Abstract
It has recently been suggested that pro-tumorigenic host-mediated processes induced in response to chemotherapy counteract the anti-tumor activity of therapy, and thereby decrease net therapeutic outcome. Here we use experimental data to formulate a mathematical model describing the host response to different doses of paclitaxel (PTX) chemotherapy as well as the duration of the response. Three previously described host-mediated effects are used as readouts for the host response to therapy. These include the levels of circulating endothelial progenitor cells in peripheral blood and the effect of plasma derived from PTX-treated mice on migratory and invasive properties of tumor cells in vitro. A first set of mathematical models, based on basic principles of pharmacokinetics/pharmacodynamics, did not appropriately describe the dose-dependence and duration of the host response regarding the effects on invasion. We therefore provide an alternative mathematical model with a dose-dependent threshold, instead of a concentration-dependent one, that describes better the data. This model is integrated into a global model defining all three host-mediated effects. It not only precisely describes the data, but also correctly predicts host-mediated effects at different doses as well as the duration of the host response. This mathematical model may serve as a tool to predict the host response to chemotherapy in cancer patients, and therefore may be used to design chemotherapy regimens with improved therapeutic outcome by minimizing host mediated effects.
Highlights
One of the major obstacles in clinical oncology is that tumors acquired resistance to therapy and relapse, despite an initial response to therapy
We focused on levels of viable CEPs [3] as well as migration and invasion of tumor cells in the presence of plasma obtained from PTX-treated mice [8]
It has been shown that such host effects in response to therapy minimize or even negate the antitumor activity of chemotherapy, thereby providing another route for resistance mechanisms [1]
Summary
One of the major obstacles in clinical oncology is that tumors acquired resistance to therapy and relapse, despite an initial response to therapy. While the main reasons for tumor relapse are related to intrinsic and acquired resistance mechanisms within tumor cells, a growing body of literature suggests that host-mediated effects generated in response to therapy may counteract the anti-tumor activity of the drug, thereby contributing to decreased net therapeutic outcome. We and others have identified several soluble factors induced in response to therapy that contribute to tumor regrowth and metastasis. These factors include metalloproteinase 9 (MMP9), IL16, IL1β, SDF-1, Osteopontin, stem cell factor, and granulocyte colony stimulating factor among others [2]. The response of the host to antiwww.impactjournals.com/oncotarget cancer drug therapy contributes to pro-tumorigenic and pro-metastatic activities by promoting angiogenesis and inhibiting immunity against tumor cells
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