Ultrasensitive response explains the benefit of combination chemotherapy despite drug antagonism

Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. 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. 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. Surprisingly, we observed that tumor cell kill is maximized by concurrent drug administration despite antagonistic drug-drug interactions. We propose that an ultrasensitive dose response, as described in radiology by the linear-quadratic (LQ) model, can reconcile these seemingly contradictory experimental observations. The LQ model describes the relationship between cell survival and dose, and in radiology has identified scenarios favoring hypofractionated radiation - the administration of fewer large doses rather than multiple smaller doses. Specifically, hypofractionated treatment can be favored when cells require an accumulation of DNA damage, rather than a 'single hit', in order to die. By adapting the LQ model to combination chemotherapy and accounting for tumor heterogeneity, we find that tumor cell kill is maximized by concurrent administration of multiple drugs, even when chemotherapies have antagonistic interactions. Thus, our study identifies a new mechanism by which combination chemotherapy can be clinically beneficial that is not reliant on positive drug-drug interactions.