Abstract 3511: Antitumor effect of metronomic chemotherapy with cyclophosphamide (CY) and doxorubicin (DOX) in the mouse mammary adenocarcinoma M-234p tumor-model
Authors: Mainetti Leandro E. , Zenobi Maria Virginia Fernández , Rozados Viviana R. , Graciela Scharovsky O. 
Published: June 2012

Metronomic chemotherapy refers to the chronic, equally spaced, delivery of low doses of different chemotherapeutic drugs, without extended interruptions. We have already demonstrated that the administration, as an intervention strategy, of metronomic CY plus DOX in M-406 mammary adenocarcinoma-bearing mice, inhibited tumor growth and metastases development, increasing the survival rate without toxicity. In order to know if that effect was unique to M-406 tumor or could be extended to other mammary carcinomas, our present aim was to study the effect of metronomic chemotherapy with CY + DOX in the M-234p tumor-model and the effect of the therapy in the level of circulating regulatory T cells (Tregs), considering the immunomodulatory effect of low doses of CY. Also, we intended to compare the therapeutic efficacy of the present schedule with that of MCT with CY + Celecoxib, previously done in the same tumor-model. CBi inbred female mice were s.c. challenged with M-234p cells (day 0). On day 10, mice were distributed in four experimental groups (n=6-8/group) that received: I) Control: 0.2ml of saline i.p. 3 times/week; II) CY (20mg/kg of body weight) daily, in the drinking water; III) Dox, i.p., 0,5mg/kg, of body weight, 3 times/week; IV) Treatment II + III. Tumors were measured and body weight was determined three times per week. Blood samples were taken at the beginning and at the end of the experiments to determine total leukocyte count and to evaluate by flow cytometry the percentage of Treg (CD4+ CD25+ Foxp3+) cells in serum. On day 31 a significant inhibition of tumor growth was evident in group III (mean ± SEM: 1166.4 ± 224.6 mm3) and IV (777.6 ± 170.6) with respect to control mice (3556.8 ± 895.3) (p&lt;0.001). Tumor volume in groups III and IV was significantly lower than that in group II (p&lt;0.005 and p&lt;0.001, respectively).The median survival of mice in group IV (49 days) was higher than that observed in groups I (31 days), II (33 days) and III (42 days). The survival in group IV was significantly higher compared to groups I (p&lt;0.0005) and III (p&lt;0.005). On day 31 the percentage of Tregs cells in serum showed no differences among the four groups. The treatment was devoid of toxicity, as evaluated by body weight evolution and, importantly, by total leukocytes count. These results clearly show that metronomic chemotherapy with a combination of cyclophosphamide and doxorubicin, administered as an intervention strategy, is able to inhibit the growth of M-234p mammary adenocarcinoma, while being devoid of toxicity. The characteristics and the effect of the therapeutic schedule herein utilized and its efficacy in two different tumor-models suggest its implementation at the clinical setting in the near future. Importantly, MCT with CY + DOX and CY + Celecoxib showed similar antitumor efficacy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3511. doi:10.1158/1538-7445.AM2011-3511