International Journal of Radiation Oncology*Biology*Physics
Biology contributionInteraction of pemetrexed disodium (ALIMTA, multitargeted antifolate) and irradiation in vitro
Introduction
Alimta (Pemetrexed disodium, LY231514: Eli Lilly and Co., Indianapolis, Indiana) is a new pyrrolopyrimidine-based folate antimetabolite. Different from classic antifolates, pemetrexed inhibits several key enzymes of thymidylate and purine synthesis 1, 2. Pemetrexed is brought into cells by a reduced folate carrier system. Intracellularly, pemetrexed is modified to a negatively charged polyglutamated form by the enzyme folypolyglutamate synthetase (FPGS). This prevents efflux from cells and aids binding to target enzymes. Cytotoxicity and cytostasis result from the inhibition of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT), as well as of other folate-requiring enzymes. Cytoprotection can only be achieved by addition of thymidine and hypoxanthine. Thus, the reversal pattern differs from other antifolates 3, 4, 5. Pemetrexed shows a significant antitumor activity for a broad spectrum of cancers, including pancreatic, colorectal, gastrointestinal, lung, head and neck, breast, and cervix cancers. Various Phase II studies are ongoing or completed (6).
Combined modality treatment with radiation and cytotoxic agents that might improve clinical outcome have gained increasing interest. The potential of antifolates to change radiation effects has been known for a long time (7). The classic antifolate, 5-fluorouracil (5-FU), is used in simultaneous combination with radiotherapy of different tumors such as anal and rectal carcinomas 8, 9. Raltitrexed, a thymidylate synthase inhibitor, increases ionizing radiation-induced cell killing in vitro (10). Although the activity of pemetrexed can be distinguished from that of common antifolates, a potential to modify radiation effects may be presumed. Therefore, the interaction of pemetrexed and ionizing radiation was studied in different human tumor cell lines by measuring clonogenic survival.
Section snippets
Tumor cell lines
Four different human carcinoma cell lines were used. Widr (colon), MCF-7 (breast), Hela (cervix uteri), and LXI (lung) were provided by the Tumorbank of the German Cancer Research Center (dkfz Heidelberg). Cells were grown as monolayers in Dulbecco’s modified Eagle’s medium with 10% fetal calf serum in 6% CO2 at 37°C and were subcultured as log-phase cells every 3 days. The population doubling times were approximately 28 h for Widr and MCF-7, 32 h for Hela, and 24 h for LXI cells, respectively.
Pemetrexed toxicity
The toxicity of a 2-h pemetrexed exposure for the different cell lines is depicted in Fig. 1. LXI was the most sensitive cell line with a decrease of clonogenic survival to 10% at concentrations of >0.1 μg/ml (>212 nM). In contrast, a 20-fold higher dose was needed for MCF-7 to reduce survival to a comparable level. Widr and Hela cells showed a response below 0.5 μg/ml (1.06 μM) that was similar to the MCF-7 cells, but also a marked threshold behavior around 1 μg/ml (2.12 μM). As it was
Discussion
Pemetrexed is a promising new antifolate/antimetabolite. Considering the possibility of its use in combined modality cancer treatment together with radiotherapy, preclinical in vitro investigations on potential interaction phenomena appeared desirable. The present results with four different human tumor cell lines clearly demonstrate that a concomitant exposure to pemetrexed and ionizing radiation inhibited clonogenic survival in excess of independent toxicities (Fig. 2, Fig. 3, Fig. 4, Fig. 5,
Acknowledgements
The authors gratefully acknowledge the excellent technical assistance of Ute Haner and Thuy Trinh.
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Randomized phase II trial of pemetrexed-cisplatin plus bevacizumab or thoracic radiotherapy followed by surgery for stage IIIA (N2) nonsquamous non–small cell lung cancer
2022, Journal of Thoracic and Cardiovascular SurgeryCitation Excerpt :We found that cisplatin + pemetrexed + concurrent TRT was well tolerated and showed high activity against stage IIIA (N2) nonsquamous NSCLC (Figure 4). Pemetrexed, a multitargeted antifolate, has selective activity against nonsquamous NSCLC18 and enhances radiation sensitivity in vitro.19 The phase III PROCLAIM trial20 failed to demonstrate the superiority of cisplatin + pemetrexed + concurrent TRT followed by consolidation pemetrexed in improving OS over standard CCRT (cisplatin + etoposide + concurrent TRT), followed by non-pemetrexed consolidation treatment for unresectable stage III NSCLC.