We propose that an ultrasensitive dose response, as described in radiology by the linear-quadratic (LQ) model, can reconcile these seemingly contradictory experimental observations. Surprisingly, we observed that tumor cell kill is maximized by concurrent drug administration despite antagonistic drug-drug interactions. We tested whether staggered treatment schedules could improve tumor cell kill by avoiding antagonism, using month-long in vitro models of concurrent or staggered treatments. We investigated pharmacodynamic interactions in the standard 4-drug ‘CHOP’ regimen in Peripheral T-Cell Lymphoma (PTCL) cell lines, and found that CHOP consistently exhibits antagonism and not synergy. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. UNIVERSE offers clinically relevant insights into radiobiological interdependencies and its versatility will allow it to follow future trends in radiotherapy. Challenges concerning the transition of oxygen and uHDR effects to ion beams as well as the vision of personalized biomarker-based patient plan adaptation based on UNIVERSE are discussed. Benchmarks against own or literature data are presented for each development. For sparsely ionizing radiation, the sparing effects at ultra-high dose-rates (uHDR) applied in FLASH radiotherapy were introduced based on oxygen depletion rates approaching measured values. The effects of radiosensitizing drugs and mutations as well as DNA repair kinetics were modeled for each radiation quality. To this end, the initial developments of the mechanistic UNIfied and VERSatile bio response Engine (UNIVERSE) are presented in this work. The capability to model their impact within a unified description of radiation action in conventional and ion beam fields would greatly enhance the ability to prescribe the optimal treatment and improve the knowledge of underlying mechanisms. However, several factors are known to modify the biological effect of radiation. Radiotherapy is a crucial pillar of cancer therapy and ion beams promise superior dose conformity and potentially enhanced biological effectiveness in comparison to conventional radiation modalities.
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