A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine)

Gandhi, Varsha; Kilpatrick, J. Michael; Plunkett, William; Ayres, Mary; Harman, L.; Du, Min; Bantia, Shanta; Davisson, Jan; Wierda, William G.; Faderl, Stefan; Kantarjian, Hagop M.; Thomas, Deborah A.

doi:10.1182/blood-2005-03-1309

Cited by 92 publications

(72 citation statements)

References 40 publications

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“…17 Furthermore, a proof-ofprinciple phase 1 investigation demonstrated that this drug inhibited PNP, elevated the plasma dGuo levels to micromolar levels, and increased intracellular dGTP to millimolar levels in immature T cells when administered to patients. 18 This proof-of-concept clinical study further elucidated the role of PNP inhibition in T-cell malignancies.…”

Section: Introductionmentioning

confidence: 85%

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: 85%

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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“…Immucillins are PNP transition state analogues, some of which have K d values as low as 7 pM (54). Immucillin-H is currently in clinical trials for treating human T-cell malignancies (23,54) and has been shown to inhibit PfPNP, as well as inhibiting P. falciparum growth, in vitro (33,34). This in vitro inhibition of parasite growth can be reversed by the addition of hypoxanthine, but not inosine, to the culture medium, indicating that PNP is the target for this drug (34).…”

Section: P Falciparum Purine Nucleoside Phosphorylasementioning

confidence: 99%

Purine Salvage Pathways in the Intraerythrocytic Malaria Parasite Plasmodium falciparum

2008

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2Malaria is caused by protozoan parasites of the genus Plasmodium. Five species of Plasmodium cause infection in humans, with the majority of lethal cases caused by Plasmodium falciparum. This species is responsible for more than 500 million clinical cases of malaria each year (59). In the past 2 decades, efforts to combat this disease have been met with the emergence of widespread resistance to most of the commonly used antimalarial drugs (68). The poor efficacy of current drugs and the lack of a promising vaccine have resulted in alarming increases in the rates of malaria morbidity and mortality worldwide, with the major toll felt in the developing world.P. falciparum is transmitted to humans via the bite of an infected female anopheline mosquito. In humans, the parasite undergoes one cycle of asexual multiplication in hepatocytes, followed by several cycles of infection and multiplication in red blood cells. Whereas the hepatocytic stage is asymptomatic, the erythrocytic stage is accompanied by the destruction of the host erythrocytes, resulting in anemia and, in the absence of treatment, death. Extensive efforts are presently under way to develop a vaccine, and advances in our understanding of the biology of the parasite and its metabolic and nutritional needs offer new routes for chemotherapy. In this regard, purine metabolism holds significant promise as a target for drug development.It has long been recognized that protozoan parasites, including Plasmodium spp., are unable to synthesize purine rings de novo (4). Consistent with this observation, the sequencing of protozoan genomes has failed to uncover any genes encoding enzymes involved in the biosynthesis of purine nucleosides or nucleobases (12). Protozoan parasites rely instead on salvage of purines from the host. The strategies used in acquiring purines vary significantly among parasite genera. This review will focus primarily on the purine salvage pathways present in the Plasmodium parasite. Recent reviews have examined the metabolic pathways for purine salvage in other protozoa (11,17,29).Initial studies on purine and pyrimidine synthesis in Plasmodium parasites were performed on erythrocytic stages of the rodent malaria species P. berghei (7,8,65), the macaque monkey malaria species P. knowlesi (46), and the avian malaria parasite P. lophurae (61,66 (46). Following on from these findings, Gutteridge and Trigg found that, in P. knowlesi, all radiolabeled purines were significantly incorporated into nucleic acids while none of the pyrimidines tested were (28). These early biochemical studies demonstrated that Plasmodium parasites lack the ability to metabolize exogenous pyrimidines and instead are entirely dependent on de novo synthesis. Conversely, Plasmodium parasites are entirely reliant upon the salvage of extracellular purines (4) and are capable of metabolizing a wide variety of exogenous purine nucleobases and nucleosides.The continuous culture of P. falciparum in serum-free media is dependent upon the supply of exogenous purines (1, 43), sug...

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A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine)

Cited by 92 publications

References 40 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

Purine Salvage Pathways in the Intraerythrocytic Malaria Parasite Plasmodium falciparum

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