Dataset Information

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

ABSTRACT:

Aim

Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen.

Methods

ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen.

Results

The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (?) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (?5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research.

Conclusion

The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.

SUBMITTER: Li JY

PROVIDER: S-EPMC4933764 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

Li Jing-Yun JY Ren Yu-Peng YP Yuan Yin Y Ji Shuang-Min SM Zhou Shu-Pei SP Wang Li-Jie LJ Mou Zhen-Zhen ZZ Li Liang L Lu Wei W Zhou Tian-Yan TY

Acta pharmacologica Sinica 20160516 7

<h4>Aim</h4>Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling a ...[more]

PMID: 27180983

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Project description:BackgroundThe study was designed to develop a platform to verify whether the extract of herbs combined with chemotherapy drugs play a synergistic role in anti-tumor effects, and to provide experimental evidence and theoretical reference for finding new effective sensitizers.MethodsInhibition of tanshinone IIA and adriamycin on the proliferation of A549, PC9 and HLF cells were assessed by CCK8 assays. The combination index (CI) was calculated with the Chou-Talalay method, based on the median-effect principle. Migration and invasion ability of A549 cells were determined by wound healing assay and transwell assay. Flow cytometry was used to detect the cell apoptosis and the distribution of cell cycles. TUNEL staining was used to detect the apoptotic cells. Immunofluorescence staining was used to detect the expression of Cleaved Caspase-3. Western blotting was used to detect the proteins expression of relative apoptotic signal pathways. CDOCKER module in DS 2.5 was used to detect the binding modes of the drugs and the proteins.ResultsBoth tanshinone IIA and adriamycin could inhibit the growth of A549, PC9, and HLF cells in a dose- and time-dependent manner, while the proliferative inhibition effect of tanshinone IIA on cells was much weaker than that of adriamycin. Different from the cancer cells, HLF cells displayed a stronger sensitivity to adriamycin, and a weaker sensitivity to tanshinone IIA. When tanshinone IIA combined with adriamycin at a ratio of 20:1, they exhibited a synergistic anti-proliferation effect on A549 and PC9 cells, but not in HLF cells. Tanshinone IIA combined with adriamycin could synergistically inhibit migration, induce apoptosis and arrest cell cycle at the S and G2 phases in A549 cells. Both groups of the single drug treatment and the drug combination up-regulated the expressions of Cleaved Caspase-3 and Bax, but down-regulated the expressions of VEGF, VEGFR2, p-PI3K, p-Akt, Bcl-2, and Caspase-3 protein. Compared with the single drug treatment groups, the drug combination groups were more statistically significant. The molecular docking algorithms indicated that tanshinone IIA could be docked into the active sites of all the tested proteins with H-bond and aromatic interactions, compared with that of adriamycin.ConclusionsTanshinone IIA can be developed as a novel agent in the postoperative adjuvant therapy combined with other anti-tumor agents, and improve the sensibility of chemotherapeutics for non-small cell lung cancer with fewer side effects. In addition, this experiment can not only provide a reference for the development of more effective anti-tumor medicine ingredients, but also build a platform for evaluating the anti-tumor effects of Chinese herbal medicines in combination with chemotherapy drugs.

Dataset Information

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

Aim

Methods

Results

Conclusion

Publications

Preclinical PK/PD model for combined administration of erlotinib and sunitinib in the treatment of A549 human NSCLC xenograft mice.

Similar Datasets

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