In vitro study of farnesyltransferase inhibitor SCH 66336, in combination with chemotherapy and radiation, in non-small cell lung cancer cell lines.
K-ras alterations have been reported in 20-30% of non-small cell lung cancer (NSCLC) and represent a suitable target for the development of novel anticancer agents, such as Farnesyl transferase inhibitors (FTi), a new class of agents inhibiting the post-translational modification of the K-ras proteins. The effectiveness of FTi SCH66336 in inhibiting cell proliferation and deranging cell cycle of NSCLC cell lines as well as its interaction with chemotherapy or radiation have been evaluated. The activity of FTi SCH66336, alone or in combination with paclitaxel, gemcitabine, and radiotherapy, was examined in 3 cell lines, A-549, LX-1 and CaLu-6, by colorimetric MTT assay. Cell cycle perturbation and apoptosis were also assessed by cytofluorimetric analysis. The activity of SCH 66336 was found to be concentration- and time-dependent. The effect of SCH 66336, as demonstrated by cell growth recovery experiments, resulted cytostatic and it was superimposable in both cell lines bearing 2 different K-ras mutations (A-549 and LX-1) and in K-ras wild-type Ca-Lu-6. In all cell lines the combination of SCH 66336 and paclitaxel resulted in a synergism of action when SCH 66336 followed paclitaxel treatment, whereas, antagonism was found when SCH 66336 preceded paclitaxel treatment. No significant synergism or addition with SCH 66336 followed by radiation treatment was noted. Different cell cycle phase blocks at various drug concentrations were observed. In conclusion, SCH 66336 displays concentration-dependent cytostatic antitumour activity and schedule-dependent synergy with 2 commonly used anticancer agents in NSCLC cell lines. Further clinical testing of these combinations is warranted.
Loprevite
Maura
M
Medical Oncology A, National Institute for Cancer Research, Largo R. Benzi 10, I-16132 Genoa, Italy.
Favoni
Roberto E
RE
De Cupis
Alessandra
A
Scolaro
Tindaro
T
Semino
Claudia
C
Mazzanti
Paola
P
Ardizzoni
Andrea
A
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes