Modified radiosensitivity of pancreatic cancer xenografts by farnesyl protein transferase inhibitor and MEK inhibitor.
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.
Matsui
Yoshifumi
Y
Department of General Surgery, Shimizu Kousei Hospital, 578-1 Ihara-chou Shimizu City, Shizuoka prefecture, Japan. ymatsui@smz.ja-shizuoka.or.jp
Goto
Miyako
M
Iwakawa
Mayumi
M
Asano
Takehide
T
Kenmochi
Takashi
T
Imai
Takashi
T
Ochiai
Takenori
T
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
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