Pharmacokinetic/pharmacodynamic modeling of etoposide tumor growth inhibitory effect in Walker-256 tumor-bearing rat model using free intratumoral drug concentrations

Pigatto, Maiara Cássia; Roman, Renatha Menti; Carrara, Letizia; Buffon, Andréia; Magni, Paolo; Costa, Teresa Dalla

doi:10.1016/j.ejps.2016.10.038

Cited by 16 publications

(7 citation statements)

References 37 publications

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“…Walker-256 tumor cells were thawed at −80 °C and cultured as previously described ( 25 ). The establishment of walker-256 tumor-bearing donor rats was performed as previously described ( 21 ).…”

Section: Methodsmentioning

confidence: 99%

The suppressing effects of VEGF-mediated angiogenesis at different administration sequences of apatinib and transarterial embolization in vivo

Li¹,

Huang²

2020

Transl Cancer Res TCR

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Background: To investigate the suppressing effects of vascular endothelial growth factor (VEGF)-mediated angiogenesis at different treatment schedules by applying apatinib combined with transarterial embolization (TAE). Methods: Forty ideal liver cancer rat models were randomly divided into four groups based on different administration methods of apatinib [control group (CG): TAE only; Combined Group 1 (CG1): apatinib administration 3 days pre-TAE; Combined Group 2 (CG2): apatinib administration simultaneously with TAE; Combined Group 3 (CG3): apatinib administration 3 days post-TAE]. The characteristics of liver cancer, the expression of VEGF and microvascular density (MVD) as determined by CD34, and the overall survival (OS) were compared among the groups.Results: The tumor sizes of the liver on the 10th day after treatment were significantly larger when compared to the baseline sizes (P<0.05), and tumor growth in the combined groups was significantly slower than that of CG (P<0.05). The OS of rats was significantly different between the combined groups and control group (P<0.05), which were 19.9±3.21, 31.2±6.48, 27.1±5.59, and 25.9±6.06 days in groups CG, CG1, CG2 and CG3, respectively. Significant differences were observed between groups CG1 and CG3.The expression levels of VEGF in groups CG1, CG2 and CG3 were 45.6±9.88, 70.8±14.11 and 75.3±9.82, and were significantly lower than that in control groups (85.8±11.26). The MVD in CG (109.7±10.32) reached the peak value when compared to those in the three combined groups (46.4±19.22, 75.7±15.97, and 90.5±12.71, all P<0.05). Furthermore, overexpression of VEGF and MVD showed significant positive correlation with poor OS.Conclusions: These findings demonstrated that apatinib treatment enhanced anti-tumor effects of TAE via reducing tumor angiogenesis, suppressing tumor growth, and prolonging the OS of rats with liver tumors. Early administration of apatinib showed better therapeutic effects.

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Section: Methodsmentioning

confidence: 99%

The suppressing effects of VEGF-mediated angiogenesis at different administration sequences of apatinib and transarterial embolization in vivo

Li¹,

Huang²

2020

Transl Cancer Res TCR

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“…The Walker 256 carcinosarcoma cells used for the establishment of the liver tumor models were thawed from − 80 °C and harvested as previously described [ 22 , 23 ]. The tumor cell suspension was then diluted to 10 7 cells/mL with phosphate-buffered saline (PBS, 16.5 mM phosphate, 137 mM NaCl, and 2.7 mM KCl, at pH 7.4) and the mixture was subcutaneously inoculated into BALB/c nude mice at a site on the lateral thigh.…”

Section: Methodsmentioning

confidence: 99%

The earlier, the better: the effects of different administration timepoints of sorafenib in suppressing the carcinogenesis of VEGF in rats

Chen

Lin

et al. 2017

Cancer Chemother Pharmacol

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PurposeTo investigate the optimal starting time point of sorafenib therapy in suppressing the tumor-promoting effects of VEGF up-regulation, which is frequently found after local therapy in clinical practice.MethodsVEGF was intravenously injected to imitate the evaluated expression after local tumor therapy, such as TACE. A total of 40 SD rats bearing hepatic tumors were randomly divided into four groups and sorafenib was administered at different timepoints: (A) control group: VEGF injection only; (B) initiating sorafenib 72 h prior to VEGF injection; (C) initiating sorafenib simultaneously with VEGF injection; (D) initiating sorafenib 72 h post-VEGF injection. The rate of tumor growth, median survival time, expression of VEGF, and microvessel density (MVD), as determined by immunohistochemical (IHC) examination, were compared.ResultsThe results revealed that the tumor size and median survival time were significantly different between the three sorafenib groups compared to the control group (p < 0.05). Median survival times were 19.6 ± 1.78, 31.2 ± 6.99, 27.4 ± 4.9, and 26.5 ± 4.6 days in group A, B, C, and D, respectively. Furthermore, there was a difference in statistical significance between the two sorafenib groups B and D (p = 0.04). Tumors were collected for HE staining and IHC examination. The expression levels of VEGF in B, C, and D were 42.8 ± 7.96, 71.9 ± 15.73, and 73.6 ± 13.73, and all of them were significantly lower than that in the control group (88.3 ± 13.61). Furthermore, the level of MVD was 109.2 ± 8.98 in the control group, which was significantly higher than in the three sorafenib groups (45.7 ± 16.92, 77.1 ± 16.29, and 93.6 ± 12.87, all p < 0.05).ConclusionsAccording to our results, the most suitable regimen for the administration of sorafenib is before the increased expression of VEGF, which showed a potential advantage for controlling the tumor growth and prolonging the survival time of test animal via inhibiting VEGF-receptor expression through the bifunction of VEGF, and the reduction of tumor angiogenesis.

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“…Other examples of PK-PD analyses utilizing tumor tissue concentrations in Table primarily focus on differences in the extent of drug entry into tumor compartments. PK-PD analyses of both etoposide and a new mode of delivery for paclitaxel focus on understanding active drugs concentrations at the tumor site. Finally, tumor to plasma ratio differences between erlotinib and gefitinib were included as part of a PK-PD analyses to investigate whether these differences in tumor disposition could explain difference in antitumor efficacy between the two EGFR inhibitors .…”

Section: Exposure: Effect Relationship Based On Tissue Concentrations...mentioning

confidence: 99%

Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation

et al. 2022

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The "free drug hypothesis" assumes that, in the absence of transporters, the steady state free plasma concentrations equal to that at the site of action that elicit pharmacologic effects. While it is important to utilize the free drug hypothesis, exceptions exist that the free plasma exposures, either at C max , C trough , and C average , or at other time points, cannot represent the corresponding free tissue concentrations. This "drug concentration asymmetry" in both total and free form can influence drug disposition and pharmacological effects. In this review, we first discuss options to assess total and free drug concentrations in tissues. Then various drug design strategies to achieve concentration asymmetry are presented. Last, the utilities of tissue concentrations in understanding exposure-effect relationships and translational projections to humans are discussed for several therapeutic areas and modalities. A thorough understanding in plasma and tissue exposures correlation with pharmacologic effects can provide insightful guidance to aid drug discovery.

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Pharmacokinetic/pharmacodynamic modeling of etoposide tumor growth inhibitory effect in Walker-256 tumor-bearing rat model using free intratumoral drug concentrations

Cited by 16 publications

References 37 publications

The suppressing effects of VEGF-mediated angiogenesis at different administration sequences of apatinib and transarterial embolization in vivo

The suppressing effects of VEGF-mediated angiogenesis at different administration sequences of apatinib and transarterial embolization in vivo

The earlier, the better: the effects of different administration timepoints of sorafenib in suppressing the carcinogenesis of VEGF in rats

Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation

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