Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells

Balakrishnan, Kumudha; Nimmanapalli, Ramadevi; Ravandi, Farhad; Keating, Michael J.; Gandhi, Varsha

doi:10.1182/blood-2006-03-007468

Cited by 73 publications

(96 citation statements)

References 37 publications

(36 reference statements)

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“…Our in vitro studies served as a proof-of-principle of this hypothesis. 19 We demonstrated that when the CLL cells were incubated in vitro with forodesine and dGuo, the lymphocytes accumulated intracellular dGTP without any effect on other deoxynucleotides. This was associated with DNA damage-induced p53 stabilization, phosphorylation of p53 at Ser15, and activation of p21.…”

Section: Introductionmentioning

confidence: 82%

“…The dGTP accumulation was related to induction of apoptosis measured by caspase activation, changes in mitochondrial membrane potential, and PARP cleavage. 19 Based on these encouraging preclinical data, a clinical trial with forodesine was initiated for patients with fludarabine-refractory CLL at the University of Texas M. D. Anderson Cancer Center. This trial recruited 8 patients.…”

Section: Introductionmentioning

confidence: 99%

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Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells

Balakrishnan¹,

Burger

Quiroga

et al. 2010

Blood

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells

Balakrishnan¹,

Burger

Quiroga

et al. 2010

Blood

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“…124,125 Although objective responses were not observed in the clinical study of forodesine for refractory T-cell malignancies, 126 large-scale phase II clinical trials of this promising antileukemic agent are clearly warranted. In Japan phase I study of forodesine for T/NK malignancies is now in progress.…”

Section: Treatment Of Atlmentioning

confidence: 99%

Treatment of Adult T-cell Leukemia

Uozumi

2010

J Clin Exp Hematopathol

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Adult T-cell Leukemia (ATL) is an aggressive malignant disease of CD4 + T-cells associated with human T-cell leukemia virus type I (HTLV-I). Prognosis of ATL patients is directly correlated to the subtype of ATL. Treatment of the aggressive forms (acute and lymphoma types) of ATL remains inadequate, as most ATL patients receive conventional chemotherapy without stem cell rescue. At present, LSG15 is the standard chemotherapy for the treatment of aggressive ATL, but the efficacy of LSG15 in most patients is transient. To prolong median survival time, additional therapies for maintenance of complete response (CR) are needed after achieving CR by induction chemotherapy. Improved outcome after allogeneic stem cell transplantation (allo-SCT), despite a high incidence of graft-versus-host disease, has been reported. Thus, allogeneic bone marrow transplantation and allogeneic peripheral blood SCT may have great potential for eradication of HTLV-1 and cure of ATL. Recently, reduced-intensity conditioning stem cell transplantation was also reported to be effective for ATL. Although several issues, including selection criteria for patients and sources of stem cells remain to be resolved, allo-SCT may be considered as a treatment option for patients with aggressive ATL. To evaluate whether allo-SCT is more effective than the standard chemotherapy (LSG15) for aggressive ATL, an upfront phase II clinical trial of JCOG-LSG is now being planned. Novel innovative targeted strategies, such as antiretroviral therapy, arsenic trioxide, nuclear factor-kB inhibitors, proteasome inhibitors, histone deacetylase inhibitors, several monoclonal antibodies including anti-CC chemokine receptor 4, anti-folate, purine nucleotide phosphorylase inhibitor, mTOR (mammalian target of rapamycin) inhibitor, bendamustine, small molecule Bcl-2 inhibitors and Tax-targeted immunotherapy, should be promptly studied in order to develop curative treatments for ATL in the near future. 〔J Clin Exp Hematopathol 50(1) : 9-25, 2010〕

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“…The cytotoxicity of this agent requires deoxycytidine kinase activity and the presence of deoxyguanosine (dGuo), suggesting that dGuo and not forodesine acts as a drug that needs to be phosphorylated (Kicska et al, 2001). Although the exact mechanism of action of forodesine is unknown, accumulation of dGTP and deregulation of the pyrimidine deoxynucleotide pools leads to inhibition of DNA synthesis and cell death after p53 stabilization, caspase activation, changes in mitochondrial membrane potential and PARP cleavage (Kicska et al, 2001;Balakrishnan et al, 2006). It is postulated that this is caused by ribonucleotide reductase inhibition by increased dGTP levels (Bantia et al, 2003;Gandhi and Balakrishnan, 2007).…”

Section: Purine Nucleoside Analogsmentioning

confidence: 99%

Nucleoside analogs: molecular mechanisms signaling cell death

2008

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Nucleoside analogs are structurally similar antimetabolites that have a broad range of action and are clinically active in both solid tumors and hematological malignancies. Many of these agents are incorporated into DNA by polymerases during normal DNA synthesis, an action that blocks further extension of the nascent strand and causes stalling of replication forks. The molecular mechanisms that sense stalled replication forks activate cell cycle checkpoints and DNA repair processes, which may contribute to drug resistance. When replication forks are not stabilized by these molecules or when subsequent DNA repair processes are overwhelmed, apoptosis is initiated either by these same DNA damage sensors or by alternative mechanisms. Recently, strategies aimed at targeting DNA damage checkpoints or DNA repair processes have demonstrated effectiveness in sensitizing cells to nucleoside analogs, thus offering a means to elude drug resistance. In addition to their DNA synthesisdirected actions many nucleoside analogs trigger apoptosis by unique mechanisms, such as causing epigenetic modifications or by direct activation of the apoptosome. A review of the cellular and molecular responses to clinically relevant agents provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies.

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Forodesine, an inhibitor of purine nucleoside phosphorylase, induces apoptosis in chronic lymphocytic leukemia cells

Cited by 73 publications

References 37 publications

Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells

Influence of bone marrow stromal microenvironment on forodesine-induced responses in CLL primary cells

Treatment of Adult T-cell Leukemia

Nucleoside analogs: molecular mechanisms signaling cell death

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