title: Enhancement of radiotherapeutic effectiveness by temperature-sensitive liposomal 1-methylxanthine.
abstract: Most of methylxanthine derivatives including caffeine have been known to radiosensitize cancer cells, but the obstacles such as toxicity, request of high dose and poor solubility hinder their preclinical evaluations and clinical applications. In this study, we evaluated the efficacy of 1-methylxanthine (1-MTX), a caffeine metabolite as a radiosensitizer and the in vivo effectiveness of the temperature-sensitive liposomal 1-methylxanthine (tsl-MTX) in combination with ionizing radiation and regional hyperthermia. In human colorectal and lung cancer cells, treatment of 1-MTX sensitized cells to ionizing radiation. To evaluate the in vivo capability of 1-MTX to radiosensitize tumors, we developed temperature-sensitive liposomal 1-MTX using DPPC:DMPC:DSPC (4:1:1 molar ratio) with intention of overcoming lethal toxicity of 1-MTX and controlling drug-release. The particle size of the liposomes was approximately 200 nm in diameter. The release of 1-MTX from the liposomes was responding to increase of temperature. In xenograft tumor-bearing mice, the tsl-MTX administered using the i.p. route showed delay of tumor growth. Importantly, tsl-MTX in combination with radiation and regional hyperthermia exhibited marked delay of tumor growth, suggesting that 1-MTX effectively enhanced radiation-induced suppression of tumor growth. In conclusion, tsl-MTX has highly efficacious anticancer competence in vivo, enhancing radiotherapeutic effectiveness, and feasibility for further clinical applications.
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Seong-Yun
authors.initials: SY
authors.lastname: Jeong
authors.forename: So Lyoung
authors.initials: SL
authors.lastname: Yi
authors.forename: Sun-Kyung
authors.initials: SK
authors.lastname: Lim
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Joohee
authors.initials: J
authors.lastname: Jung
authors.forename: Ha Na
authors.initials: HN
authors.lastname: Woo
authors.forename: Si Yeol
authors.initials: SY
authors.lastname: Song
authors.forename: Jin-Seok
authors.initials: JS
authors.lastname: Kim
authors.forename: Jung Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Jin Seong
authors.initials: JS
authors.lastname: Lee
authors.forename: Heon Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011838:Radiation-Sensitizing Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013696:Temperature; D014970:Xanthines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D008081:Liposomes; D011838:Radiation-Sensitizing Agents; D014970:Xanthines; C053085:1-methylxanthine