gms | German Medical Science

Introduction: Anaplastic thyroid cancer (ATC) is still afflicted with unfavorable prognosis due to the failure of established therapy options. Besides the classical chemotherapeutics the “Small molecule inhibitors”, which were shown to be effective when evaluated in vitro, failed to reach success when applied in the clinic as a monotherapeutic option. Presumably this is caused by intrinsic tumor cell resistance as well as by secondary mechanisms of resistance. Therefore, combined treatment with two or more drugs might be an option to overcome this problem.

Material and methods: Three ATC cell lines (C643, Hth74 and MB1) were used to evaluate the effect of combined treatment targeting tyrosin kinases (sorafenib, vandetanib), Aurora kinases (MLN8054) and the proteasom (bortezomib). The experiments were performed using a 2x3 factorial design, whereby each drug was applied using three different fixed concentrations based on the half maximal effective concentrations (EC₅₀), which were evaluated for each drug and cell line before. Cell viability was assed by MTT-Assay and the Loewe interaction index (Ki) was estimated to fix the kind of interaction.

Results: In vitro, all drugs were shown to exert antiproliferative effects when used in nano- or micromolar concentrations, documented by the particular EC₅₀ values (sorafenib1-4µM, vandetanib 3-8 µM; MLN8054 0.1-10µM and bortezomib 2-5nM). Using two drugs at a time, we were able to show interactions for each combination. But synergistic effects (Ki<1) were infrequent and occurred only when the two drugs were applied in concentrations which met exactly the EC₅₀ value for a certain cell line. They never reached a level of significance. In fact, generally we found a trend towards antagonism (K >1), whereby often a level of significance (p<0.05) was reached.

Conclusion: In conclusion, our data demonstrate that combined treatment with two different “Small molecule inhibitors” might be an option to augment antiproliferative effects compared to monotherapeutic approaches, but the kind of interaction depends on the drug combination as well as the individual cell line /tumor. Possibly, combined with “Small molecule inhibitors” and classical chemotherapeutics, like taxanes, might be a better way to optimize therapeutic strategies for ATC.

Moreover, due to some problems concerning Ki calculation using a factorial experiment design, the fixed-ratio or Ray-design, which seems to be more suited for estimation of drug interactions, should be used in the future to evaluate drug combinations