It's all in the timing

Enhanced anti‐tumour effects of Vinca alkaloids given separately from cytostatic therapies

“…Vinca alkaloids are not the only cytotoxic drugs requiring active cell cycling for induction of cell death in tumour cells; several classes of cytotoxic drugs and γ‐irradiation induce cell cycle arrest (Jänicke et al ., ; Mattern et al ., ; Rixe and Fojo, ; Ewald et al ., ; Ehrhardt et al ., ). Similar to the combination of Vinca alkaloids and anthracyclines, cytotoxic and cytostatic drugs are frequently combined in current polychemotherapy protocols (Jänicke et al ., ; Mattern et al ., ; Rixe and Fojo, ; Ewald et al ., ; Bendall, ; Ehrhardt et al ., ). On a more general level, the data presented suggest the premise that cytotoxic and cytostatic drugs are most effective at inducing antitumour effects, when given on the same day in polychemotherapy, should be re‐evaluated.…”

“…The reason for combining certain drugs, but not others, derives from empirical studies (Frei, ; Ramaswamy, ; Dy and Adjei, ). Unfortunately, detailed systematic optimization of drug combinations in clinical trials has not been possible due to limited resources (Benz et al ., ; Bendall, ).…”

“…Furthermore, a basic understanding of the mechanisms of the mode of action of chemotherapeutic drugs has not been fully elucidated. In fact, the interaction between two or more drugs is rarely unravelled on a molecular level, which has meant that, so far, the choice of favourable drug combinations is not based on a mechanistic understanding of their interactions (Bonadonna et al ., 1995; 2004; Kaspers et al ., ; Ling et al ., ; Müller and Boos, ; Akutsu et al ., ; Barone et al ., ; Benz et al ., ; Li et al ., ; Mayer and Janoff, ; Bendall, ).…”

“…Here we investigated whether this combination allows the optimal antitumour effects of Vinca alkaloids to be elicited. In a recent study on acute leukaemia cells, we showed that combining anthracyclines with Vinca alkaloids significantly reduced their antitumour effects as compared with separate applications (Bendall, ; Ehrhardt et al ., ). Here we investigated whether this negative interaction also occurs in solid tumour cells, which signalling steps are responsible for it and, most importantly, how Vinca alkaloids should be applied for maximum efficacy in cancer patients.…”

Tubulin‐targeting agent combination therapies: dosing schedule could matter

“…A rationale design of drug combinations, based on molecular correlates, remains a difficult task as a number of parameters can affect the drug response. For example, crizotinib, an oral tyrosine kinase inhibitor that inhibits c‐Met and ALK is also a P‐glycoprotein inhibitor that may improve the efficacy of tubulin‐binding agents in ABCG1 expressing tumour cells (Zhou et al ., ), but this beneficial effect will be negated if crizotinib has a cytostatic effect (Bendall, ). Since the schedule‐dependent antagonism between vincristine and doxorubicin depends on the status of p53, the simultaneous administration of vinca alkaloids and anthracycline might be more effective in patients with a p53‐mutated compared to those with a p53‐wild‐type tumour; this could easily be checked in ongoing combination trials.…”