Mechanistic Pharmacokinetic/Pharmacodynamic Model of Sunitinib and Dopamine in MCF-7/Adr Xenografts: Linking Cellular Heterogeneity to Tumour Burden.

The self-renewal and differentiation of cancer stem-like cells (CSCs) leads to cellular heterogeneity, causing one of the greatest challenges in cancer therapy. Growing evidence suggests that CSC-targeting therapy enhances the effect of concomitant antitumour therapy. To gain an in-depth understanding of this enhanced effect, the kinetic profile of estimated CSC frequency (the fraction of CSCs in tumour) was evaluated for in vivo characterization of cellular heterogeneity using sunitinib and dopamine as a paradigm combination therapy. Female MCF-7/Adr xenografted Balb/c nude mice were treated with sunitinib (p.o., 20 mg/kg) and dopamine (i.p., 50 mg/kg), alone or in combination. Estimated CSC frequency and tumour size were measured over time. Mechanistic PK/PD modelling was performed to quantitatively describe the relationship between drug concentration, estimated CSC frequency and tumour size. Sunitinib reduced tumour size by inducing apoptosis of differentiated tumour cells (DTCs) and enriched CSCs by stimulating its proliferation. Dopamine exhibited anti-CSC effects by suppressing the capacity of CSCs and inducing its differentiation. Simulation and animal studies indicated that concurrent administration was superior to sequential administration under current experimental conditions. Alongside tumour size, the current study provides mechanistic insights into the estimation of CSC frequency as an indicator for cellular heterogeneity. This forms the conceptual basis for in vivo characterization of other combination therapies in preclinical cancer studies.

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

PURPOSE: To investigate the anti-tumor effect of sunitinib in combination with dopamine in the treatment of nu/nu nude mice bearing non-small cell lung cancer (NSCLC) A549 cells and to develop the combination PK/PD model. Further, simulations were conducted to optimize the administration regimens. METHODS: A PK/PD model was developed based on our preclinical experiment to explore the relationship between plasma concentration and drug effect quantitatively. Further, the model was evaluated and validated. By fixing the parameters obtained from the PK/PD model, simulations were built to predict the tumor suppression under various regimens. RESULTS: The synergistic effect was observed between sunitinib and dopamine in the study, which was confirmed by the effect constant (GAMA, estimated as 2.49). The enhanced potency of dopamine on sunitinib was exerted by on/off effect in the PK/PD model. The optimal dose regimen was selected as sunitinib (120 mg/kg, q3d) in combination with dopamine (2 mg/kg, q3d) based on the simulation study. CONCLUSIONS: 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.

Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen.

AIM: Dexamethasone (DEX) is a widely used synthetic glucocorticoid, which has shown anti-cancer efficacy and anti-estrogenic activity. In this study we explored the possibility that DEX might be used as an endocrine therapeutic agent to treat human non-small cell lung cancer (NSCLC). METHODS: The viability and proliferation of human NSCLC cell lines A549 and H1299 were assessed in vitro. Anti-tumor action was also evaluated in A549 xenograft nude mice treated with DEX (2 or 4 mg·kg(-1)·d(-1), ig) or the positive control tamoxifen (50 mg·kg(-1)·d(-1), ig) for 32 d. The expression of estrogen sulfotransferase (EST) in tumor cells and tissues was examined. The intratumoral estrogen levels and uterine estrogen responses were measured. RESULTS: DEX displayed mild cytotoxicity to the NSCLC cells (IC50 >500 µmol/L) compared to tamoxifen (IC50 <50 µmol/L), but it was able to inhibit the cell proliferation at low micromolar ranges. Furthermore, DEX (0.1-10 µmol/L) dose-dependently up-regulated EST expression in the cells, and inhibited the cell migration in vitro. Triclosan, a sulfation inhibitor, was able to diminish DEX-caused inhibition on the cell viability. In A549 xenograft nude mice, DEX or tamoxifen administration remarkably suppressed the tumor growth. Moreover, DEX administration dose-dependently increased EST expression in tumor tissues, and reduced intratumoral estrogen levels as well as the volumes and weights of uterine. CONCLUSION: DEX suppresses the growth of A549 xenograft tumors via inducing EST and decreasing estradiol levels in tumor tissues, suggesting that DEX may be used as anti-estrogenic agent for the treatment of NSCLC.