Aphidicolin potentiates apoptosis induced by arabinosyl nucleotides in human myeloid leukemia cell lines

Kuwakado, Katsuji; Kubota, Masaru; Hirota, Haruyo; Adachi, Souichi; Matsubara, Kousaku; Kasai, Yasufumi; Akiyama, Yuichi; Mikawa, Harukí

doi:10.1016/0006-2952(93)90631-6

Cited by 9 publications

(2 citation statements)

References 20 publications

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“…Several studies have shown aphidicolin can increase sensitivity to a variety of drugs, both in cell lines (Kuwakado et al, 1993;Moreland et al, 1999) and in fresh cells obtained from patients with chronic lymphocytic leukaemia (Bramson and Panasci, 1995). Nevertheless, there is one recent report using human lung cancer cell lines where sensitivity to cisplatin was unaffected by aphidicolin, possibly because a 1000-fold lower concentration was used (Heim et al, 2000).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…First, many studies relied on T cell hybridomas or leukemic cell lines, in which control of the cell cycle is abnormal. Second, the variety of pharmacological reagents that were used to synchronize cells in different phases of the cell cycle, such as mimosine, aphidocolin, or nocodazole, possess cell cycle-specific toxic effects of their own (Kuwakado et al, 1993;Bumbasirevic et al, 1995;Jha et al, 1995;Ji et al, 1997). Finally, it is not clear how closely the combination of ionophores and phorbol esters, commonly used to induce activation or cycling of peripheral T cells, mimics the normal response to activation through the TCR.…”

Section: Introductionmentioning

confidence: 99%

T Cell Receptor-induced Activation and Apoptosis In Cycling Human T Cells Occur throughout the Cell Cycle

Karas

Zaks

Liu

et al. 1999

MBoC

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Previous studies have found conflicting associations between susceptibility to activation-induced cell death and the cell cycle in T cells. However, most of the studies used potentially toxic pharmacological agents for cell cycle synchronization. A panel of human melanoma tumorreactive T cell lines, a CD8ϩ HER-2/neu-reactive T cell clone, and the leukemic T cell line Jurkat were separated by centrifugal elutriation. Fractions enriched for the G0 -G1, S, and G2-M phases of the cell cycle were assayed for T cell receptor-mediated activation as measured by intracellular Ca 2ϩ flux, cytolytic recognition of tumor targets, and induction of Fas ligand mRNA. Susceptibility to apoptosis induced by recombinant Fas ligand and activation-induced cell death were also studied. None of the parameters studied was specific to a certain phase of the cell cycle, leading us to conclude that in nontransformed human T cells, both activation and apoptosis through T cell receptor activation can occur in all phases of the cell cycle.

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Cytosine Arabinoside

Hubeek

Kaspers

Ossenkoppele

et al.

Cancer Drug Discovery and Development

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Aphidicolin potentiates apoptosis induced by arabinosyl nucleotides in human myeloid leukemia cell lines

Cited by 9 publications

References 20 publications

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

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

T Cell Receptor-induced Activation and Apoptosis In Cycling Human T Cells Occur throughout the Cell Cycle

Cytosine Arabinoside

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