Effect of the farnesyl transferase inhibitor L-744,832 on the colon cancer cell line DLD-1 and its combined use with radiation and 5-FU.
BACKGROUND
Ras oncogenes are found in 25% of human tumors and they significantly affect prognosis. One of the major fields studied to improve anticancer drugs is blockade of the oncogenic ras protein function. One of the mechanisms to block the function of these proteins is to block farnesylation using a farnesyl transferase inhibitor (FTI) and thus to prevent the ras from anchoring to the cell membrane.


METHODS
In this study, we investigated the effects of FTI L-744,832 either alone or in combination with 5-fluorouracil (5-FU; 1 microM/l) and radiotherapy (2, 6, and 10 Gy) on the colon cancer cell line DLD-1 with mutations in K-, N- and H-ras, c-myb, c-myc, p53, fos, sis and DNA repair genes. Drugs were added 3 h after cultivation. Radiotherapy was performed on the 3rd day of the study. On the 3rd day, medium and drugs were changed. Evaluations were performed on the 6th day.


RESULTS
Administration of L-744,832, neither alone nor its combination with 5-FU and radiation, affected the number of DLD-1 cells and apoptosis rates. Regarding its effects on the cell cycle, L-744,832 was shown to lead to G(0)/G(1) and G(2)/M accumulation in a dose-dependent manner when administered alone. However, in combination with 5-FU, only a G(0)/G(1) accumulation was observed.


CONCLUSIONS
Our study showed that FTI L-744,832 does not effect the cell number and apoptosis rate of DLD-1 cells and it cannot overcome 5-FU and radiation resistance, although it is able to modify some phases of the cell cycle.
Kavgaci
Halil
H
Department of Medical Oncology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. hkavgaci@meds.ktu.edu.tr
Ozdemir
Feyyaz
F
Ovali
Ercument
E
Yavuz
Aydin
A
Yavuz
Melek
M
Aydin
Fazil
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects
D000970:Antineoplastic Agents; C096898:L 744832; D008715:Methionine; D051231:Farnesyltranstransferase; D005472:Fluorouracil