Relationship between plasma adriamycin levels and the outcome of remission induction therapy for acute nonlymphocytic leukemia

Preisler, Harvey D.; Gessner, Teresa; Azarnia, Nozar; Bolanowska, Wanda E.; Epstein, Joshua; Early, Amy P.; D'Arrigo, Peter; Vogler, Ralph; Winton, Lee; Chervenik, Paul; Joyce, Robert A.; Lee, Howard; Steele, Robert; Goldberg, Jack; Gottlieb, Arlan J.; Browman, George P.; Miller, Kenneth B.; Grünwald, Hans; Larson, Richard A.; Brennan, James K.

doi:10.1007/bf00254604

Cited by 56 publications

(15 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although anthracyclines have been studied for more than four decades, a clear correlation between their pharmacokinetics and therapeutic effect has not been shown, with exception of one study reporting a relationship between plasma concentrations of doxorubicin and the outcome of induction therapy [7].…”

Section: Introductionmentioning

confidence: 99%

Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response

Bogason

Bhuiyan

Masquelier

et al. 2009

Eur J Clin Pharmacol

View full text Add to dashboard Cite

Aims To study anthracycline-induced apoptosis in leukemic cells isolated from patients with acute myelogenous leukemia (AML) in vitro and to compare intracellular anthracycline concentrations causing apoptosis in vitro with those obtained in vivo during anthracycline treatment. Methods Mononuclear blood cells from AML patients were isolated before (n=20) and after anthracycline infusion (n= 24). The pre-treated cells were incubated in vitro with daunorubicin (DNR) and/or idarubicin (IDA). Anthracycline concentrations were determined by high-performance liquid chromatography, and apoptosis was detected by propidium iodine staining using a flow cytometer. Results There was a clear concentration-response relationship between intracellular anthracycline levels and apoptosis albeit with a large interindividual variation. Intracellular levels >1200 μM always led to high apoptosis development (>60%) in vitro. The intracellular concentrations of DNR in vivo (n=24) were more than tenfold lower than the concentrations needed to induce effective apoptosis in vitro, although a significant relation between in vivo concentrations and clinical remission was found. We also found a significant relation between apoptosis induction in leukemic cells by IDA in vitro and clinical remission. Conclusions Our results indicate that intracellular anthracycline levels in vivo are suboptimal and that protocols should be used that increase intracellular anthracycline levels.

show abstract

Section: Introductionmentioning

confidence: 99%

Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response

Bogason

Bhuiyan

Masquelier

et al. 2009

Eur J Clin Pharmacol

View full text Add to dashboard Cite

show abstract

“…Individual plasma concentrations and area under the curve (AUC) values of DOX differ up to 10-fold (Frost et al, 2002 and references therein). High plasma DOX correlates with remission in children with acute myeloid leukemia (Palle et al, 2006) and in adult patients with acute nonlymphocytic leukemia (Preisler et al, 1984). On the other hand, high DOX plasma concentrations may lead to cardiotoxicity (Minotti et al, 2004).…”

mentioning

confidence: 99%

Carbonyl Reductase 1 Is a Predominant Doxorubicin Reductase in the Human Liver

Kassner¹,

Huse²,

Martin³

et al. 2008

Drug Metab Dispos

164

146

View full text Add to dashboard Cite

ABSTRACT:A first step in the enzymatic disposition of the antineoplastic drug doxorubicin (DOX) is the reduction to doxorubicinol (DOX-OL). Because DOX-OL is less antineoplastic but more cardiotoxic than the parent compound, the individual rate of this reaction may affect the antitumor effect and the risk of DOX-induced heart failure. Using purified enzymes and human tissues we determined enzymes generating DOX-OL and interindividual differences in their activities. Human tissues express at least two DOX-reducing enzymes. High-clearance organs (kidney, liver, and the gastrointestinal tract) express an enzyme with an apparent K m of ϳ140 M. Of six enzymes found to reduce DOX, K m values in this range are exhibited by carbonyl reductase 1 (CBR1) and aldo-keto reductase (AKR) 1C3. CBR1 is expressed in these three organs at higher levels than AKR1C3, whereas AKR1C3 has higher catalytic efficiency. However, inhibition constants for DOX reduction with 4-amino-1-tert-butyl-3-(2-hydroxyphenyl)pyrazolo[3,4-d]pyrimidine(an inhibitor that can discriminate between CBR1 and AKR1C3) were identical for CBR1 and human liver cytosol, but not for AKR1C3. These results suggest that CBR1 is a predominant hepatic DOX reductase. In cytosols from 80 human livers, the expression level of CBR1 and the activity of DOX reduction varied >70-and 22-fold, respectively, but showed no association with CBR1 gene variants found in these samples. Instead, the interindividual differences in CBR1 expression and activity may be mediated by environmental factors acting via recently identified xenobiotic response elements in the CBR1 promoter. The variability in the CBR1 expression may affect outcomes of therapies with DOX, as well as with other CBR1 substrates.

show abstract

“…As a some success. High doxorubicin levels were associated with ; , the dosage reductions recommended for epirubicin prolonged remission duration in patients with acute nonlymmorubicin data sheet, Farmitalia Carlo Erba) were phocytic leukaemia (Preisler et al, 1984). Similarly, Robert et ir to those for doxorubicin.…”

Section: Comparison Ofpharmacokinetic Parametersmentioning

confidence: 96%

“…Indeed, subsequent reports failed demonstrated a relationship between liver biochemistry, in Infirm a close relationship between abnormal liver bioparticular AST, and epirubicin pharmacokinetics. The study istry and either clinical toxicity or pharmacokinetic design, with weekly low dose chemotherapy for most neters in patients receiving doxorubicin (Brenner et al, patients, and split-dose treatment for many others, precludes Preisler et al, 1984;Preiss et al, 1987;Frenay et al, an evaluation of the relationship between liver biochemistry, l.…”

Section: Comparison Ofpharmacokinetic Parametersmentioning

confidence: 99%

Clinical pharmacokinetics of epirubicin: the importance of liver biochemistry tests

Twelves

Dobbs²,

Michael³

et al. 1992

Br J Cancer

View full text Add to dashboard Cite

Relationship between plasma adriamycin levels and the outcome of remission induction therapy for acute nonlymphocytic leukemia

Cited by 56 publications

References 12 publications

Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response

Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response

Carbonyl Reductase 1 Is a Predominant Doxorubicin Reductase in the Human Liver

Clinical pharmacokinetics of epirubicin: the importance of liver biochemistry tests

Contact Info

Product

Resources

About