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Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies.
Abstract
PURPOSE: The phosphoprotein p53 is involved in transcriptional regulation and is detected in hematologic malignancies. In vitro incubation of acute myelogenous leukemia with OL(1)p53, a 20-mer phosphorothioate oligonucleotide complementary to p53 mRNA, results in leukemic cell death. A phase I dose-escalating trial was conducted to determine the toxicity of OL(1)p53 following systemic administration to patients with hematologic malignancies. PATIENTS AND METHODS: Sixteen patients with either refractory acute myelogenous leukemia (n = 6) or advanced myelodysplastic syndrome (n = 10) participated in the trial. Patients were given OL(1)p53 at doses of 0.05 to 0.25 mg/kg/h for 10 days by continuous intravenous infusion. RESULTS: No specific toxicity was directly related to the administration of OL(1)p53. One patient developed transient nonoliguric renal failure. One patient died of anthracycline-induced cardiac failure. Approximately 36% of the administered dose of OL(1)p53 was recovered intact in the urine. Plasma concentrations and area under the plasma concentration curves were linearly correlated with dose. Leukemic cell growth in vitro was inhibited as compared with pretreatment samples. There were no clinical complete responses. CONCLUSION: A phosphorothioate oligonucleotide, OL(1)p53, can be administered systemically without complications. This type of modified oligonucleotide can be administered without complete degradation, as it was recovered from the urine intact. This oligonucleotide may be useful in combination with currently available chemotherapy agents for the treatment of malignancies.
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“Unfortunately, few desired results have been obtained in clinical trials, and no further advancement has been made since 2012.558–560”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [558]
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Metadata
- Authors
- Bishop, M. R., Iversen, P. L., Bayever, E., Sharp, J. G., Greiner, T. C., Copple, B. L., Ruddon, R., Zon, G., Spinolo, J., Arneson, M., Armitage, J. O., & Kessinger, A.
- Affiliations
- University of Nebraska Medical Center (US)
- Venue
- Journal of Clinical Oncology
- Published
- 1996-04
- Volume
- 14
- Issue
- 4
- Pages
- 1320-1326
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W1821878109
- Cited by
- 136
- References
- 20
- Citations by year
- 2026: 2 · 2023: 2 · 2020: 3 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 1
- FWCI
- 7.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Nebraska Medical Center
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- antisense oligonucleotides, phosphorothioate oligonucleotides, p53 mRNA, acute myeloid leukemia, myelodysplastic syndrome, hematologic malignancies, drug toxicity, renal failure, pharmacokinetics, dose escalation
- MeSH terms
- Adult, Aged, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Myelodysplastic Syndromes, Thionucleotides, Leukemia, Myeloid, Acute, Oligonucleotides, Antisense, Treatment Outcome, Oligodeoxyribonucleotides, Antisense
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