Augmentation of 1-β-d-Arabinofuranosylcytosine (Ara-C) cytotoxicity in leukaemia cells by co-administration with antisignalling drugs

Freund, Anna; Boos, Joachim; Harkin, Siobhan T.; Schultze-Mosgau, Marcus; Veerman, G.; Peters, Godefridus J.; Gescher, Andreas J.

doi:10.1016/s0959-8049(97)10149-6

Cited by 13 publications

(2 citation statements)

References 27 publications

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“…Synergy between RNRi and ara‐C has been reported previously in vivo as well as in ex vivo experiments of primary patient blasts and in cell lines (Plagemann et al , ; Walsh et al , ; Streifel & Howell, ; Howell et al , ; Rauscher & Cadman, ; Tanaka et al , ; Kubota et al , , ; Gandhi & Plunkett, ; Bhalla et al , ; Colly et al , ; Santini et al , ; Iwasaki et al , ; Freund et al , ; Heinemann et al , ; Ahlmann et al , ; Hubeek et al , ; Sigmond et al , ) (for further detail, see ). Our study provides a mechanistic framework of this synergy in its dependence on functional SAMHD1 and expression levels thereof.…”

Section: Discussionmentioning

confidence: 64%

Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy

et al. 2020

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The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.

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Section: Discussionmentioning

confidence: 64%

Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy

et al. 2020

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“…Resistance to ara-C can be attributed to many factors but alterations in phosphorylation of ara-C to its active metabolite ara-CTP has been widely believed to be the rate-limiting step leading to the incorporation of ara-CTP into DNA with subsequent induction of DNA strand breaks (Freund et al, 1998). This is thought to cause termination of chain elongation and switch on apoptosis by a mechanism not yet fully understood.…”

mentioning

confidence: 99%

Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML

Sargent¹,

Elgie²,

Williamson³

et al. 2001

Br J Cancer

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Summary Treatment failure in AML is often attributed to P-glycoprotein-associated multidrug resistance. However, the importance of increased DNA repair in resistant cells is becoming more apparent. In order to investigate the ability of the DNA repair inhibitor aphidicolin to modulate drug resistance, we continually exposed blasts cells, isolated from 22 patients with AML, to a variety of agents ± 15 µM aphidicolin for 48 hours. Cell survival was measured using the MTT assay. Overall, there was no significant effect of aphidicolin on sensitivity to daunorubicin, doxorubicin, etoposide or fludarabine. However, there was a marked increase in sensitivity to ara-C with a median 4.75-fold increase overall (range 0.8-80-fold; P < 0.005). The effect of aphidicolin was significantly greater in blast cells found resistant in vitro to ara-C (8.9-fold compared to 2.12-fold, P < 0.01). This observation was further validated by the correlation between ara-C LC 50 and extent of modulation effect (P < 0.05). Cells isolated from 10 cord blood samples were also tested in order to establish the haematological toxicity of combining ara-C and aphidicolin. The therapeutic index (LC 50 normal cells/tumour cells) for ara-C + aphidicolin was higher than that for ara-C alone suggesting no increased myelotoxicity for the combination. Increased cytotoxicity without increased haematotoxicity makes the combination of ara-C plus aphidicolin ideal for inclusion in future clinical trials.

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Flavonoids as Chemosensitizers in Leukemias

Huseynova,

Çetinkaya,

Baran

et al. 2024

Advances in Experimental Medicine and Biology

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Augmentation of 1-β-d-Arabinofuranosylcytosine (Ara-C) cytotoxicity in leukaemia cells by co-administration with antisignalling drugs

Cited by 13 publications

References 27 publications

Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy

Ribonucleotide reductase inhibitors suppress SAMHD 1 ara‐ CTP ase activity enhancing cytarabine efficacy

Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML

Flavonoids as Chemosensitizers in Leukemias

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