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Abstract: Anaplastic thyroid carcinoma (ATC) is a severe thyroid malignancy with poor prognosis, due to its early metastasis and unresponsiveness to both radiation and chemotherapy. Nevirapine, a non-nucleoside reverse transcriptase inhibitor, has been used as a re-differentiation agent to treat cancers in several human cancer models. So far, the effects of nevirapine on human thyroid anaplastic carcinoma cells have not been documented. The aim of this study was to evaluate the therapeutic potential of nevirapine in treatment of human thyroid anaplastic carcinoma. Cell proliferation was determined by methly thiazolyl tetrazolium (MTT) assay. Cell apoptosis was analyzed by Hoechst 33258 staining. The mRNA expression of NIS and TSHR was determined by real-time quantitative reverse transcription-polymerase chain reaction (real time RT-PCR). Iodine uptake was determined by 125I radioactivity assay. At all doses (100, 200, 350, 500μmol/L) tested, nevirapine significantly inhibited cell proliferation after 48h treatment. At high dose (500μmol/L), nevirapine significantly increased the percentage of apoptotic cells compared with control (P <0.01). At lower doses (200μmol/L and 350μmol/L), nevirapine did not induce cell apoptosis, but up-regulated NIS and THSR mRNA expression in a dose-dependent manner. In FRO cells pre-treated with nevirapine, the increase in NIS expression had no obvious effect on iodine uptake. These findings indicate that nevirapine has an anti-proliferative effect on FRO cells, which correlates with an induction of cell differentiation. [Copyright &y& Elsevier]

Abstract Metastatic disease is a major cause of mortality in cancer patients. While many drug delivery strategies for anticancer therapeutics have been developed in preclinical studies of primary tumors, the drug delivery properties of metastatic tumors have not been sufficiently investigated. Therapeutic efficacy hinges on efficient drug permeation into the tumor microenvironment, which is known to be heterogeneous thus potentially making drug permeation heterogeneous, also. In this study, we have identified that 4 T1 liver metastases, treated with pegylated liposomal doxorubicin, have unfavorable and heterogeneous transport of doxorubicin. Our drug extravasation results differ greatly from analogous studies with 4 T1 tumors growing in the primary site. A probabilistic tumor population model was developed to estimate drug permeation efficiency and drug kinetics of liver metastases by integrating the transport and structural properties of tumors and delivered drugs. The results demonstrate significant heterogeneity in metastases with regard to transport properties of doxorubicin within the same animal model, and even within the same organ. These results also suggest that the degree of heterogeneity depends on the stage of tumor progression and that differences in transport properties can define transport-based tumor phenotypes. These findings may have valuable clinical implications by illustrating that therapeutic agents can permeate and eliminate metastases of "less resistant" transport phenotypes, while sparing tumors with more "resistant" transport properties. We anticipate that these results could challenge the current paradigm of drug delivery into metastases, highlight potential caveats for therapies that may alter tumor perfusion, and deepen our understanding of the emergence of drug transport-based therapeutic resistance. Graphical abstract Unlabelled Image Highlights • Metastases may have heterogeneous and progression-dependent transport properties in drug delivery • The permeability of the extravascular space is the most fundamental barrier for drug permeation • Transport heterogeneity in tumors may create transport phenotypes rendering some tumors resistant to treatments • Permeation Time and Cumulative Permeation Probability of all tumors in a subject judge the efficency of drug delivery • Anti-vascular strategies can be detrimental to drug delivery as they augment the barrier of poor extravascular permeability [ABSTRACT FROM AUTHOR]