Inhibition of carrier‐mediated uptake of epirubicin reduces cytotoxicity in primary culture of rat hepatocytes

Iwakiri, Tomomi; Okumura, Manabu; Hidaka, Muneaki; Kumagai, Yoshinao; Ichihara, Emi; Kawano, Yoshinobu; Arimori, Kazuhiko

doi:10.1002/jat.1283

Cited by 12 publications

(2 citation statements)

References 37 publications

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“…Hypothermia not only helps with targeting tumor cells with cytotoxics 33 but also prevents the uptake of EPI into healthy cells by inhibiting a transport protein. 34 Although our ITCH technique of serial, slow, smalldose marginal, and single-site injection diverges from conventional intratumoral chemoablative methods, [35][36][37][38] it insured an adequate monitoring and good IT distribution of the injectate to more than 70% of the target tumor with moderate leakage. Larger series are needed to confirm those results.…”

Section: Safetymentioning

confidence: 99%

Percutaneous Tumor Ablation

Xiao

et al. 2016

Technol Cancer Res Treat

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This acute study was aimed at exploring the ability of a cryoablative lesion to drive the distribution of a concomitant in situ injection of a free epirubicin-ethanol-ethiodol-methylene blue mixture. We report the feasibility and safety of this new percutaneous computed tomography-guided combinatorial ablative procedure on VX2 tumors. Eight New Zealand white rabbits bearing 16 tumors on both side of the back muscle were randomly selected and treated on the same day with the following procedures: (1) 8 concomitant cryoablation and interstitial chemotherapy and (2) 8 intratumor marginal chemotherapy. For the latter, an injection needle was positioned at the inner distal margin of a first selected tumor side, where the chemotherapy was delivered during 5 serial sequences. For the concomitant therapy, a single cryoneedle maintained the ice front at the tumor margin, where a needle delivered the drug dose during 5 freeze-injection-thaw sequences. Enhanced computed tomography scans on days 3, 7, and 10 assessed the tumor contours and the tracer localization. Two rabbits were killed on days 0, 3, 7, and 10 for gross and histopathological analyses. During the concomitant therapy, ioversol was distributed at the tumor and iceball margins along with the methylene blue. Enhanced computed tomography on days 3, 7, and 10 showed a focal enlarging defect of the tumor marginal enhancing rim. The rim coincided with focal necrosis at histopathology. During the intratumor chemotherapy procedure, computed tomography showed that the tracers distributed mostly over the tumor mass. No marginal necrosis was detected at histopathology. On day 10, the tumor size for the intratumor chemotherapy group was twice that of the concomitant therapy group. No adverse events were observed. In this VX2 tumor model, our image-guided concomitant therapy is feasible and may enhance the effectiveness of a free epirubicin tracer mixture at the tumor margin.

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Section: Safetymentioning

confidence: 99%

Percutaneous Tumor Ablation

Xiao

et al. 2016

Technol Cancer Res Treat

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“…The drug ratios used in the MAGIC study in mg/m 2 were one part epirubicin to 1.2 parts of cisplatin and to 4 parts 5FU. These ratios were adapted for cell culture conditions to the clinical concentration of 7.5× 10 −7 M epirubicin [16]. Deduced from those data the three component mixture ECF (0.75 μM epirubicin/0.90 μM cisplatin/3.0 μM 5FU) were prepared and their cytostatic activity in comparison to those of the duplex drug was investigated on both adenocarcinoma cell lines.…”

Section: Adenocarcinoma Cell Linesmentioning

confidence: 99%

Cytostatic activity of the duplex drug linking 2′-deoxy-5-fluorouridine (5FdU) with 3′-C-ethynylcytidine (ECyd) against gastric adenocarcinoma cell lines

et al. 2010

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The cytostatic potential of the new duplex drug 2'-deoxy-5-fluorouridylyl-(5'5')-3'-C-ethynylcytidine (5FdU(5'-5')ECyd) was evaluated in comparison to those of 5-fluorouracil (5FU), 2'-deoxy-5-fluorourindine (5FdU), 3'-C-ethynylycytidine (ECyd), cisplatin, an equimolar mixture of 5FdU + ECyd and a three component-mixture of 0.75 μM epirubicin/0.90 μM cisplatin/3.0 μM 5FU (ECF) by incubation of the two human gastric adenocarcinoma cell lines 23132/87 and MKN-45. The molar composition of ECF was taken from data of a triple combination chemotherapy for human gastric cancer. Time and dose depending inhibition of cell growth was determinated using the CASY technology. A growth decrease of both cell lines from 100% to about 20% was observed by treatment with ECF over a course of 14 days. This result provided basis to estimate the cytostatic potential of all tested drugs and combinations thereof. Corresponding high activities in respect to ECF were achieved by incubation of 23132/87 cells with single drugs 49 μM 5FU, 10 μM cisplatin, 3.4 μM 5FdU, 0.65 μM ECyd, the mixture 0.32 μM 5FdU + 0.32 μM ECyd and 0.32 μM 5FdU(5'-5')ECyd. The less sensitive MKN-45 cells require a 1.5-4 fold higher dose of the standard chemotherapeutics in order to achieve an equivalent cytostatic effect, in respect to the 23132/87 cell line,. However, the effect of the duplex drugs on MKN-45 cells was gained with a 5-fold lower dose than ECF. Due to its high cytostatic potential the duplex drug, which covalently links two active anticancer compounds, could be a new therapeutic alternative for chemotherapy in gastric cancer, currently treated with different combinations.

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Docetaxel, cyclophosphamide, and epirubicin: application of PBPK modeling to gain new insights for drug-drug interactions

Li,

Zhou,

Wang

et al. 2024

J Pharmacokinet Pharmacodyn

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The new adjuvant chemotherapy of docetaxel, epirubicin, and cyclophosphamide has been recommended for treating breast cancer. It is necessary to investigate the potential drug-drug Interactions (DDIs) since they have a narrow therapeutic window in which slight differences in exposure might result in signi cant differences in treatment e cacy and tolerability. To guide clinical rational drug use, this study aimed to evaluate the DDI potentials of docetaxel, cyclophosphamide, and epirubicin in cancer patients using physiologically based pharmacokinetic (PBPK) models. The GastroPlus™ was used to develop the PBPK models, which were re ned and validated with observed data. The established PBPK models accurately described the pharmacokinetics (PKs) of three drugs in cancer patients, and the predicted-to-observed ratios of all the PK parameters met the acceptance criterion. The PBPK model predicted no signi cant changes in plasma concentrations of these drugs during co-administration, which was consistent with the observed clinical phenomenon. Furthermore, the veri ed PBPK models were then used to predict the effect of other Cytochrome P450 3A4 (CYP3A4) inhibitors/inducers on these drug exposures. In the DDI simulation, strong CYP3A4 modulators changed the exposure of three drugs by 0.71-1.61 fold. Therefore, patients receiving these drugs in combination with strong CYP3A4 inhibitors should be monitored regularly to prevent adverse reactions. Furthermore, co-administration of docetaxel, cyclophosphamide, or epirubicin with strong CYP3A4 inducers should be avoided. In conclusion, the PBPK models can be used to further investigate the DDI potential of each drug and to develop dosage recommendations for concurrent usage by additional perpetrators or victims.

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Inhibition of carrier‐mediated uptake of epirubicin reduces cytotoxicity in primary culture of rat hepatocytes

Cited by 12 publications

References 37 publications

Percutaneous Tumor Ablation

Percutaneous Tumor Ablation

Cytostatic activity of the duplex drug linking 2′-deoxy-5-fluorouridine (5FdU) with 3′-C-ethynylcytidine (ECyd) against gastric adenocarcinoma cell lines

Docetaxel, cyclophosphamide, and epirubicin: application of PBPK modeling to gain new insights for drug-drug interactions

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