Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer.
OBJECTIVE
Lung cancer has a dismal prognosis and comprises 5.5% of post-transplant malignancies. We explored whether rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer (NSCLC).


METHODS
Murine KLN-205 NSCLC was used as the model tumor in syngeneic DBA/2 mice to explore the effect of rapamycin on tumor growth and metastastic progression. We also examined the effect of rapamycin on cell cycle progression, apoptosis, and proliferation using murine KLN-205 NSCLC cells and human A-549 NSCLC cells as targets. The in vivo and in vitro effects of cyclosporine and those of rapamycin plus cyclosporine were also investigated.


RESULTS
Rapamycin but not cyclosporine inhibited tumor growth; s.c. tumor volume was 1290 +/- 173 mm(3) in untreated DBA/2 mice, 246 +/- 80 mm(3) in mice treated with rapamycin, and 1203 +/- 227 mm(3) in mice treated with cyclosporine (P < 0.001). Rapamycin but not cyclosporine prevented the formation of distant metastases; eight of eight untreated mice and four of six mice treated with cyclosporine developed pulmonary metastases whereas only one of six mice treated with rapamycin developed pulmonary metastases (P = 0.003). In vitro, rapamycin induced cell cycle arrest at the G(1) checkpoint and blocked proliferation of both KLN-205 and A-549 cells but did not induce apoptosis. Cyclosporine did not prevent cell cycle progression and had a minimal antiproliferative effect on KLN-205 and A-549 cells.


CONCLUSIONS
The immunosuppressive macrolide rapamycin but not cyclosporine prevents the growth and metastatic progression of NSCLC. A rapamycin-based immunosuppressive regimen may be of value in recipients of allografts.
Boffa
Daniel J
DJ
Department of Medicine and Transplantation Medicine, Division of Nephrology, The New York Presbyterian Hospital, Weill Cornell Medical Center, New York, USA.
Luan
Fulung
F
Thomas
Dolca
D
Yang
Hua
H
Sharma
Vijay K
VK
Lagman
Milagros
M
Suthanthiran
Manikkam
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D016572:Cyclosporine / Q000627:therapeutic use; D018450:Disease Progression; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D020123:Sirolimus / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000637:transplantation
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus