title: Modified radiosensitivity of pancreatic cancer xenografts by farnesyl protein transferase inhibitor and MEK inhibitor.
abstract: We investigated the effects of the farnesyl transferase inhibitor (FTI) manumycin and the MEK inhibitor PD98059 on growth of human pancreatic cancer, with mutant (SUIT2) or wild-type (BxPC-3) K-ras, xenografted into nude mice. Tumor growth was not reduced by either of the agents at a dose of 3 mg/kg without irradiation. Growth of SUIT2 irradiated at 15 Gy or 30 Gy was reduced by manumycin and PD98059: at 15 Gy, tumor volume doubling time (TVDT) increased from 18.6+/-3.8 to 36.3+/-14.2 days with PD98059 (p<0.05); at 30 Gy, TVDT increased from 32.8+/-6.8 to 70.5+/-10.5 days and 70.7+/-1.5 days, respectively. Manumycin tended to reduce growth of BxPC-3, but the difference in TVDT was not statistically significant. PD98059 significantly increased the TVDT of BxPC-3 at 30 Gy from 34.4+/-18 to 62.6+/-9.8 at 30 Gy. The present results suggest that Ras signaling pathways are potential targets for manipulation of radiosensitivity, and that induction of an alternative pathway may enhance radiosensitivity of pancreatic cancer.
authors.affiliation: Department of General Surgery, Shimizu Kousei Hospital, 578-1 Ihara-chou Shimizu City, Shizuoka prefecture, Japan. ymatsui@smz.ja-shizuoka.or.jp
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Matsui
authors.forename: Miyako
authors.initials: M
authors.lastname: Goto
authors.forename: Mayumi
authors.initials: M
authors.lastname: Iwakawa
authors.forename: Takehide
authors.initials: T
authors.lastname: Asano
authors.forename: Takashi
authors.initials: T
authors.lastname: Kenmochi
authors.forename: Takashi
authors.initials: T
authors.lastname: Imai
authors.forename: Takenori
authors.initials: T
authors.lastname: Ochiai
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D005260:Female; D005419:Flavonoids / Q000627:therapeutic use*; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000532:radiotherapy*; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D011838:Radiation-Sensitizing Agents; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; C054474:manumycin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one