Interaction of pemetrexed disodium (ALIMTA, multitargeted antifolate) and irradiation in vitro.
OBJECTIVE
Pemetrexed disodium (Alimta, multitargeted antifolate, LY231514; Eli Lilly and Co., Indianapolis, Indiana) ("pemetrexed") is a new folate antimetabolite with significant antitumor activity. Different from classic antifolates, pemetrexed inhibits several key enzymes of thymidylate and purine synthesis, but a radiosensitizing potential may also be presumed. Therefore, the interaction of pemetrexed and ionizing radiation was studied for in vitro clonogenic survival of different human tumor cell lines.


METHODS
Human colon (Widr), breast (MCF-7), cervix (Hela), and lung (LXI) carcinoma cells from log-phase cultures were exposed to pemetrexed (2 h) in combination with different radiation doses given 1 h before pemetrexed washout (all cell lines) or at different points of time before or after pemetrexed addition (Widr). Survival curves were analyzed according to the linear-quadratic (LQ) model, and mean inactivation doses (MID) and radiation enhancement ratios were calculated from the survival curve parameters. Cell-cycle progression of serum-stimulated and pemetrexed- or mock-treated Widr cells was monitored by flow cytometry.


RESULTS
Radiosensitization was found for all cell lines at moderately toxic pemetrexed exposures (0.05-0.3 microg/ml [106-636 nM]), but this was cell-type dependent and was most pronounced at roughly isotoxic concentrations, for the least pemetrexed-sensitive Widr cells. Enhancement ratios ranged from about 1.2 (MCF-7 and Hela) to 1.8 (Widr), with a tendency to increase with pemetrexed concentration. Little, if any, change of radiosensitization was observed (Widr) when the time of irradiation was varied from 4 h before to 10 h after the beginning of pemetrexed treatment. Cell-cycle progression of serum-stimulated Widr cells was only marginally affected by pemetrexed.


CONCLUSIONS
Pemetrexed enhances radiation-induced cell inactivation at moderately toxic exposures and over many hours after drug removal. This effect is not due to disturbed cell-cycle progression, but likely involves an interaction of pemetrexed with long-lived (>4 h) cellular radiation damage and needs to be considered when introducing a combined clinical application.
Bischof
Marc
M
Department of Radiotherapy, Laboratory for Radiobiology, University of Heidelberg, Heidelberg, Germany. marc_bischof@med.uni-heidelberg.de
Weber
Klaus-Josef
KJ
Blatter
Johannes
J
Wannenmacher
Michael
M
Latz
Detlev
D
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D000068437:Pemetrexed; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000528:radiation effects*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine