Development of a Preclinical PK/PD Model to Assess Antitumor Response of a Sequential Aflibercept and Doxorubicin-Dosing Strategy in Acute Myeloid Leukemia

Fetterly, Gerald J.; Aras, Urvi; Lal, Deepika; Murphy, Michael P.; Meholick, Patricia D.; Wang, Eunice S.

doi:10.1208/s12248-013-9480-8

Cited by 14 publications

(9 citation statements)

References 52 publications

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“…Daunorubicinol was quantified using a high performance liquid chromatography (UPLC) fluorescent detection method (28). The metabolite was extracted, and then quantified using a daunorubicinol standard (Toronto Research Chemicals, Toronto, ON) as previously described (29). …”

Section: Methodsmentioning

confidence: 99%

Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome

et al. 2014

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Purpose The intracardiac synthesis of anthracycline alcohol metabolites (e.g., daunorubicinol) contributes to the pathogenesis of anthracycline-related cardiotoxicity. Cancer patients with Down syndrome (DS) are at increased risk for anthracycline-related cardiotoxicity. We profiled the expression of anthracycline metabolizing enzymes in hearts from donors with- and without- DS. Methods Cardiac expression of CBR1, CBR3, AKR1A1, AKR1C3 and AKR7A2 was examined by quantitative real time PCR, quantitative immunoblotting, and enzyme activity assays using daunorubicin. The CBR1 polymorphism rs9024 was investigated by allelic discrimination with fluorescent probes. The contribution of CBRs/AKRs proteins to daunorubicin reductase activity was examined by multiple linear regression. Results CBR1 was the most abundant transcript (average relative expression; DS: 81%, non-DS: 58%), and AKR7A2 was the most abundant protein (average relative expression; DS: 38%, non-DS: 35%). Positive associations between cardiac CBR1 protein levels and daunorubicin reductase activity were found for samples from donors with- and without- DS. Regression analysis suggests that sex, CBR1, AKR1A1, and AKR7A2 protein levels were significant contributors to cardiac daunorubicin reductase activity. CBR1 rs9024 genotype status impacts on cardiac CBR1 expression in non-DS hearts. Conclusions CBR1, AKR1A1, and AKR7A2 protein levels point to be important determinants for predicting the synthesis of cardiotoxic daunorubicinol in heart.

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Section: Methodsmentioning

confidence: 99%

Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome

et al. 2014

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“…PIGF expression is also upregulated by anti-VEGF therapy in cancer patients, indicating that PIGF may also play a role in the resistance to anti-VEGF treatment 50,51. In addition, aflibercept was shown to inhibit tumor proliferation, angiogenesis, and metastases in tumor-bearing mouse model 52,53…”

Section: Aflibercept a Fusion Proteinmentioning

confidence: 99%

Molecularly targeted drugs for metastatic colorectal cancer

Cheng¹,

Yang²,

Zhang³

2013

DDDT

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The survival rate of patients with metastatic colorectal cancer (mCRC) has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin)–fluorouracil–irinotecan (FOLFIRI) chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS, the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin)–fluorouracil–oxaliplatin (FOLFOX) or FOLFIRI. Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs.

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“…Doxorubicin (DOX) is mostly known as an anthracycline agent for the treatment of variety of malignancies (Fetterly et al, 2013;Lin et al, 2014). DOX can also be applied on proliferative vitreoretinopathy (PVR) (Sunalpa et al, 1985), which manifests itself by the formation of fibrocellular membranes on the retinal and posterior hyaloid surfaces (Hiscott & Wong, 2010).…”

Section: Introductionmentioning

confidence: 99%

Preparation and ocular pharmacokinetics of hyaluronan acid-modified mucoadhesive liposomes

Lin

Wang

et al. 2014

Drug Delivery

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The aim of this research was to formulate a liposomal preparation of DOX to be applied topically, and to investigate the in vitro and in vivo performance of the prepared liposomes. DOX liposomes were prepared by the solvent evaporation method, and then modified with bioadhesive material HA. Through MTT assay, we found that the safe concentration of liposomes delivered would hit 1 mg/mL. Cellular uptake studies showed that DOX liposomes coated with HA are much more targetable to cell nucleus. Their ocular pharmacokinetics in rabbits were investigated through the comparison with those obtained after dosing with nonmodified liposomes and DOX solution. The in vitro transcorneal permeability of DOX in both kinds of liposomes was found to be slower than that of the solution because of sustained release. After in vivo instillation in rabbits, HA-modified liposomes had the longest retention time, following with naked liposomes. Significantly, the area under the curve of the aqueous humor concentration-time profiles of DOX liposomes was found to be 1.7-fold higher than that of DOX solution. The confocal experiment confirmed that HA-modified liposomes were able to maintain a higher DOX concentration and residence time than that of non-modified liposomes and free DOX. These results suggest that our liposomal preparation was of great help to improve the bioavailability of DOX.

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Development of a Preclinical PK/PD Model to Assess Antitumor Response of a Sequential Aflibercept and Doxorubicin-Dosing Strategy in Acute Myeloid Leukemia

Cited by 14 publications

References 52 publications

Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome

Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome

Molecularly targeted drugs for metastatic colorectal cancer

Preparation and ocular pharmacokinetics of hyaluronan acid-modified mucoadhesive liposomes

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