Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies
| Autor: | John G Sharp, Mark A. Arneson, Patrick L. Iversen, Raymond W. Ruddon, Anne Kessinger, Bryan L. Copple, E. Bayever, J Spinolo, James O. Armitage, Michael R. Bishop, Timothy C. Greiner, Gerald Zon |
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| Rok vydání: | 1996 |
| Předmět: |
Adult
Male Cancer Research Myeloid medicine.medical_treatment Molecular Sequence Data Pharmacology Oligodeoxyribonucleotides Antisense Myelogenous Pharmacokinetics Refractory medicine Humans Aged Chemotherapy business.industry Middle Aged Oligonucleotides Antisense Thionucleotides medicine.disease Leukemia Myeloid Acute Leukemia Treatment Outcome medicine.anatomical_structure Oncology Myelodysplastic Syndromes Toxicity Immunology Systemic administration Female business |
| Zdroj: | Journal of Clinical Oncology. 14:1320-1326 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.1996.14.4.1320 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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