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.

Contactless dielectrophoretic spectroscopy: Examination of the dielectric properties of cells found in blood

“…In addition, isolation of these cells could provide a workbench for clinicians to screen drug therapies prior to patient treatment. This would enable oncologists to tailor treatment on a patient-specific level and to ensure that the most effective treatment is being utilized [1][2][3][4][5]. Since many symptoms associated with cancers can be attributed to multiple diseases, diagnosis must be accomplished via medical analysis.…”

Modeling Life

“…Details of design and operation are given elsewhere. 17,22,25,28 The system has been used to determine response to naphthalene as a model toxicant. Naphthalene is not toxic itself, but activated in the liver to a reactive form, which causes cell death in other organs, such as the lung.…”

“…25 Multidrug resistant (MDR) cancer is problematic for treatment. It typically arrives when the cancer is subjected to a chemotherapeutic agent (which often causes significant shrinkage in the tumor).…”

“…We constructed a microCCA with liver, bone marrow, and uterine cancer cell lines. 25 The liver represents metabolism of the drugs and generates metabolites that may be physiologically important. The marrow represents the doselimiting response to the MDR suppressing compounds and chemotherapeutic agents.…”

Exploitation of physical and chemical constraints for three-dimensional microtissue construction in microfluidics

“…It has been hypothesized that using a combination of chemotherapeutics with a mixture of multidrug resistant ͑MDR͒ modulators ͑each with different side effects͒ may lead to useful treatment strategies. 185 Sung et al 186 used the CCA with 3D hydrogel to culture multiple cell types and measure the metabolism-dependent cytotoxicity of anticancer drugs. Shuler's group recently developed a three-chamber CCA for testing the toxicity of anticancer drug 5-fluorouracil and analyzed the results in light of a PK-PD model of the device.…”