Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies

M. R. Bishop, P. L. Iversen, E. Bayever, John G Sharp, Timothy Charles Greiner, B. L. Copple, R. Ruddon, G. Zon, J. Spinolo, M. Arneson, James Olen Armitage, A. Kessinger

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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.

Original languageEnglish (US)
Pages (from-to)1320-1326
Number of pages7
JournalJournal of Clinical Oncology
Volume14
Issue number4
DOIs
StatePublished - Jan 1 1996

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Antisense Oligonucleotides
Hematologic Neoplasms
Phosphorothioate Oligonucleotides
Acute Myeloid Leukemia
Oligonucleotides
Urine
Anthracyclines
Phosphoproteins
Myelodysplastic Syndromes
Intravenous Infusions
Renal Insufficiency
OL(1)p53
Cell Death
Heart Failure
Drug Therapy
Messenger RNA
Growth
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies. / Bishop, M. R.; Iversen, P. L.; Bayever, E.; Sharp, John G; Greiner, Timothy Charles; Copple, B. L.; Ruddon, R.; Zon, G.; Spinolo, J.; Arneson, M.; Armitage, James Olen; Kessinger, A.

In: Journal of Clinical Oncology, Vol. 14, No. 4, 01.01.1996, p. 1320-1326.

Research output: Contribution to journalArticle

Bishop, MR, Iversen, PL, Bayever, E, Sharp, JG, Greiner, TC, Copple, BL, Ruddon, R, Zon, G, Spinolo, J, Arneson, M, Armitage, JO & Kessinger, A 1996, 'Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies', Journal of Clinical Oncology, vol. 14, no. 4, pp. 1320-1326. https://doi.org/10.1200/JCO.1996.14.4.1320
Bishop, M. R. ; Iversen, P. L. ; Bayever, E. ; Sharp, John G ; Greiner, Timothy Charles ; Copple, B. L. ; Ruddon, R. ; Zon, G. ; Spinolo, J. ; Arneson, M. ; Armitage, James Olen ; Kessinger, A. / Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies. In: Journal of Clinical Oncology. 1996 ; Vol. 14, No. 4. pp. 1320-1326.
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AU - Iversen, P. L.

AU - Bayever, E.

AU - Sharp, John G

AU - Greiner, Timothy Charles

AU - Copple, B. L.

AU - Ruddon, R.

AU - Zon, G.

AU - Spinolo, J.

AU - Arneson, M.

AU - Armitage, James Olen

AU - Kessinger, A.

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N2 - 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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