|Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
Recently it has been reported that clarithromycin (CAM), a 14-membered ring macrolide, prolongs the survival of patients with advanced lung cancer and that 14-member macrolides have immunomodulatory effects on a variety of cells including airway epithelial cells. On the basis of the above results, we hypothesized that 14-member macrolides would have some anticancer therapeutic effects. To evaluate this hypothesis, we examined the effect of macrolide antibiotics on chemotherapeutic drug-induced apoptosis of human non-small lung cancer (NSLC) cells. Tumor cells were incubated for 3 days with 14-member macrolides, CAM and erythromycin, or 16-member macrolides, josamycin and midecamycin, prior to cisplatin (CDDP) or doxorubicin treatment. Both of 14-member macrolides enhanced chemotherapeutic agent-induced apoptosis of NSLC cells carrying wild-type (wt) p53 (RERF-LC-MS, A549, EBC-1, and SQ-5) whereas 16-member macrolides did not. In p53 null NCI-H358 cells, neither anticancer agent alone nor the combination of 14-member macrolide and anticancer agent induced apoptosis.
Chemotherapeutic agents induced the cell surface Fas and Fas ligand expression in wt p53 tumor cells, and the combination of 14-member macrolide and anticancer agent enhanced this effect. Pretreatment with a vector expressing dominant-negative p53 abrogated the apoptosis of wt p53 NSLC cells induced by CAM and CDDP. Clarithromycin suppressed the function of P- glycoprotein in NSLC cells carrying wt p53. Fourteen-member macrolides increased the level of p53 in wt p53 NSLC cells. These results indicate that 14-member macrolides enhanced chemotherapeutic agent-induced apoptosis in human NSLC cells by p53-dependent fashion.