In vitro cytotoxic effects of fludarabine (2-F-ara-A) in combination with commonly used antileukemic agents by isobologram analysis

Kano, Yasuhiko; Akutsu, Miyuki; Tsunoda, Saburo; Suzuki, Kenichi; Ichikawa, Akira; Furukawa, Yusuke; Bai, Liyan; Kon, Kenji

doi:10.1038/sj.leu.2401684

Cited by 28 publications

(20 citation statements)

References 36 publications

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“…These results were supported by further in vitro and in vivo studies, demonstrating a high response of B-CLL cells to combinations of alkylating drugs with purine analogs. 42,[50][51][52][53][54][55] The underlying mechanism for the synergistic interaction of bendamustine with fludarabine in B-CLL cells is unknown. As mentioned above, bendamustine induces long-lasting DNA double strand breaks, while fludarabine inhibits DNA and RNA synthesis, as well as DNA repair.…”

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia

et al. 2002

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Bendamustine is a novel cytostatic agent, with activity in nonHodgkin's lymphomas including B-chronic lymphocytic leukemia (B-CLL). The knowledge about its mode of action, however, is still limited. Here, we investigated the in vitro ability of bendamustine to induce apoptosis on freshly isolated peripheral lymphocytes in B-CLL and analyze the potential underlying mechanisms of action for inducing apoptosis. In CLL cells taken from 37 previously treated and untreated CLL patients, we investigated the influence of bendamustine alone, and in combination with fludarabine, on the induction of apoptosis and changes of Bcl-2 and Bax expression on mRNA and protein level using the RNase protection assay or flow cytometry, respectively. Apoptotic cells were determined with flow cytometry using the fluorescent DNA-binding agent 7-ADD. Using bendamustine alone in concentrations from 1 g/ml to 50 g/ml, a dose-and time-dependent manner of cytotoxicity from 30.4% to 94.8% after 48 h could be observed. The LD50 for untreated and pretreated CLL cells was 7.3 or 4.4 g/ml, respectively. The median apoptotic rate was similar in both groups. The combination of bendamustine with fludarabine led to a highly synergistic effect in inducing apoptosis, which was 150% higher than expected for bendamustine plus fludarabine. The level of the initial Bcl-2 and Bax protein and the m-RNA expression remained unchanged during the incubation with bendamustine. In conclusion, this study demonstrates for the first time the in vitro efficacy of bendamustine in inducing apoptosis in B-CLL cells alone and in combination with fludarabine.

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Section: Discussionmentioning

confidence: 99%

In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia

et al. 2002

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“…24,25 Nonetheless, fludarabine can interact synergistically with multiple cytotoxic agents, partly due to its role in inhibiting the ribonucleotide reductase M1 subunit. 26 Myeloproliferative neoplasms are a varied group of disorders that can have prolonged chronic phases, but eventually accelerate and can transform into a secondary acute myeloid leukemia that is ultimately fatal. Triapine is a novel inhibitor of the M2 subunit of ribonucleotide reductase.…”

Section: Introductionmentioning

confidence: 99%

A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o nand children, and revealed the potentiation of cytarabine cytotoxicity ex vivo. [27][28][29][30] Preclinical studies demonstrated that triapine administration was associated with decreases in intracellular circulating leukemic blast dNTP pools with subsequent inhibition of DNA synthesis. 16 On the basis of these data, we conducted a phase I clinical trial of triapine followed by escalating doses of fludarabine in adults with relapsed and refractory acute leukemias, high-risk myelodysplastic syndrome, or transformed MPN including CMML. 31 We tested two schedules: schedule A, consisting of daily doses of triapine at 105 mg/m 2 over 4 h for 5 days followed by a 30-min infusion of fludarabine within 1 h of completion of triapine, and schedule B, consisting of triapine at 200 mg/m 2 over 24 h followed by fludarabine for 5 days. There were no dose-limiting toxicities in this study; however, the dose of fludarabine (30 mg/m 2 daily) was not further escalated due to concern about neurotoxicity. Schedule A (triapine 105 mg/m 2 daily) led to a 21% complete remission + partial remission rate, with the majority of responses being in patients with underlying MPN (29% response rate in MPN). In contrast, schedule B (triapine 200 mg/m 2 over 24 h) did not lead to any clinical responses.Given the promising results of schedule A, we designed and conducted a phase II study of triapine 105 mg/m 2 daily followed by fludarabine 30 mg/m 2 daily for 5 days in 37 patients with aggressive MPN and secondary, transformed AML. We confirm our previous findings that this combination of agents is clinically active in accelerated MPN and secondary AML derived from MPNs, and further identify the JAK2 V617F mutation as a potential predictor of response to sequential ribonucleotide reductase inhibition. Methods PatientsBetween August 2006 and November 2010, 37 adults with pathological confirmation of accelerated MPN (>5% blasts in bone marrow, new onset/worsening myelofibrosis, new onset or >25% increase in hepatomegaly/splenomegaly, or new onset/worsening constitutional symptoms), CML-BC, CMML (>5% blasts), or secondary AML, arising from a preexisting MPN or CMML, defined by standard criteria, 32 were entered on study at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. This study was approved by the Johns Hopkins Medical Institutional Review Board. Treatment planTriapine was administered as a 4-h intravenous infusion daily for 5 consecutive days at a dose of 105 mg/m 2 /day. Fludarabine 30 mg/m 2 /day was administered as a 30-min intravenous infusion daily, beginning within 1 h of completion of the triapine infusion, on each of the 5 consecutive days. Each cycle was 21 days in duration. Patients were eligible to receive additional cycles of treatment until disease progression or toxicity. Measurement of toxicitiesNon-hematologic toxicities were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Treatment of tria...

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“…[3][4][5][6] In vitro, fludarabine combined with cyclophosphamide demonstrates additive or synergistic cytotoxic effects in leukemic cells. 7,8 This cell-killing activity led to their development as a combination therapy, 9 demonstrating an improvement of patient outcomes and remission times.…”

Section: Introductionmentioning

confidence: 99%

An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia

Montillo

Tedeschi

Petrizzi³

et al. 2011

Blood

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In vitro cytotoxic effects of fludarabine (2-F-ara-A) in combination with commonly used antileukemic agents by isobologram analysis

Cited by 28 publications

References 36 publications

In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia

In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia

A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia

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