Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft

Hao, Fangran; Wang, Siyuan; Zhu, Xiao; Xue, Jing; Li, Jingyun; Wang, Lijie; Li, Jian; Lu, Wei; Zhou, Tianyan

doi:10.1007/s11095-016-2071-5

Cited by 13 publications

(11 citation statements)

References 33 publications

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“…Tumor growth dynamics of two cell lines of breast cancer (HER2+ and Triple Negative) were modelled in the absence (unperturbed) or presence (perturbed) of MBQ-167 using the model proposed by Simeoni et al [ 10 ]. There is vast scientific evidence regarding the ability of the model to quantitatively characterize the time-course of tumor dynamics in xenograft experiments and evaluate the efficacy of anticancer drugs early in discovery and development [ 15 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. The mathematical framework allowed for an adequate prediction of the tumor dynamics under the different groups considered.…”

Section: Discussionmentioning

confidence: 99%

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

et al. 2020

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MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mouse tissues (e.g., lungs, heart, liver, kidneys, spleen, plasma) and tumor, since the predicted results were consistent with the experimental data. The developed PBPK-PD model successfully predicts tumor shrinkage in HER2+ and triple-negative breast tumors after the intraperitoneal administration of 1 and 10 mg/kg body weight (BW) dose level of MBQ-167 three times a week. The findings from this study suggest that MBQ-167 has a higher net effect and potency inhibiting Triple Negative mammary tumor growth compared to HER2+ and that liver metabolism is the major route of elimination of this drug.

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Section: Discussionmentioning

confidence: 99%

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

et al. 2020

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“…Wang et al [22] have found that dopamine (DA) may have the function inhibiting the growth of BCSCs characterized by CD44 + / CD24 −/low via the activation of D1 DA receptor, thus enhancing the response of SUN in breast cancer MCF-7/ADR. The combination therapy of SUN and DA was afterwards experimented on A549 non-small-cell lung cancer xenograft model, resulting in stronger response than SUN monotherapy [23]. These findings provide a potential solution that AX co-administered with DA could hopefully overcome the unsatisfactory outcome of AX as a single agent.…”

Section: Introductionmentioning

confidence: 94%

“…For example, studies have revealed that AX is primarily cleared via metabolism by CYP3A4, which is one kind of phase I metabolic enzymes, in human bodies [33,34]. While the small polar compound DA is metabolized by phase II metabolic enzymes, which are monoamine oxidase and catechol-O-methyl transferase [23]. Neither of them has been reported to impact the activity of the enzymes above.…”

Section: Pk-pd Modelingmentioning

confidence: 99%

“…To further explore the potential information from the experimental data, pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation is an appropriate instrument that has many advantages [24,25]. A series of PK-PD studies focused on TKI therapies have been developed to provide new thoughts regarding predicting outcomes, making decisions, and optimizing dosage regimens, which gave good examples for the present study to take advantage of [23,[26][27][28]. With the help of PK-PD modeling and simulation, the quantitative relationship between drug plasma concentration and antitumor effect would be understood deeply and precisely, thus making it possible to optimize experimental designs, which is time-saving and efficiency-increasing [25].…”

Section: Introductionmentioning

confidence: 99%

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Antitumor effect of axitinib combined with dopamine and PK-PD modeling in the treatment of human breast cancer xenograft

Wang

Ren

et al. 2018

Acta Pharmacol Sin

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Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX's efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA. The results showed that AX up-regulated the expression of breast CSC (BCSC) markers (CD44/CD24) in vivo, and DA significantly synergized the inhibitory effect on tumor growth by deducting the BCSC frequency. The PK-PD model quantitatively confirmed the synergistic interaction with the parameter estimate of interaction factor ψ 2.43. The dose regimen was optimized as 60 mg/kg AX i.g. b.i.d. combined with 50 mg/kg DA i.p. q3d in the simulation study on the basis of the PK-PD model. The model where DA synergistically enhances the effect of AX in an all-or-none manner provides a possible solution in modeling the agents like DA. Moreover, the outcome of AX and DA combination therapy in MCF-7/ADR breast cancer provided further insight of co-administering DA in the treatment of the possible CSC-causing AX-resisting breast cancer. And this combination therapy has the prospect of clinical translation.

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“…In the present work, we evaluated the in vitro inhibitory effect of a novel multikinase inhibitor, namely R8 (Figure 1 ), on several different types cancer cells. We further focused on the mechanism for its inhibition on lung cancer cells specifically, which showed distinct characteristics compared to Sunitinib, a clinically available MKI which has been investigated extensively in many types of cancer including lung cancer, either used alone or in combination with other therapeutics [ 9 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

A novel multikinase inhibitor R8 exhibits potent inhibition on cancer cells through both apoptosis and autophagic cell death

Xie

Huang

et al. 2017

Oncotarget

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Chemotherapy is an important treatment for cancer patients, especially for those with unresectable lesions. Targeted therapy of cancer by specific inhibition of aberrant tyrosine kinase activities in cancer cells with chemically synthesized tyrosine kinase inhibitors (TKIs), shows better responses while less side effects than traditional chemotherapeutic drugs. It is common that cancer cells often exhibit deregulation of several tyrosine kinases simultaneously, multikinase TKIs (MKIs) therefore have greater advantages over single-target TKIs. Currently more MKIs are under developing for better efficacy for different types of cancer. In the present work, we evaluated the in vitro therapeutic potential of a novel MKI, namely R8, with comparison to the clinically available MKI Sunitinib. Results showed that R8 has stronger inhibition on six different types of cancer cell lines with lower IC50 than Sunitinib does. Cell cycle analysis showed that R8 induced significant G0/G1 arrest phase of lung cancer A549 and NCI-H226 cells. The inhibition was also confirmed by colony formation and migration assays in both lung cancer cell lines in a dose-dependent manner. R8 could significantly inhibit the phosphorylation of multiple receptor tyrosine kinases (RTKs) included PDGFRβ, VEGFR2, EGFR and C-Kit, leading to the down-regulation of PI3K-Akt-mTOR signaling. Further analysis revealed that R8 treatment induced more significant apoptosis than Sunitinib did, which might be the consequence of the autophagic cell death. In conclusion, this work suggested R8 to be a promising novel anticancer MKI, and provided the basis for further in vivo investigation on its potential in treatment of lung cancer.

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Pharmacokinetic-Pharmacodynamic Modeling of the Anti-Tumor Effect of Sunitinib Combined with Dopamine in the Human Non-Small Cell Lung Cancer Xenograft

Abstract: The synergistic effect of sunitinib and dopamine was demonstrated by the preclinical experiment and confirmed by the developed PK/PD model. In addition, the regimens were optimized by means of modeling as well as simulation, which may be conducive to clinical study.

Cited by 13 publications

References 33 publications

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

Antitumor effect of axitinib combined with dopamine and PK-PD modeling in the treatment of human breast cancer xenograft

A novel multikinase inhibitor R8 exhibits potent inhibition on cancer cells through both apoptosis and autophagic cell death

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