title: Assessment of antitumor activity and acute peripheral neuropathy of 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016).
abstract: Oxaliplatin, a third-generation platinum compound incorporating oxalate and 1,2-diaminocyclohexane platinum, has been widely used in chemotherapy regimens for the treatment of metastatic colorectal cancer. Because of its wide spectrum of antitumor activity, oxaliplatin has been applied for the treatment of other carcinomas. However, the antitumor activity of single-agent oxaliplatin is insufficient. To increase its antitumor effects, polymeric micellar nanoparticles incorporating 1,2-diaminocyclohexane platinum (NC-4016) have been developed. The present study was designed to evaluate the efficacy of NC-4016 and its association with peripheral neuropathy, which is a primary dose-limiting factor in oxaliplatin therapy. The in vitro antitumor activity of NC-4016 was investigated using human carcinoma cell lines. To investigate the antitumor effects of NC-4016 in vivo, nude mice bearing the human carcinoma cell line KB were administered NC-4016 or oxaliplatin. The in vitro growth-inhibiting effect of NC-4016 was significantly weaker than that of oxaliplatin. However, the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in vivo. Moreover, we compared the severity of peripheral neuropathy induced by oxaliplatin and NC-4016 in a rat model. Oxaliplatin, NC-4016, or 5% glucose (control) were administered by a single tail vein injection. In the oxaliplatin-treated rats, neither mechanical nor heat allodynia was observed during the experimental period, whereas cold hyperalgesia/allodynia was observed from day 1 to 7. Conversely, cold hyperalgesia/allodynia was not observed in the NC-4016-treated rats. The present study demonstrated that the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in a mouse model of human carcinoma cell line KB. In addition, NC-4016-treated rats did not develop acute cold hypersensitivity, which is frequently experienced by patients after oxaliplatin administration.
authors: Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Takayoshi
authors: T
authors: Ueno
authors: Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Kazuhira
authors: K
authors: Endo
authors: Department of Functional Anatomy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Kiyomi
authors: K
authors: Hori
authors: Department of Functional Anatomy, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Noriyuki
authors: N
authors: Ozaki
authors: Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Akira
authors: A
authors: Tsuji
authors: Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Satoru
authors: S
authors: Kondo
authors: Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Naohiro
authors: N
authors: Wakisaka
authors: Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Shigeyuki
authors: S
authors: Murono
authors: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan ; Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Kazunori
authors: K
authors: Kataoka
authors: Research Division, NanoCarrier Co., Ltd, Chiba, Japan.
authors: Yasuki
authors: Y
authors: Kato
authors: Division of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Tomokazu
authors: T
authors: Yoshizaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000175:diagnosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: C554217:((1R,2R)-1,2-diaminocyclohexane)platinum(II); D000970:Antineoplastic Agents; D008823:Micelles; D053769:Nanocapsules; D009944:Organoplatinum Compounds
keywords: carcinoma; chemotherapy; drug delivery system; oxaliplatin