Population pharmacokinetics of Daunorubicin in adult patients with acute myeloid leukemia

Varatharajan, Savitha; Panetta, John C.; Abraham, Ajay; Karathedath, Sreeja; Mohanan, Ezhilpavai; Lakshmi, Kavitha M; Arthur, Nancy Beryl Janet; Srivastava, Vivi M.; Nemani, Sandeep; George, Biju; Srivastava, Alok; Balasubramanian, Poonkuzhali

doi:10.1007/s00280-016-3166-8

Cited by 21 publications

(17 citation statements)

References 28 publications

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“…ANT toxicity was induced with clinically relevant concentration of DAU (1.2 μM) (Paul et al, 1989;Varatharajan et al, 2016). The protective effects of DEX and its derivatives were tested in a clinically relevant range of concentrations (10-100 μM).…”

Section: Downloaded Frommentioning

confidence: 99%

Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase IIβInteraction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity

Kollárová-Brázdová¹,

Jirkovská²,

Karabanovich³

et al. 2020

J Pharmacol Exp Ther

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Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SAR) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogues and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase II beta (Top2B) activity in chronic anthracycline cardiotoxicity. Dexrazoxane was alkylated in positions that should not interfere with the metal-chelating mechanism of cardioprotective action; that is, on dioxopiperazine imides or directly on the dioxopiperazine ring. The protective effects of these agents were assessed in vitro in neonatal cardiomyocytes. All studied modifications of dexrazoxane molecule, including simple methylation, were found to abolish the cardioprotective effects. As this challenged the prevailing mechanistic concept and previously reported data, the two closest derivatives (GK-627 and GK-580) were thoroughly scrutinized in vivo using a rabbit model of chronic anthracycline cardiotoxicity. In contrast to dexrazoxane, both compounds failed to protect the heart as demonstrated by mortality, cardiac dysfunction, and myocardial damage parameters, although the pharmacokinetics and metal-chelating properties of their metabolites were comparable to those of dexrazoxane. The loss of cardiac protection was shown to correlate with their abated potential to inhibit and deplete Top2B both in vitro and in vivo. These findings suggest a very tight SAR between bisdioxopiperazine derivatives and their cardioprotective effects, and support Top2B as a pivotal upstream druggable target for effective cardioprotection against anthracycline cardiotoxicity.

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Section: Downloaded Frommentioning

confidence: 99%

Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase IIβInteraction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity

Kollárová-Brázdová¹,

Jirkovská²,

Karabanovich³

et al. 2020

J Pharmacol Exp Ther

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“…Because daunorubicin remains the key drug component in conventional AML therapy, its inactivation by CREs constitutes another mechanism that might be responsible for diminished intracellular drug concentrations and lead to cellular resistance. We therefore screened the effect of CDKI on recombinant CREs isoforms that previously had been suggested to be related to cellular resistance to AML [23][24][25][26][27][28]. None of the tested drugs, however, achieved 50% inhibition in the applied 50 µM concentration.…”

Section: Discussionmentioning

confidence: 99%

Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors

Sorf

Sucha

Morell

et al. 2020

Cancers

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Pharmacotherapy of acute myeloid leukemia (AML) remains challenging, and the disease has one of the lowest curability rates among hematological malignancies. The therapy outcomes are often compromised by the existence of a resistant AML phenotype associated with overexpression of ABCB1 and ABCG2 transporters. Because AML induction therapy frequently consists of anthracycline-like drugs, their efficiency may also be diminished by drug biotransformation via carbonyl reducing enzymes (CRE). In this study, we investigated the modulatory potential of the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib on AML resistance using peripheral blood mononuclear cells (PBMC) isolated from patients with de novo diagnosed AML. We first confirmed inhibitory effect of the tested drugs on ABCB1 and ABCG2 in ABC transporter-expressing resistant HL-60 cells while also showing the ability to sensitize the cells to cytotoxic drugs even as no effect on AML-relevant CRE isoforms was observed. All tested CDK4/6 inhibitors elevated mitoxantrone accumulations in CD34+ PBMC and enhanced accumulation of mitoxantrone was found with abemaciclib and ribociclib in PBMC of FLT3-ITD- patients. Importantly, the accumulation rate in the presence of CDK4/6 inhibitors positively correlated with ABCB1 expression in CD34+ patients and led to enhanced apoptosis of PBMC in contrast to CD34− samples. In summary, combination therapy involving CDK4/6 inhibitors could favorably target multidrug resistance, especially when personalized based on CD34− and ABCB1-related markers.

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“…Daunorubicin ( Figure 1B) is widely used in the treatment of cancers through inducing arrest cell growth and apoptosis [26]. Disappointedly, the clinical application of DA is limited due to its severe side effects, such as cardiotoxicity, bleeding, and gastrointestinal disorders [27,28]. Thus, it is important to explore a novel formulation to the co-deliver HE and DA to prevent gastric cancer effectively considering their high hydrophobicity and side effects, respectively.…”

Section: Introductionmentioning

confidence: 99%

Hesperitin enhances the ability of daunorubicin by co-loading with MPEG-PCL nanoparticles to induce apoptosis in gastric cancer

Zhen¹,

T²,

Tang³

et al. 2017

Oncotarget

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Tumor targeting delivery system has been suggested as an attractive strategy against tumor progression. And combination chemotherapy is essential and effective in preventing gastric cancer. Hesperitin (HE) has been suggested to exhibit anticancer ability through inducing apoptosis in many tumors without obvious toxicity, and it exerts synergistic anti-cancer ability with other drugs. Clinical application of daunorubicin (DA) in treatment of various cancers has been restricted. Targeted delivery of anti-cancer drugs could reduce their off-target effects and promote their efficacy. In our paper, HE and DA co-loaded methoxy poly (ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) nanoparticles were prepared through an assembly method. The morphology, particle size (about 38 nm), zeta potential, release profile in vitro, cell proliferation and cytotoxicity effects were investigated. The results suggested that HE and DA could be efficiently loaded into MPEG-PCL nanoparticles synchronously, and in vitro study indicated that they could be released from the nanoparticles in an extended period. in vitro, HE/DA/MPEG-PCL exerted an enhanced cytotoxicity and high apoptosis-inducing activities of gastric cancer cells. Importantly, HE/DA/MPEG-PCL exhibited better cancer targeting and accumulation, enhancing the anti-tumor efficacy with little toxicity. Together, HE/DA/MPEG-PCL promoted the drug target on tumor site with preferable anti-tumor effects, which could be a promising therapeutic strategy against human gastric cancer.

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Population pharmacokinetics of Daunorubicin in adult patients with acute myeloid leukemia

Abstract: Further validation of these findings in a larger cohort of AML patients is warranted before establishing a therapeutic window for plasma Dnr levels and targeted dose adjustment.

Cited by 21 publications

References 28 publications

Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase IIβInteraction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity

Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase IIβInteraction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity

Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors

Hesperitin enhances the ability of daunorubicin by co-loading with MPEG-PCL nanoparticles to induce apoptosis in gastric cancer

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