A novel system for evaluation of drug mixtures for potential efficacy in treating multidrug resistant cancers

Abstract

Multidrug resistant (MDR) cancer is difficult to treat. Chemicals that are effective MDR modulators have never exited clinical trials as FDA approved products due to side effects. It has been hypothesized that using a combination of chemotherapeutics with a mixture of MDR modulators (each with different side effects) may lead to useful treatment strategies. Because the experimental space for combination treatments can be large, this space may be impracticable to explore using animal studies. Here we describe an in vitro system based on microfabrication and cell culture that can potentially be used to explore large experimental spaces efficiently. The Microscale Cell Culture Analog (microCCA) concept mimics the body's response using interconnected compartments that represent various tissues or organs. A microCCA is based on the structure of an appropriate physiologically based pharmacokinetic (PBPK) model and emulates the body's dynamic response to exposure to various drugs and chemicals. For this problem we have chosen a microCCA with living cells representing the liver (HepG2/C3A), bone marrow (MEG-01), uterine cancer (MES-SA), and a MDR variant of uterine cancer (MES-SA/DX-5). In proof of concept experiments we found in 24 h "acute" exposures and 72 h treatments that the microCCA system predicts combining the chemotherapeutic, doxorubicin, with cyclosporine and nicardipine, as MDR modulators will have greater efficacy than using doxorubicin by itself or with either modulator alone. This combined strategy is selective in inhibiting MES-SA/DX-5 cell proliferation and may prove to be advantageous in vivo by specifically targeting MDR cancer with acceptable side-effects. This cell specific synergy was not observed in traditional 96-well plate assays. By combining the microCCA with a PBPK model, appropriate drug doses and area under the curve exposure for in vivo trials can be extrapolated directly from the results obtained with this device. This device and approach should be useful in screening potential drug/modulator combinations to determine candidate treatments for MDR cancer. Indeed this approach may be useful for in vitro evaluation of human response to a wide range of exposures to mixtures of chemicals or drugs.