Metronomic chemotherapy with cyclophosphamide (Cy) and celecoxib (Cel) in murine mammary adenocarcinoma tumor models: mechanism of action.

LE MAINETTI, VR ROZADOS, A ROSSA, E ROGGERO, MJ RICO, SI GERVASONI, R GIORDANO, OG SCHAROVSKY

Washington DC

Congreso; 101st Annual Meeting de la American Association for Cancer Research; 2010

Metronomic chemotherapy (MCT) refers to the chronic, equally spaced, delivery of low doses of different chemotherapeutic drugs, without extended interruptions. CY, administered in low dose, is able to modulate the immune response. It can also reduce tumor angiogenesis, like the COX-2 inhibitor CEL does. We have already demonstrated that the administration, as an intervention strategy, of metronomic CY + CEL in M-406 and M-234p mammary adenocarcinomas-bearing mice inhibited tumor growth, increasing the survival rate. Our present aim was to study the mechanism by which that therapeutic effect was achieved. CBi and Balb/c inbred mice were s.c. challenged on day 0 with M-406 or M-234p mammary tumors, respectively, and treated from day 8 (M-406) and 5 (M-234p) on with: I) no further treatment (controls); II) CY in the drinking water (25-30 mg/kg body weight/day); III) CEL (30 mg/kg p.o.), five times/week; IV) Treated as II + III. Blood samples were taken on days 0, 20 (M-406) and 30 (M-324p) to evaluate VEGF serum level determined by ELISA and the % of circulating regulatory T cells (Tregs) by flow cytometry. The same tumor challenges and therapeutic schedules were performed in nude mice. Tumors were excised on days 20 and 30 for M-406 and M-234p, respectively, fixed and paraffin embedded for detection by immunohistochemistry of CD34 and Ki67 molecules. The VEGF serum level of M-406-bearing control animals (group I) was, on day 20, significantly higher than that measured on day 0 (p