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Targeting p53 in Vi...
Targeting p53 in Vivo : a First-in-Human Study With p53-Targeting Compound APR-246 in Refractory Hematologic Malignancies and Prostate Cancer
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- Lehmann, Sören (author)
- Karolinska Institutet
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- Bykov, Vladimir J N (author)
- Karolinska Institutet
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Ali, Dina (author)
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Andrén, Ove (author)
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- Cherif, Honar (author)
- Uppsala universitet,Hematologi
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Tidefelt, Ulf (author)
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Uggla, Bertil (author)
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- Yachnin, Jeffrey (author)
- Uppsala universitet,Enheten för onkologi
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- Juliusson, Gunnar (author)
- Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine
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- Moshfegh, Ali (author)
- Karolinska Institutet
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Paul, Christer (author)
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- Wiman, Klas G (author)
- Karolinska Institutet
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Andersson, Per-Ola (author)
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(creator_code:org_t)
- 2012
- 2012
- English.
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In: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 30:29, s. 3633-3639
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http://dx.doi.org/10...
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Abstract
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- PURPOSEAPR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.PATIENTS AND METHODSAPR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.RESULTSMTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.CONCLUSION We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Lehmann, Sören
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Bykov, Vladimir ...
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Ali, Dina
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Andrén, Ove
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Cherif, Honar
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Tidefelt, Ulf
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show more...
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Uggla, Bertil
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Yachnin, Jeffrey
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Juliusson, Gunna ...
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Moshfegh, Ali
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Paul, Christer
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Wiman, Klas G
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Andersson, Per-O ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Journal of Clini ...
- By the university
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Uppsala University
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Lund University
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Karolinska Institutet