The effect of active hexose correlated compound in modulating cytosine arabinoside-induced hair loss, and 6-mercaptopurine- and methotrexate-induced liver injury in rodents Buxiang Sun a , Koji Wakame a , Eri Sato a , Hiroshi Nishioka a , Okezie I. Aruoma b, *, Hajime Fujii a, * a Amino Up Chemical Co., Ltd., 363-32 Shin-ei, Kiyota-ku, Sapporo 004-0839, Japan b Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, 230 West 125th, New York, NY 10027, USA 1. Introduction Chemotherapy to patients with cancer remains an effective mode of treatment of the disease, but it is associated with many side effects including mild or dose-limiting toxicities such as alopecia (hair loss), myelosuppression, gastrointestinal dysfunc- tions, neurologic toxicities, and immune suppression which results in infections and cancer cell proliferation [1,2]. Although economic analysis of treatment in health care systems may be applied to the full range of interventions that make up a cancer service (including cancer screening programmes and early treatments, diagnostic test and referral processes, surgical procedures, radiotherapy, chemotherapy, and palliative care) [3,4], the economic impact of cancer in health care systems remains one that much attention, in the context of complementary medicine, needs to be directed. Cytosine arabinoside (cytarabine, Ara-C, a cell cycle-specific cytotoxic drug that selectively kills cells in the S phase) has been used in the treatment of human acute myeloblastic and lymphoblastic leukaemia, some head and neck cancers, and non-Hodgikin’s lymphoma (NHL), and its effectiveness has been associated with cytotoxic effects on blast progenitors in self- renewal [5–10]. Dormant leukemic progenitors are recruited in response to growth stimulation by hematopoietic growth factors that not only stimulate their growth but also provide Ara-C sensitivity [5,6]. Ara-C induces various side effects such as fatigue, loss of appetite, diarrhea, sore mouth, nausea and vomiting, bone marrow suppression, and alopecia (hair loss) [7–10]. Cutaneous or dermatologic toxicities (which may occur in various forms and occasionally cause dose-limiting toxicities) may lead to the desensitization of the immune system, which leads to the production of substances that provoke alopecia attack (e.g., white blood cells attack hair follicles as they mistake them for foreign Cancer Epidemiology 33 (2009) 293–299 ARTICLE INFO Article history: Accepted 20 July 2009 Keywords: Active hexose correlated compound (AHCC) 6-Mercaptopurine Methotrexate Cytosine arabinoside Alopecia (hair loss) Drug-induced liver injury Anticancer drugs Cancer chemotherapy-side effects Complementary medicine Economics of cancer therapy ABSTRACT Background: Active hexose correlated compound (AHCC) (a mixture of polysaccharides, amino acids, lipids and minerals derived from cultured mycelia of a Basidiomycete mushroom, Lentinula edodes) was used to assess amelioration of alopecia (hair loss) caused by cytosine arabinoside (Ara-C) and modulation of liver injury caused by single doses 6-mercaptopurine (6-MP) plus methotrexate (MTX). Methods: Follicular integrity and hair growth was assessed in male and female SD neonatal rats (8 days old) treated with a single dose of Ara-C (30 mg/kg/day, i.p.) and AHCC (500 mg/kg/day, p.o.) for 7 consecutive days. The side effects of a single oral dose of 6-MP (2.5 mg/kg body weight) plus MTX (30 mg/kg body weight) and their amelioration by treatment with AHCC (1000 mg/kg body weight) for 28 days were assessed in male ddY mice (8 weeks old). Results: Of the Ara-C treated rats 71.4% showed severe alopecia and 28.6% showed moderate alopecia. However, the AHCC (p.o.)-treated Ara-C group was significantly protected from alopecia. Ara-C treated rats had profound loss of hair follicles but the Ara-C plus AHCC-treated group had mild losses of follicles. AHCC supplementation to the 6-MP- and MTX- treated mice significantly increased body weight, erythrocytes, leukocytes and serum albumin, improved liver hypertrophy and degeneration, normalized the activities of serum glutamic oxaloacetic transaminase (sGOT) and serum glutamic pyruvic transaminase (sGPT), and enhanced liver drug- metabolizing enzymes. Conclusion: Co-administration of AHCC significantly reduced the side effects associated with Ara-C, 6-MP and MTX. However, the molecular mechanism for AHCC activity and its clinical integrity for use needs defining. ß 2009 Elsevier Ltd. All rights reserved. * Corresponding authors. E-mail addresses: okezie.aruoma@touro.edu (O.I. Aruoma), hfujii@aminoup.co.jp (H. Fujii). Contents lists available at ScienceDirect Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net 1877-7821/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2009.07.006