Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia [published erratum appears in Blood 1992 Aug 1;80(3):855]
Open accessAbstract
Although all-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), all groups have described clinical relapses despite continued RA treatment. This finding suggests that resistance to the cytodifferentiating effects of the retinoid had been acquired. To investigate potential mechanisms of clinical resistance to RA, we serially evaluated the clinical pharmacology of the drug in APL patients treated with this agent. Leukemic cells from patients relapsing from RA treatment were cultured in the presence of RA and examined for evidence of morphologic maturation. We also studied messenger RNA expression of the newly described gene product of the (15;17) translocation in APL, PML/RA receptor-alpha (PML/RAR-alpha). Serial pharmacokinetic studies showed that continuous daily RA treatment was associated with a marked decrease in plasma drug concentrations at the time of relapse compared with the initial day of therapy. Doubling the RA dose in six patients failed to reinduce response at the time of relapse and also failed to significantly augment plasma RA concentrations. However, leukemic cells obtained at the time of relapse from four patients retained in vitro sensitivity to the differentiating activity of RA (10(-6) mol/L). No change was observed in the pattern of PML/RAR-alpha expression assessed by Northern blot analysis at the time of relapse compared with pretreatment in two patients who were tested. These results indicate that clinical relapse and “resistance” to continuous treatment with all- trans RA in APL is associated with progressive reduction of plasma concentrations, potentially to levels below those that sustain differentiation of leukemic cells in vivo. Long-term success of this treatment will require the development of strategies that circumvent this pharmacologic phenomenon.
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RA induces undesirable side effects (congenital malformations as well as mucocutaneous dryness, headache, and hypertriglyceridemia) when administered at high concentrations.
“Moreover, it induces undesirable side effects (congenital malformations40 as well as mucocutaneous dryness, headache, and hypertriglyceridemia41) when administered at high concentrations.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [41]
In vivo tests showed that rats or human patients treated with ATRA-containing liposomes by intravenous administration had no decrease in plasma ATRA levels while animals/humans treated with oral formulation of ATRA (nonliposomal) had a significant decrease in plasma ATRA levels.
“In vivo tests showed that rats49 or human patients70 treated with ATRA-containing liposomes by intravenous administration had no decrease in plasma ATRA levels while animals/humans treated with oral formulation of ATRA (nonliposomal) had a significant decrease in plasma ATRA levels41,49.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [41]
Resistance to ATRA in patients treated with daily oral administration was due to the decrease of ATRA concentration in the plasma, and thus the inability of the drug to differentiate leukemic cells.
“Follow-up studies indicated that resistance was due to the decrease of ATRA concentration in the plasma, and thus the inability of the drug to differentiate leukemic cells41.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [41]
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Research works printed but not linked: 2
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- Francis PA, Riggs JR, Muindi JR, Kris MG, Young CW, Warrell RP Jr: Modulation of all-trans retinoic acid (RA) pharma- cokinetics by a cytochrome P-450 enzyme system inhibitor. Proc Am Soc Clin Oncol (in press)
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Chemotherapeutic strategies for renal cell carcinoma
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- Authors
- Muindi, J., Frankel, Sr., Miller, W. J., Jakubowski, A., Scheinberg, D., Young, C., Dmitrovsky, E., & Warrell, R. J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 1992-01-15
- Volume
- 79
- Issue
- 2
- Pages
- 299-303
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W4246713397
- Cited by
- 314
- References
- 0
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 9 · 2021: 6 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 6 · 2016: 6 · 2015: 12 · 2014: 9 · 2012: 7
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- all-trans retinoic acid, acute promyelocytic leukemia, relapse, drug resistance, plasma drug concentration, pharmacokinetics, leukemia cell differentiation, dose escalation
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