Rapamycin Inhibits the Growth and Metastatic Progression of Non-Small Cell Lung Cancer

• Published in: Clinical cancer research Vol. 10; no. 1; pp. 293 - 300
• Main Authors: BOFFA, Daniel J, LUAN, Fulung, THOMAS, Dolca, HUA YANG, SHARMA, Vijay K, LAGMAN, Milagros, SUTHANTHIRAN, Manikkam
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.01.2004
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - secondary; Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell Cycle - drug effects; Cyclosporine - therapeutic use; Disease Progression; Drug Therapy, Combination; Humans; Immunosuppressive Agents - therapeutic use; In Vitro Techniques; Lung Neoplasms - drug therapy; Lung Neoplasms - secondary; Male; Medical sciences; Mice; Mice, Inbred DBA; Pharmacology. Drug treatments; Sirolimus - therapeutic use; Tumor Cells, Cultured - transplantation; Tumors; Lung disease; Sirolimus; Respiratory disease; Bronchus disease; Advanced stage; Metastatic; Malignant tumor; Metastasis; non-small cell lung carcinoma; Macrolide
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-0629-3

Purpose: 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). Experimental Design: 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.