23P - Prolonged pemetrexed pretreatment increases efficiency of ionizing radiation combination therapy and correlates with the persistence of treatment-i...

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Anti-Cancer Agents & Biologic Therapy
Lung and other Thoracic Tumours
Translational Research
Surgery and/or Radiotherapy of Cancer
Presenter Thomas Marti
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors T.M. Marti1, P. Dorn2, C.C. Tièche2, R. Peng2, L. Froment2, R.A. Schmid2
  • 1Division Of General Thoracic Surgery, Inselspital Bern, 3010 - Bern/CH
  • 2Division Of General Thoracic Surgery, Inselspital Bern, Bern/CH

Abstract

Background

Lung cancer is the leading cause of cancer death globally, thus there is an urgent need to develop new treatment options. Chemo-radiotherapy treatment has become the most widely used treatment strategy for non-resectable solid tumors including non-small cell lung cancer. Pemetrexed is an antifolate agent that inhibits folate-requiring enzymes, which are essential for the synthesis of precursors of purine nucleotides, whereas ionizing radiation induces DNA damage, the repair of which is dependent on sufficiently high nucleotide levels. In the clinical setting, the pemetrexed-ionizing radiation combination therapy is administered concomitantly. We hypothesized that prolonged pretreatment with pemetrexed could be beneficial, as prior depletion of nucleotide pools could sensitize cancer cells to subsequent irradiation.

Methods

Non-small cell lung cancer A549 cells were treated with 1 µM pemetrexed for 72 hours. In addition, cells were exposed to 5 gray ionizing radiation either 1 hour, 48 hours or 71 hours after the initiation of the pemetrexed treatment. Cell growth, senescence induction, cell cycle distribution and DNA damage marker accumulation were analysed at different time points during the treatment and the recovery phase.

Results

Independent treatments of 5 gray ionizing radiation and 1 µM pemetrexed resulted in an intermediate cell growth inhibition of A549 cells and were therefore applied as the combination regimen. Prolonged pemetrexed pretreatment for 71 hours resulted in a significant S-phase accumulation. Irradiation and prolonged pemetrexed pretreatment maximally delayed long term cell growth, augmented senescence and recovery from treatment-induced DNA damage.

Conclusions

Prolonged pemetrexed pretreatment increases anticancer efficiency of pemetrexed-ionizing radiation combination therapy. Therefore, this study warrants further investigations to elucidate whether a similar adaptation to the standard treatment regimen could enhance the effectiveness of the non-small cell lung cancer clinical treatment regimen.

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

Supported by the Bernese Cancer League and the Swiss Cancer Research (KFS-3530–08–2014) to TMM

Disclosure

All authors have declared no conflicts of interest.