ArticleClinical cancer research : an official journal of the American Association for Cancer Research2008
Phase I study of GTI-2040, an antisense to ribonucleotide reductase, in combination with high-dose cytarabine in patients with acute myeloid leukemia.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 39 citations in OpenAlex.
- Trial
- Advances in antisense oligonucleotide treatment for cancer.Japanese journal of clinical oncology · 2026Review
- Molecularly targeted therapy and immunotherapy in leukemias.Journal of hematology & oncology · 2026Review
- Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation.Cancers · 2021Review
- Liposomal Grb2 antisense oligodeoxynucleotide (BP1001) in patients with refractory or relapsed haematological malignancies: a single-centre, open-label, dose-escalation, phase 1/1b trial.The Lancet. Haematology · 2018Article
- Anticancer activity of the intraperitoneal-delivered DFP-10825, the cationic liposome-conjugated RNAi molecule targeting thymidylate synthase, on peritoneal disseminated ovarian cancer xenograft model.Drug design, development and therapy · 2018Article
- Clinical pharmacology and clinical trials of ribonucleotide reductase inhibitors: is it a viable cancer therapy?Journal of cancer research and clinical oncology · 2017Review
- A phase I pharmacodynamic study of GTI-2040, an antisense oligonucleotide against ribonuclotide reductase, in acute leukemias: a California Cancer Consortium study.Leukemia & lymphoma · 2016Article
- Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma.Molecular cancer research : MCR · 2016Article
- Non-covalent complexes of folic acid and oleic acid conjugated polyethylenimine: An efficient vehicle for antisense oligonucleotide delivery.Colloids and surfaces. B, Biointerfaces · 2015Article
- CD33-Targeted Lipid Nanoparticles (aCD33LNs) for Therapeutic Delivery of GTI-2040 to Acute Myelogenous Leukemia.Molecular pharmaceutics · 2015Article
- A microfluidic method to synthesize transferrin-lipid nanoparticles loaded with siRNA LOR-1284 for therapy of acute myeloid leukemia.Nanoscale · 2014Article
- Phase I study of GTI-2040, a ribonucleotide reductase antisense, with high dose cytarabine in patients with relapsed/refractory acute myeloid leukemia.Leukemia & lymphoma · 2014Article
- The efficacy of the ribonucleotide reductase inhibitor Didox in preclinical models of AML.PloS one · 2014Article
- [Ribonucleotide reductase and non-small cell lung cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2012Review
- Target mRNA inhibition by oligonucleotide drugs in man.Nucleic acids research · 2012Article
- Biochemical modulation of aracytidine (Ara-C) effects by GTI-2040, a ribonucleotide reductase inhibitor, in K562 human leukemia cells.The AAPS journal · 2011Article
- Targeted delivery of antisense oligodeoxynucleotide by transferrin conjugated pH-sensitive lipopolyplex nanoparticles: a novel oligonucleotide-based therapeutic strategy in acute myeloid leukemia.Molecular pharmaceutics · 2010Article
- Phase I trial of GTI-2040, oxaliplatin, and capecitabine in the treatment of advanced metastatic solid tumors: a California Cancer Consortium Study.Cancer chemotherapy and pharmacology · 2009Article
- New agents in acute myeloid leukemia: beyond cytarabine and anthracyclines.Current oncology reports · 2009Review
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
purposeInhibition of ribonucleotide reductase reduces the availability of the endogenous pool of deoxycytidine and may increase cytarabine (AraC) cytotoxicity. We performed a phase I dose escalation trial of AraC combined with GTI-2040, a 20-mer antisense oligonucleotide shown in preclinical studies to decrease levels of the R2 subunit of ribonucleotide reductase, to determine the maximum tolerated dose in adults with relapsed/refractory acute myeloid leukemia. EXPERIMENTAL
designTwenty-three adults (ages 18-59 years) were enrolled in this dose escalation phase I trial, receiving high-dose AraC twice daily combined with infusional GTI-2040. An ELISA-based assay measured plasma and intracellular concentrations of GTI-2040. R2 protein changes were evaluated by immunoblotting in pretreatment and post-treatment bone marrow samples.
resultsThe maximum tolerated dose was 5 mg/kg/d GTI-2040 (days 1-6) and 3 g/m2/dose AraC every 12 hours for 8 doses. Neurotoxicity was dose limiting. Eight patients (35%) achieved complete remission. Mean bone marrow intracellular concentration of GTI-2040 were higher at 120 hours than at 24 hours from the start of GTI-2040 (P = 0.002), suggesting intracellular drug accumulation over time. Reductions in bone marrow levels of R2 protein (>50%) were observed at 24 and 120 hours. Higher baseline R2 protein expression (P = 0.03) and reductions after 24 hours of GTI-2040 (P = 0.04) were associated with complete remission.
conclusionsGTI-2040 and high-dose AraC were coadministered safely with successful reduction of the intended R2 target and encouraging clinical results. The clinical efficacy of this combination will be tested in an upcoming phase II study.
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