Antitumor activity of 2-fluoro-2′-deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase

Parker, William B.; Allan, Paula W.; Hassan, Abdalla E. A.; Secrist, John A.; Sorscher, Eric J.; Waud, William R.

doi:10.1038/sj.cgt.7700520

Cited by 72 publications

(73 citation statements)

References 14 publications

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“…Clofarabine has several significant differences compared with fludarabine and cladribine including: i) increased resistance to deamination and phosphorolysis and hence better stability of the active cytotoxic species; ii) higher affinity to deoxycytidine kinase; iii) prolonged retention of the triphosphate compound in malignant cells (shown in leukemic blasts); and iv) potent inhibition of DNA synthesis and of ribonucleotide reductase (RNR) (8)(9)(10)31,32). Clofarabine has a very different pattern of cytotoxicity than fludarabine and cladribine.…”

Section: Discussionmentioning

confidence: 99%

“…Clofarabine triphosphate competes with dATP for DNA polymerases-· and -Â leading to chain termination and strand breaks. Clofarabine triphosphate is also a potent inhibitor of ribonucleotide reductase through binding to the regulatory subunit (8,9). The cellular damage produced by these events and direct effects of clofarabine on mitochondria result in the release of cytochrome c from the mitochondria and activation of apoptotic pathways (10).…”

Section: Introductionmentioning

confidence: 99%

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Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs

Roth¹,

Kurtzberg²,

Rouleau³

et al. 2009

Int J Oncol

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Abstract. Nucleoside analogs are rationally designed anticancer agents that disrupt DNA and RNA synthesis. Fludarabine and cladribine have important roles in the treatment of hematologic malignancies. Clofarabine is a next generation nucleoside analog which is under clinical investigation. The bone marrow toxicity, tumor cell cytotoxicity and human tumor xenograft activity of fludarabine, cladribine and clofarabine were compared. Mouse and human bone marrow were subjected to colony forming (CFU-GM) assays over a 5-log concentration range in culture. NCI-60 cell line screening data were compared. In vivo, a range of clofarabine doses was compared with fludarabine for efficacy in several human tumor xenografts. The IC 90 concentrations for fludarabine and cladribine for mouse CFU-GM were >30 and 0.93 μM, and for human CFU-GM were 8 and 0.11 μM, giving mouse to human differentials of >3.8-and 8.5-fold. Clofarabine produced IC 90 s of 1.7 μM in mouse and 0.51 μM in human CFU-GM, thus a 3.3-fold differential between species. In the NCI-60 cell line screen, fludarabine and cladribine showed selective cytotoxicity toward leukemia cell lines while for clofarabine there was no apparent selectivity based upon origin of the tumor cells. In vivo, clofarabine produced a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI-8226 multiple myeloma, and HT-29 colon carcinoma models. The PC3 prostate carcinoma was equally responsive to clofarabine and fludarabine. Bringing together bone marrow toxicity data, tumor cell line cytotoxicity data, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs

Roth¹,

Kurtzberg²,

Rouleau³

et al. 2009

Int J Oncol

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“…48 Both prodrug-activating systems induce apoptosis in Transduction of PNP gene followed by treatment with nucleoside analogues has been studied in vivo on bladder tumors, pancreatic adenocarcinomas, gliomas, ovarian or prostate tumors and showed different levels of growth inhibition. 40,44,[49][50][51][52][53][54][55][56] To increase the effect obtained with this gene-therapy approach by using new genes and new drugs, a study based on crystallographic and computer modeling of E. coli PNP, was performed. The mutated protein (M64V) had a more than 100-fold increased enzymatic efficiency (kcat/Km) toward the nontoxic 9-(6-deoxy-a-L-talofuranosyl)-6-methylpurine as compared to the wt protein.…”

Section: Gene Therapy and Nucleoside Analogues C Hébrard Et Almentioning

confidence: 99%

Development of gene therapy in association with clinically used cytotoxic deoxynucleoside analogues

2009

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The clinical use of cytotoxic deoxynucleoside analogues is often limited by resistance mechanisms due to enzymatic deficiency, or high toxicity in nontumor tissues. To improve the use of these drugs, gene therapy approaches have been proposed and studied, associating clinically used deoxynucleoside analogues such as araC and gemcitabine and suicide genes or myeloprotective genes. In this review, we provide an update of recent results in this area, with particular emphasis on human deoxycytidine kinase, the deoxyribonucleoside kinase from Drosophila melanogaster, purine nucleoside phosphorylase from Escherichia coli, and human cytidine deaminase. Data from literature clearly show the feasibility of these systems, and clinical trials are warranted to conclude on their use in the treatment of cancer patients.

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“…It inhibits DNA repair and activates the mitochondrial apoptotic pathway leading to cell death (Xie and Plunkett, 1996;Parker et al, 2003). Clofarabine showed promising activity in phase 1 and 2 studies in patients with relapsed and refractory acute leukemias in adults and children.…”

Section: Introductionmentioning

confidence: 99%

Clofarabine in the Treatment of Elderly Patients with Acute Myeloid Leukemia

Aleem

Anjum²,

Algahtani³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Elderly patients with acute myeloid leukemia (AML) have a poor outcome because of comorbidities, poor tolerance to intensive chemotherapy and inherently more resistant disease. Clofarabine is a second generation nucleoside analogue which has shown promising activity in elderly patients with AML. This study was conducted to review the outcome of treatment with clofarabine in a group of such patients. Methods: The records of 5 elderly patients who were diagnosed to have AML and treated with clofarabine over a 12 month period were reviewed retrospectively. Results: There were 2 female and 3 male patients with a median age of 68 years (range 65-82). At the time of treatment, 2 patients had newly diagnosed AML not considered suitable for intensive therapy, while 3 patients had partial or no response to conventional chemotherapy. The overall response rate was 100%, all patients achieving a complete remission. Induction and consolidation were well tolerated. All patients developed neutropenia with a median duration of 20 days (range 17-42). One patient developed hand and foot syndrome and a generalized rash but recovered. There was no mortality and all patients remained in remission after a median follow-up of 5.2 months (Range 3-10). Conclusion: Clofarabine (alone or in combination) is active in elderly AML patients with an acceptable safety profile and should be considered a potential option in this group.

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Antitumor activity of 2-fluoro-2′-deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase

Cited by 72 publications

References 14 publications

Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs

Bone marrow CFU-GM and human tumor xenograft efficacy of three antitumor nucleoside analogs

Development of gene therapy in association with clinically used cytotoxic deoxynucleoside analogues

Clofarabine in the Treatment of Elderly Patients with Acute Myeloid Leukemia

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