Abstract 360: Therapeutic potential of EC-18 as a chemotherapy adjuvant for 5-fluorouracil-induced neutropenia

Abstract

Abstract Chemotherapy-induced neutropenia (CIN) is a complication that arises during cancer treatment and necessitates dose reduction. Preventing CIN and maintaining absolute neutrophil counts (ANC) is critical for successful chemotherapy because a rapid decline of neutrophils increases susceptibility to infection. Here, we investigated whether administration of EC-18 has therapeutic effects on the treatment of CIN in 5-fluorouracil (5-FU)-induced neutropenia mouse model. A single injection of 5-FU 100mg/kg reduced the ANC in the control, EC-18 125 and EC-18 250mg/kg-treated cohort from pre-injection values to <500 cells/μL by 5.2±0.45, 5.8±0.45 and 5.8±0.45 days, respectively. The administration of EC-18 in 5-FU-injected mice resulted in significant reduction in the duration of neutropenia and the time to recovery of ANC >1000 cells/μL. EC-18 125 or 250mg/kg significantly reduced the duration of neutropenia from 7.4±1.14 days to 2.6±0.55 or 3.0±0.71 days, respectively. Moreover, the ANC of all individuals in the control cohort fell to severely neutropenic range (ANC <100 cells/μL), while only 20% of individuals in both EC-18 125 and 250mg/kg-treated cohorts experienced severe neutropenia. EC-18 also reduced the duration of severe neutropenia from 5.2±1.48 days to 2 days. EC-18 125 or 250mg/kg administration significantly increased the mean nadir after 5-FU injection from 2.0±4.47 cells/μL to 236±4.47 or 158±11.32 cells/μL, respectively. The time of recovery to an ANC ≥500 or 1000 cells/ μL was significantly reduced in EC-18 125 and 250 mg/kg-treated cohorts. Besides neutropenia, a single treatment of 5-FU induced the reduction of blood monocytes and eosinophils, similar to the pattern of the decrease of neutrophil counts. The administration of EC-18 125 or 250mg/kg in 5-FU-injected mice remarkably prevented the reduction of blood monocytes and eosinophils. In this study, thrombocytopenia is defined as a 50% or greater reduction in platelet count from baseline, and 2-fold or greater increase of platelet count from baseline for thrombocytosis. 5-FU treatment induced the moderate thrombocytopenia from 4 to 6 days and followed by a more pronounced and prolonged rebound thrombocytosis. EC-18 significantly reduced the extreme change in platelet counts, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis. Moreover, EC-18 effectively prevented a constant reduction of red blood cell (RBC) count induced by 5-FU treatment. Based on the observations in this study, we concluded that EC-18 has therapeutic potential as a chemotherapy adjuvant for the treatment of 5-FU-induced CIN as well as chemotherapy-associated other hematologic disorders. Citation Format: Yong-Jae Kim, Jinseon Jeong, Ki-Young Sohn, Do Young Lee, Sun Young Yoon, Jae Wha Kim. Therapeutic potential of EC-18 as a chemotherapy adjuvant for 5-fluorouracil-induced neutropenia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 360.