Abstract 795: Metronomic chemotherapy with cyclophosphamide and metformin inhibits tumor and metastasis growth M-406 murine mammary adenocarcinoma

Abstract

Abstract Metronomic chemotherapy (MCT) refers to the chronic, equally spaced, delivery of low doses of different chemotherapeutic drugs, without extended interruptions. We have already demonstrated that MCT, as an intervention strategy, of metronomic Cy combined with celecoxib or doxorubicin inhibits mammary tumors growth. Our present aim was to analyze the antitumor and antimetastatic effects of MCT of Cy combined with Met. Inbred CBi mice were s.c. or i.v. challenged with M-406 tumor (Day 0), and treated when the tumors reached a volume of 100 a 150 mm3 (s.c.) or from Day 3 (i.v.) on, with: I) no further treatment (controls); II) Cy in the drinking water (20-30 mg/kg body weight/day); III) Met 3 times/week by gavage (100 mg/kg); IV) Treated as II + III. Tumors were measured and animals weighed twice a week and blood samples for glycemia determination were taken. On day 36 tumor volume in group IV (mm3, mean ± SEM: 929.7 ± 213.8) was lower than in groups I (2880.0 ± 1530.0), II (2896.4 ± 976.9) and III (3772.0 ± 68.0). On day 46, with only two groups remaining, tumor volume in group IV was lower than that in group II (p=0.032). All the groups differed in tumor volume doubling time (days, mean ± SEM; I: 3.8 ± 0.3, II: 5.3 ± 0.7, III: 3.6 ± 0.4, IV: 5.4 ± 0.2) (p<0.05). All the groups differed in survival (days, median, I: 30.5; II: 44; III: 29; IV: 50) (p=0.0063), showing group IV the highest one. There were neither weight losses nor changes in the glycemia with respect to basal values both in s.c. and i.v. experiments. In the i.v. experiment, animals were sacrificed on day 13, when the first mouse showed signs of metastatic illness. The number and diameter of lung metastasis were determined and total metastatic volume (TMV) was calculated. The experimental groups differed in TMV (p<0.0001), being those of groups II (mm3, mean ± SEM: 162.1 ± 41.4) and IV (218.6 ± 31.3) significantly lower (p<0.001 and p<0.01, respectively) than those in groups I (491.3 ± 80.6) and III (432.3 ± 54.5). These results clearly show that metronomic chemotherapy with a combination of cyclophosphamide and metformin significantly inhibits tumor growth and increase survival, also decreasing the development of metastasis of a murine mammary adenocarcinoma, while being devoid of toxicity. Citation Format: Antonela S. Asad, Jesús Basualdo, Lucía Micheletti, María C. Capello Gardenal, Herman A. Perroud, María J. Rico, Viviana R. Rozados, O. Graciela Scharovsky. Metronomic chemotherapy with cyclophosphamide and metformin inhibits tumor and metastasis growth M-406 murine mammary adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 795. doi:10.1158/1538-7445.AM2014-795