Clinical pharmacology of intermediate and low-dose cytosine arabinoside (ara-C) therapy in patients with hematologic malignancies

Ueda, T; Wataya, S; Yamauchi, Takeyoshi; Kishi, Satomi; Fukushima, Tsuneo; Tsutani, Hiroshi; Nakamura, Takashi

doi:10.1016/s0009-9120(97)87820-4

Cited by 3 publications

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“…All drugs were stored at -80°C. Drugs were thawed on the same day they were used in experiments and based on previous studies of in vivo levels the drugs were tested at the following concentrations that are relevant to low-toxicity AML treatment: valproic acid 1000 μM and 500 μM [ 16 ], cytarabine 0.35 μM and 0.01 μM [ 17 - 19 ], and ATRA 1 μM [ 20 - 22 ]. Cytarabine was also tested at 44 μM and 1 μM corresponding to high-dose therapy [ 23 , 24 ].…”

Section: Methodsmentioning

confidence: 99%

Effects of cytarabine on activation of human T cells – cytarabine has concentration-dependent effects that are modulated both by valproic acid and all-trans retinoic acid

Ersvær

Brenner

Vetås

et al. 2015

BMC Pharmacol Toxicol

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BackgroundCytarabine is used in the treatment of acute myeloid leukemia (AML). Low-dose cytarabine can be combined with valproic acid and all-trans retinoic acid (ATRA) as AML-stabilizing treatment. We have investigated the possible risk of immunotoxicity by this combination. We examined the effects of cytarabine combined with valproic acid and ATRA on in vitro activated human T cells, and we tested cytarabine at concentrations reached during in vivo treatment with high doses, conventional doses and low doses.MethodsT cells derived from blood donors were activated in vitro in cell culture medium alone or supplemented with ATRA (1 μM), valproic acid (500 or 1000 μM) or cytarabine (0.01-44 μM). Cell characteristics were assessed by flow cytometry. Supernatants were analyzed for cytokines by ELISA or Luminex. Effects on primary human AML cell viability and proliferation of low-dose cytarabine (0.01-0.5 μM) were also assessed. Statistical tests include ANOVA and Cluster analyses.ResultsOnly cytarabine 44 μM had both antiproliferative and proapoptotic effects. Additionally, this concentration increased the CD4:CD8 T cell ratio, prolonged the expression of the CD69 activation marker, inhibited CD95L and heat shock protein (HSP) 90 release, and decreased the release of several cytokines. In contrast, the lowest concentrations (0.35 and 0.01 μM) did not have or showed minor antiproliferative or cytotoxic effects, did not alter activation marker expression (CD38, CD69) or the release of CD95L and HSP90, but inhibited the release of certain T cell cytokines. Even when these lower cytarabine concentrations were combined with ATRA and/or valproic acid there was still no or minor effects on T cell viability. However, these combinations had strong antiproliferative effects, the expression of both CD38 and CD69 was altered and there was a stronger inhibition of the release of FasL, HSP90 as well as several cytokines. Cytarabine (0.01-0.05 μM) showed a dose-dependent antiproliferative effect on AML cells, and in contrast to the T cells this effect reached statistical significance even at 0.01 μM.ConclusionsEven low levels of cytarabine, and especially when combined with ATRA and valproic acid, can decrease T cell viability, alter activation-induced membrane-molecule expression and decrease the cytokine release.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-015-0012-2) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Effects of cytarabine on activation of human T cells – cytarabine has concentration-dependent effects that are modulated both by valproic acid and all-trans retinoic acid

Ersvær

Brenner

Vetås

et al. 2015

BMC Pharmacol Toxicol

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“…This concentration is achievable in the plasma by intermediate-to high-dose ara-C administration. 24) Thus, the mechanistic interaction of ara-C with DNA repair described here may be applicable in the clinic.…”

Section: Discussionmentioning

confidence: 88%

l‐β‐D‐Arabinofuranosylcytosine Is Cytotoxic in Quiescent Normal Lymphocytes Undergoing DNA Excision Repair

Yamauchi

Kawai

Ueda

2002

Japanese Journal of Cancer Research

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We have sought to clarify the potential activity of the S-phase-specific antileukemic agent 1-β β β β-Darabinofuranosylcytosine (ara-C), an inhibitor of DNA synthesis, in quiescent cells that are substantially non-sensitive to nucleoside analogues. It was hypothesized that the combination of ara-C with DNA damaging agents that initiate DNA repair will expand ara-C cytotoxicity to non-cycling cells. The repair kinetics, which included incision of damaged DNA, gap-filling by DNA synthesis and rejoining by ligation, were evaluated using the single cell gel electrophoresis (Comet) assay and the thymidine incorporation assay. When normal lymphocytes were treated with ultraviolet C or with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), the processes of DNA excision repair were promptly initiated and rapidly completed. When the cells were incubated with ara-C prior to irradiation or BCNU treatment, the steps of DNA synthesis and rejoining in the repair processes were both inhibited. The ara-C-mediated inhibition of the repair processes was concentration-dependent, with the effect peaking at 10 µ µ µ µM. The combination of ara-C with these DNA repair initiators exerted subsequent cytotoxicity, which was proportional to the extent of the repair inhibition in the presence of ara-C. In conclusion, ara-C was cytotoxic in quiescent cells undergoing DNA repair. This might be attributed to unrepaired DNA damage that remained in the cells, thereby inducing lethal cytotoxicity. Alternatively, ara-C might exert its own cytotoxicity by inhibiting DNA synthesis in the repair processes. Such a strategy may be effective against a dormant subpopulation in acute leukemia that survives chemotherapy.

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“…All drugs were stored at -80 °C. Drugs were thawed on the same day they were used in experiments and based on studies of in vivo levels the drugs were tested at the following concentrations that are relevant to low-toxicity treatment: cytarabine and cyclocytidine 0.1 μM [21][22][23] and at 10 μM and 1 μM corresponding to high-dose therapy [24,25]. Emoxipine was added always at equimolar concentrations.…”

Section: Drugsmentioning

confidence: 99%

Emoxipine Modulates Concentration-Dependent Effects of Cytarabine and Cyclocytidine on Activation of Human T Cells

Nizheharodava

Kvasyuk

Zafranskaya

et al. 2021

JPRI

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Title: Emoxipine modulates concentration-dependent effects of cytarabine and cyclocytidine on activation of human T cells. Introduction: Both cytarabine and cyclocytidine are used in the treatment of acute myeloid leukemia. Well known that cytarabine and other related cytosine-based nucleoside analogues are being toxic to tumor cells by increasing levels of cellular oxidative stress as it could be abrogated by antioxidants. However, very little is known both about both the effects of combinations of antimetabolites with antioxidants on the cytotoxic innate and adaptive immune cells and whether lymphocytes toxicity affects its anticancer efficiency. Aim: To estimate effects of cytarabine and cyclocytidine with emoxipine on in vitro activated human T cells at concentrations reached during in vivo treatment with high doses, conventional doses and low doses. Materials and Methods: T cells derived from blood donors were activated in vitro in cell culture medium alone or supplemented with cytarabine 0.1-10.0 μM or cyclocytidine 0.1-10.0 μM. Cell characteristics were assessed by flow cytometry. Results: Only cytarabine 1.0-10.0 μM had both antiproliferative and proapoptotic effects. Additionally, these cytarabine concentrations increased the γIFN-producing by CD3+CD4+ T cells and did not affect the release of this cytokine by CD3+CD8+ T cells. In contrast, the lowest concentration (0.1 μM) did not have or showed minor antiproliferative or cytotoxic effects, did not alter the release of γIFN. Cyclocytidine did not affect viability of normal peripheral blood mononuclear cells but decreased the proliferative capacity of activated normal T cells in dose-dependent manner. Additionally, cyclocytidine altered the percentage of γIFN-producing proliferative CD3+CD8+ cytotoxic T cells for any concentration tested (0.1, 1.0, 1 and 10.0 μM) meanwhile highly suppressed the number of the whole amount of CD3+CD8+ cells and did not affect the release of cytokines by CD3+CD4+ T cells. The study of the expression of the CD107a marker showed a significant stimulating effect of 10 µm of citarabine on the activation of subpopulations of T-lymphocytes (CD3+) and cytotoxic T-lymphocytes (CD3+CD8+).

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Clinical pharmacology of intermediate and low-dose cytosine arabinoside (ara-C) therapy in patients with hematologic malignancies

Cited by 3 publications

References 0 publications

Effects of cytarabine on activation of human T cells – cytarabine has concentration-dependent effects that are modulated both by valproic acid and all-trans retinoic acid

Effects of cytarabine on activation of human T cells – cytarabine has concentration-dependent effects that are modulated both by valproic acid and all-trans retinoic acid

l‐β‐D‐Arabinofuranosylcytosine Is Cytotoxic in Quiescent Normal Lymphocytes Undergoing DNA Excision Repair

Emoxipine Modulates Concentration-Dependent Effects of Cytarabine and Cyclocytidine on Activation of Human T Cells

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