Biometric Evaluation of the Interaction Between Anticancer Agents and Multidrug-resistance Modulators

Abstract

The objective of the study was to evaluate the interaction of multidrug-resistance modulators with anticancer agents using combination index analysis. In cancer chemotherapy, combinations of drugs and adjuvants are routinely used, and it is important to determine if the nature of the combined effect is additive, antagonistic, or synergistic. In recent years efforts have been made to identify compounds that can lower drug resistance in multidrug-resistant tumour cells. For the therapy of multidrug-resistant cancer, synergistic potentiation of the cytotoxic activity of anticancer drugs by compounds that modulate drug resistance is highly desirable. We have evaluated the nature of interaction between clinically used anticancer agents (doxorubicin and etoposide) and investigational modulators of multidrug resistance (dipyridamole and tamoxifen). Multidrug-resistant tumour cells, B16VDXR murine melanoma and MCF-7/ADR human breast carcinoma, were used as in-vitro models to evaluate the cytotoxicity of individual drugs or drug combinations using colony-formation assays. The nature of drug interactions was assessed using combination index analysis as a function of fraction affected (fraction of cells that did not survive drug treatment). Interactions were considered antagonistic when the combination index was greater than 1, additive when equal to 1, and synergistic when less than 1. For doxorubicin and dipyridamole as well as mitoxantrone and tamoxifen interactions, the combination index vs fraction affected plot indicated that both these drug combinations resulted in synergistic interaction for fraction affected values greater that 0.1. The etoposide and dipyridamole combination was synergistic over the entire range of cell kill. The combination index at the 50% level of cell kill (CI50), suggested that in B16VDXR cells the synergistic potentiation of cytotoxicity was markedly stronger for the etoposide and dipyridamole combination (CI50 = 0.25) relative to the synergy observed for the doxorubicin and dipyridamole combination (CI50 = 0.48). The CI50 for the mitoxantrone and tamoxifen combination was about 0.35. This study thus demonstrates the use of combination index analysis in the evaluation of the interaction between anticancer agent and multidrug-resistance modulators. Such biometric evaluations can help to identify drug combinations that result in synergistic potentiation of cytotoxicity against multidrug-resistant cells.