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

Sargent, J. M.; Elgie, Alena W.; Williamson, Christine J.; Lewandowicz, G.; Taylor, C. G.

doi:10.1054/bjoc.2000.1639

Cited by 8 publications

(5 citation statements)

References 23 publications

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“…There was a wide range of sensitivity to the cytotoxic agents tested, particularly to the anthracyclines, even in this small group of patients. The median values are shown in Table I and are similar to those previously reported (Sargent et al , 2001). The range from the most sensitive to the most resistant varied by up to 5 × 10 3 ‐fold.…”

Section: Resultssupporting

confidence: 89%

Breast cancer resistance protein expression and resistance to daunorubicin in blast cells from patients with acute myeloid leukaemia

Sargent¹,

Williamson²,

Maliepaard

et al. 2001

Br J Haematol

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Summary. Breast cancer resistance protein (BCRP) is a recently described member of the ATP binding cassette transporter superfamily. It has been shown to confer resistance to mitoxantrone, topotecan, doxorubicin and daunorubicin in human tumour cell lines. We describe a study of BCRP expression in blast cells derived from 20 patients with acute myeloid leukaemia (AML). Twelve samples were from patients who had received previous cytotoxic therapy. BCRP expression was measured by immunocytochemistry using the BXP-34 monoclonal antibody. In vitro drug sensitivity was assessed using the methyl thiazol tetrazoliumbromide assay. BCRP expression varied between patients, and six out of 22 (27%) samples had . 10% cells staining positively (median 37%, range 13± 95%). BCRP positivity was seen in both de novo samples and those from previously treated patients. There was a marked variation in the effect of all drugs tested between patients. Although there was no correlation between BCRP positivity and the effect of mitoxantrone, topotecan or doxorubicin, the median daunorubicin LC 50 value of BCRP 1 cells was fourfold higher than that of BCRP 2 cells (0´89 mmol/l compared with 0´21 mmol/l, P , 0´05). These results suggest that BCRP may be involved in resistance to the agents commonly used in AML and may explain some of the anomalous results found when studying other membrane transporters, such as P-gp or MRP.

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Section: Resultssupporting

confidence: 89%

Breast cancer resistance protein expression and resistance to daunorubicin in blast cells from patients with acute myeloid leukaemia

Sargent¹,

Williamson²,

Maliepaard

et al. 2001

Br J Haematol

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“…Different strategies to circumvent nucleoside analogue resistance have included dCK stimulation (51-54), inhibition or stimulation of DNA repair (55), modulation of membrane transport (56), or intracellular deoxynucleotide triphosphate pools. UA911, a pronucleotide of ara-C, is more efficient than ara-C against L1210 10K cells, thereby demonstrating that this approach allows at least partial sensitization of totally dCK-deficient tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

Jordheim

Cros

Gouy

et al. 2004

Clinical Cancer Research

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Resistance to cytotoxic nucleoside analogues is a major problem in cancer treatment. The cellular mechanisms involved in this phenomenon have been studied for several years, and some factors have been identified. Various strategies to overcome resistance have been suggested, but none has yet shown efficacy in vivo. We developed a gemcitabineresistant cell line (L1210 10K) from the murine leukemic L1210 strain (L1210 wt) by continuous exposure to increasing concentrations of gemcitabine. L1210 10K is highly resistant to gemcitabine (14,833-fold), 1-␤-D-arabinofuranosylcytosine (ara-C; 2,100-fold), troxacitabine (>200-fold), and cladribine (160-fold) and slightly resistant to trimidox (7.22-fold), but does not display cross-resistance to fludarabine or nonnucleoside anticancer drugs. Deoxycytidine kinase mRNA was not detected by quantitative real-time reverse transcription-PCR in L1210 10K cells, whereas expression of thymidine kinase 1 and ribonucleotide reductase subunit R2 gene was moderately reduced. L1210 10K cells also demonstrated in vivo resistance to nucleoside analogues: gemcitabine-or ara-C-treated mice carrying L1210 10K had significantly shorter survival than gemcitabine-or ara-C-treated mice carrying L1210 wt (P < 0.05). UA911, a mononucleotide prodrug (pronucleotide) of ara-C was found to significantly sensitize L1210 10K cells in vitro. These results suggest that reduced deoxycytidine kinase expression is a mechanism of resistance to gemcitabine that is relevant in vivo and can be circumvented by a prodrug approach.

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“…In contrast, the addition of aphidicolin enhanced AzC incorporation into the AML cell line OCI-AML3 as well as PBMCs from healthy human donors (Figures D and S3). These results help explain the synergistic toxicities of aphidicolin and ara-C in white blood cells. − Indeed, ara-CTP and aphidicolin can target the same pathway by stimulating accumulation of RNA primers of DNA synthesis in leukemia cells . The resulting short fragments of RNA are likely to be toxic …”

Section: Discussionmentioning

confidence: 92%

RNA Targeting in Acute Myeloid Leukemia

Messikommer

Seipel

Byrne

et al. 2020

ACS Pharmacol. Transl. Sci.

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Nucleosides and their analogues constitute an essential family of anticancer drugs. DNA has been the presumptive target of the front-line prodrug for acute myeloid leukemia (AML), cytarabine (ara-C), since the 1980s. Here, the biomolecular targeting of ara-C was evaluated in primary white blood cells using the ara-C mimic “AzC” and azide–alkyne “click” reactions. Fluorescent staining and microscopy revealed that metabolic incorporation of AzC into primary white blood cells was unexpectedly enhanced by the DNA polymerase inhibitor aphidicholine. According to RNaseH digestion and pull-down-and-release experiments, AzC was incorporated into short RNA fragments bound to DNA in peripheral blood monocytes (PBMCs) collected from all six healthy human donors tested. Samples from 22 AML patients (French–American–British classes M4 and M5) exhibited much more heterogeneity, with 27% incorporating AzC into RNA and 55% into DNA. The overall survival of AML patients whose samples incorporated AzC into RNA was approximately 3-fold higher as compared to that of the DNA cohort (p ≤ 0.056, χ2 = 3.65). These results suggest that the RNA primers of DNA synthesis are clinically favorable targets of ara-C, and that variable incorporation of nucleoside drugs into DNA versus RNA may enable future patient stratification into treatment-specific subgroups.

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

Cited by 8 publications

References 23 publications

Breast cancer resistance protein expression and resistance to daunorubicin in blast cells from patients with acute myeloid leukaemia

Breast cancer resistance protein expression and resistance to daunorubicin in blast cells from patients with acute myeloid leukaemia

Characterization of a Gemcitabine-Resistant Murine Leukemic Cell Line

RNA Targeting in Acute Myeloid Leukemia

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