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Targeting p53 in vi...
Targeting p53 in vivo : a first-in-man study with the p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer
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Lehmann, S (författare)
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Bykov, VJ (författare)
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Ali, D (författare)
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- Andrén, Ove, 1963- (författare)
- Örebro universitet,Institutionen för hälsovetenskap och medicin
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Cherif, H (författare)
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- Tidefelt, Ulf, 1951- (författare)
- Örebro universitet,Institutionen för läkarutbildning
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- Uggla, Bertil, 1962- (författare)
- Örebro universitet,Institutionen för läkarutbildning
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Yachnin, J (författare)
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Juliusson, G (författare)
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Moshfegh, A (författare)
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Paul, C (författare)
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Wiman, KG (författare)
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Andersson, PO (författare)
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(creator_code:org_t)
- American Society of Clinical Oncology, 2012
- 2012
- Engelska.
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 30:29, s. 3633-3639
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- PURPOSE: APR-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 METHODS: APR-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.RESULTS: MTD 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- Onkologi
- Oncology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Lehmann, S
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Bykov, VJ
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Ali, D
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Andrén, Ove, 196 ...
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Cherif, H
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Tidefelt, Ulf, 1 ...
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visa fler...
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Uggla, Bertil, 1 ...
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Yachnin, J
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Juliusson, G
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Moshfegh, A
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Paul, C
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Wiman, KG
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Andersson, PO
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Cancer och onkol ...
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Örebro universitet