Interlink between improved formulations, inhibitory concentrations and cell death mechanism investigations of cytotoxic drugs: What really matters?

Abstract In this article, IC50 concentrations derived from MTT assay for further evaluating of cell death induced by new formulations were discussed. This review attempts to introduce an enhanced approach for evaluation of cell death mechanisms based on routine cytotoxicity assays for anti-cancer medications. It is highly desirable for anti-cancer drugs to induce apoptotic cell death in order to have better efficacy and less complications. According to our previous results and other comparable studies, cell death mechanisms and phenotypes followed by cytotoxic drugs are rigorously concentration dependent; therefore, calculated IC50s obtained through cytotoxicity assays should be exactly employed for evaluating of cell death mechanisms. More appropriately, it is better to select concentrations which are closer to the efficient plasma levels for additional cell death evaluations. If enough amounts of new formulated materials are available, it is suggested to calculate and compare IC50s for old and improved formulations at different concentration ranges; otherwise, when materials are not sufficiently available or the toxicity of new formulation is not high enough to yield an IC50, then some specific point to point comparison between corresponding concentrations within a reasonable range should be made. Another important point is that IC50 values obtained via in vitro assays are frequently higher than in vivo or therapeutic plasma concentrations and it seems better to use improved formulation's IC50s which are more comparable to clinical plasma concentrations or consider IC25s of free drugs for determination of cell death mechanisms.