It takes two to tango, and the right music: Synergistic drug combinations with cell-cycle phase-dependent sensitivities

Abstract

The basic principle of cancer therapy is the specific killing of cancer cells while sparing normal cells and tissues from the detrimental effects of treatment. Since the application of anticancer drugs, including “classic chemotherapy”, the importance of “cycling kinetics” have been recognized. The therapeutic window of cancer therapy is in a large part attributed to the observation that proliferating cells display higher sensitivity than nonproliferating cells. More than three decades ago, a distinction was already made between “cycle-specific” and “cell cycle stage-specific” drugs. It was argued that such distinction could provide the means to avoid increased toxicity associated with combination chemotherapy without loss of therapeutic effects [2]. In addition, around that time it was also shown that cell cycle synchronization by pre-treatment with hydroxyurea, a DNA synthesis blocker, could increase the effects of cytostatic drugs like vincristine, predominantly acting in S-phase cells in an in vivomodel [9]. In recent years, the repertoire of cancer drug targets has further expanded with components of deregulated pathways in cancer such as cell cycle control, DNA damage, replication stress, aberrant metabolic activity and proteotoxic stress. For many of these processes, it is expected that cancer cells display different sensitivities not only determined by their proliferation rate but also by specific phases in the cell-cycle. It has become clear that single drug treatments are limited in their effectiveness. In most cases clinical responses are short-lived, patients’ tumors rapidly develop resistance, leading to recurrence with modest effects on overall survival. As a consequence, it is thought that combinations of drugs are needed to overcome resistance and increase the overall clinical benefit. An important consequence of cell cycle phase-specific sensitivity is that combinations of drugs can be synergistic or antagonistic, where one drug prevents the progression of the cell cycle to a phase where the second drug