Dose- and time-dependence of the host-mediated response to paclitaxel therapy: a mathematical modeling approach

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.

CD163+ immune cell infiltrates and presence of CD54+ microvessels are prognostic markers for patients with embryonal rhabdomyosarcoma

“…As to the first option, there is evidence of macrophage functional placity, i.e. their potential to switch from an immunoregulatory to an immunostimulatory function due to environmental cues or pharmacological intervention 48,51,52 . However, in light of the paucity of intratumoral T cells compared to the relative abundance of macrophages in the TME of RMS, the second mechanism may also be operative considering the high susceptible of RMS to macrophage-mediated cytotoxicity in vitro 53 .…”

Microfragmented human fat tissue is a natural scaffold for drug delivery: Potential application in cancer chemotherapy

“…In addition, if compared to treatment with free PTX, a significant lower systemic toxicity was observed with DMFAT-PTX. To note, the dose of 10 mg PTX /kg, free or uploaded in DMFAT, here used was established based on clinical studies in humans [58].…”

Biological Evaluation of Graphene Quantum Dots and Nitrogen-Doped Graphene Quantum Dots as Neurotrophic Agents

“…The dosage concentration and time have an impact on the compound’s effectiveness. As the compound is incubated for a longer period of time, the drug’s effects on a given concentration get stronger over time and become diluted . In the present investigation, the compound’s efficacy peaks after 48 h and then begins to diminish after that point.…”