsenic speciation in plasma of BM were thus investigated and compared with those of PB plasma from a relapsed APL patient. The total arsenic concentrations in high molecular weight fraction (HMW-F) of BM and PB plasma were also determined.MethodsResponse assessment was evaluated by BM aspirate examination and fluorescence in situ hybridization analysis. The analyses of total arsenic concentrations and speciation were preformed by inductively coupled plasma mass spectrometry (ICP-MS), and high-performance liquid chromatography (HPLC)/ICP-MS, respectively.ResultsResponse assessment showed that the patient achieved complete remission. The total arsenic concentrations in BM plasma increased with time during the consecutive administration. The PB plasma concentrations of methylated arsenic metabolites substantially increased after the start of administration, while those of inorganic arsenic were still kept at a low level, followed by substantially increase from day-14 after administration. The arsenic speciation profiles of PB plasma were very similar to those of BM plasma. Furthermore, the total arsenic concentrations of HMW-F in BM plasma were much higher than those in PB plasma.ConclusionsThe behaviors of arsenic speciation suggested for the first time that arsenic speciation analysis of PB plasma could be predicative for BM speciation, and showed relatively higher efficiency of drug metabolism in the patient. These results may further provide not only significance of clinical application of ATO, but also a new insight into host defense mechanisms in APL patients undergoing ATO treatment, since HMW proteins-bound arsenic complex could be thought to protect BM from the attack of free arsenic species.

Granulocyte colony-stimulating factor potentiates differentiation induction by all-trans retinoic acid and arsenic trioxide and enhances arsenic uptake in the acute promyelocytic leukemia cell line HT93A

“…It is noteworthy that CD34 expression, well-known to be present in hematopoietic progenitor cells and absent in NB4 cells (8,18), significantly decreased after treatment with ATRA in HT93A cells. These results suggest that CD34, CD11b and CD15 could be used as a parameter to evaluate the level of differentiation in clinical therapy as shown in our previous clinical observation (25). There are only a few APL cell lines and most in vitro experiments are performed with NB4 cells.…”

“…Lower concentration of ATO induced differentiation of HT93A cells. On the basis of our previous study, in which the blood level of ATO in APL patients was investigated (24,25), plasma concentration of ATO in either bone marrow or peripheral blood kept the effective level of differentiation induction for HT93A cells. Next, we demonstrated that both ATRA and ATO induced differentiation in HT93A cells.…”

Cytocidal Effects of Polyphenolic Compounds, Alone or in Combination with, Anticancer Drugs Against Cancer Cells: Potential Future Application of the Combinatory Therapy

“…Furthermore, we have demonstrated for the first time that these arsenic metabolites also existed in cerebrospinal fluid [67], in which the concentrations of arsenic reached levels necessary for differentiation induction [68,69]. We further investigated for the first time the arsenic speciation in plasma of bone marrow (BM), and demonstrated that speciation profiles of BM plasma were very similar to those of PB plasma, suggesting that speciation analysis of PB plasma could be predicative for BM speciation [70]. These findings on the pharmacokinetics of ATO in APL patients provide a new insight into clinical applications of ATO, and may contribute to better therapeutic protocols [4].…”

Malignant melanoma and melanocortin 1 receptor

“…This lack of progress in the treatment of malignant melanoma is caused in part by the high invasiveness of melanomas, thus making surgical treatment lowly effective. Conventional chemotherapy of this cancer is also inefficient [4]. Median survival of patients with non-cutaneous metastasis is less than one year, with a 5-year survival not more than 10% even in developed countries [5].…”

“…Median survival of patients with non-cutaneous metastasis is less than one year, with a 5-year survival not more than 10% even in developed countries [5]. Thus, the search for specific markers of this disease, especially specific surface markers [6] and altered signaling pathways, for development of immunotherapy and different types of targeted therapy [4, 7] is of great interest.…”