Abstract
BackgroundBased 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.MethodsThe 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 24 h MTA combined with 1 h or 24 h dFdC were analysed.ResultsIncluding 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 8 h after drug removal. Among different MTA/dFdC combinations tested, the highest synergistic interaction was produced by 24 h MTA followed by 1 h dFdC. Combined with irradiation, this schedule showed a clear radiosensitising effect.ConclusionsResults from our in vitro model suggest that the sequence 24 h MTA → 1 h dFdC → RT is the most rational design and would, after confirmation in an in vivo setting, possibly provide the greatest benefit in the clinic.
Highlights
Based on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed and gemcitabine (2′,2′difluorodeoxycytidine, dFdC) with irradiation (RT) seems promising
The availability of several new active compounds has led to the development of promising new combinations. Many of those chemoradiotherapy combinations include antimetabolites, because of their efficacy, their generally well-defined mechanisms of action and mostly manageable toxicities [2]. In this in vitro study, we describe for the first time the triple combination of the antimetabolites gemcitabine and pemetrexed with irradiation in two human tumour cell lines
Cytotoxicity of pemetrexed alone A clear concentration-dependent cytotoxic effect of pemetrexed was observed in CAL-27 and A549 cells, with IC50 values of 118.77 ± 17.28 nM and 629.89 ± 68.77 nM respectively
Summary
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. The availability of several new active compounds has led to the development of promising new combinations Many of those chemoradiotherapy combinations include antimetabolites, because of their efficacy, their generally well-defined mechanisms of action and mostly manageable toxicities [2]. In this in vitro study, we describe for the first time the triple combination of the antimetabolites gemcitabine and pemetrexed with irradiation in two human tumour cell lines
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
