In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells
Faculty of Medicine and Health Sciences
BMC cancer. - London
, p. 441,1-441,14
University of Antwerp
Background Based on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed (multitargeted antifolate, MTA) and gemcitabine (2',2'-difluorodeoxycytidine, dFdC) with irradiation (RT) seems promising. This in vitro study, for the first time, presents the triple combination of MTA, dFdC and irradiation using various treatment schedules. Method The cytotoxicity, radiosensitising potential and cell cycle effect of MTA were investigated in A549 (NSCLC) and CAL-27 (SCCHN) cells. Using simultaneous or sequential exposure schedules, the cytotoxicity and radiosensitising effect of 24h MTA combined with 1h or 24h dFdC were analysed. Results Including a time interval between MTA exposure and irradiation seemed favourable to MTA immediately preceding or following radiotherapy. MTA induced a significant S phase accumulation that persisted for more than 8h after drug removal. Among different MTA/dFdC combinations tested, the highest synergistic interaction was produced by 24h MTA followed by 1h dFdC. Combined with irradiation, this schedule showed a clear radiosensitising effect. Conclusions Results from our in vitro model suggest that the sequence 24h MTA -> 1h dFdC -> RT is the most rational design and would, after confirmation in an in vivo setting, possibly provide the greatest benefit in the clinic.