Sex-Dependent Adverse Drug Reactions to 5-Fluorouracil in Colorectal Cancer

• Published in: Biological & pharmaceutical bulletin 2019/04/01, Vol.42(4), pp.594-600
• Main Authors: Lim, Hyesol, Kim, Sun Young, Lee, Eunhye, Lee, Seungeun, Oh, Sungryong, Jung, Joohee, Kim, Kwi Suk, Moon, Aree
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; adverse drug reaction; Aged; Alopecia; Animal models; Animals; Antimetabolites, Antineoplastic - adverse effects; Asian Continental Ancestry Group; Cell culture; Cell Line, Tumor; Cell lines; Cell Survival - drug effects; Chemotherapy; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Cytotoxicity; Female; Fluorouracil - adverse effects; Hematology; Humans; Leukopenia; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Patients; Sex; Sex Characteristics; Sex differences; Side effects; toxicity; Tumor Burden; Tumor cell lines; Xenografts
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b18-00707

Sex-related incidence and outcomes were reported in various cancers, including colorectal cancer. 5-Fluorouracil (5-FU) is widely used as an essential chemotherapeutic agent for colorectal cancer. However, sex-based differences in 5-FU toxicity have yet to be reported in human cancer cell lines and xenograft mouse models to date. Here, we investigated, for the first time, sex-based differences in 5-FU toxicity using human colon cancer cell lines, xenograft mouse models, and Korean patients’ data. Female-derived colon cancer cell lines exhibited greater 5-FU-induced cytotoxicity than male-derived colon cancer cell lines. We established two xenograft mouse models: one with a male-derived human colon cancer cell line injected into male mice (a male-xenograft model) and another involving a female-derived human colon cancer cell line injected into female mice (a female xenograft model). Treatment with 5-FU inhibited tumor growth and led to hematological toxicity in a female xenograft model more potently than in a male xenograft model. We analyzed the data obtained from Korean patients with colorectal cancer to examine sex differences in adverse drug reactions caused by 5-FU. Korean female patients with colorectal cancer who received 5-FU chemotherapy experienced more frequent adverse drug reactions including alopecia and leukopenia than male patients. Taken together, we demonstrated that female may be associated with increased risk of toxicity to 5-FU treatment in colorectal cancer based on in vitro and in vivo investigations and clinical data analysis. Our study suggests sex as an important clinical factor, which predicts induction of toxicity related to 5-FU treatment.