PURPOSE: 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 AND MATERIALS: 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.
PURPOSE: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 humantumor cell lines. METHODS AND MATERIALS: 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.
Authors: A Argiris; M V Karamouzis; R Smith; A Kotsakis; M K Gibson; S Y Lai; S Kim; B F Branstetter; Y Shuai; M Romkes; L Wang; J R Grandis; R L Ferris; J T Johnson; D E Heron Journal: Ann Oncol Date: 2011-03-01 Impact factor: 32.976
Authors: A Argiris; J E Bauman; J Ohr; W E Gooding; D E Heron; U Duvvuri; G J Kubicek; D M Posluszny; M Vassilakopoulou; S Kim; J R Grandis; J T Johnson; M K Gibson; D A Clump; J T Flaherty; S I Chiosea; B Branstetter; R L Ferris Journal: Ann Oncol Date: 2016-05-13 Impact factor: 32.976
Authors: An Wouters; Bea Pauwels; Filip Lardon; Greet G O Pattyn; Hilde A J Lambrechts; Marc Baay; Paul Meijnders; Jan B Vermorken Journal: BMC Cancer Date: 2010-08-19 Impact factor: 4.430
Authors: Hak Choy; Lee S Schwartzberg; Shaker R Dakhil; Edward B Garon; David E Gerber; Janak K Choksi; Ramaswamy Govindan; Guangbin Peng; Andrew Koustenis; Joseph Treat; Coleman Obasaju Journal: J Thorac Oncol Date: 2013-10 Impact factor: 15.609
Authors: David Scott Miller; John A Blessing; Lois M Ramondetta; Huyen Q Pham; Krishnansu S Tewari; Lisa M Landrum; Jubilee Brown; Robert S Mannel Journal: J Clin Oncol Date: 2014-07-28 Impact factor: 44.544
Authors: Xinglei Shen; Albert Denittis; Maria Werner-Wasik; Rita Axelrod; Paul Gilman; Thomas Meyer; Joseph Treat; Walter J Curran; Mitchell Machtay Journal: Radiat Oncol Date: 2011-02-16 Impact factor: 3.481
Authors: Patrick Dorn; Colin Charles Tièche; Ren-Wang Peng; Laurène Froment; Ralph Alexander Schmid; Thomas Michael Marti Journal: Cancer Cell Int Date: 2016-09-02 Impact factor: 5.722