Antitumour activity of NK012, SN-38-incorporating polymeric micelles, in hypovascular orthotopic pancreatic tumour.
Human pancreatic cancer is refractory to chemotherapy partly because of blockage to penetration of anticancer agents. This issue must be taken into account particularly for the drug delivery system (DDS). The aim of the present study is to investigate how NK012 (SN-38-incorporating polymeric micelles) categorised as DDS exerts its antitumour effect in an orthotopic pancreatic tumour model compared with gemcitabine and irinotecan hydrochloride (CPT-11), a low-molecular-weight prodrug of a 7-ethyl-10-hydroxy-camptothecin (SN-38). The maximum tolerated doses (MTDs) of NK012 (30 mg/kg/d), CPT-11 (66.7 mg/kg/d) and gemcitabine (16.5mg/kg/d) were administered to mice bearing human pancreatic cancer cell (SUIT-2) xenografts implanted orthotopically. Antitumour effects of these compounds were evaluated. Drug distribution within the tumour was examined by fluorescence microscopy and high performance liquid chromatography (HPLC). NK012 exerted potent antitumour effects compared with CPT-11 and gemcitabine. A high concentration of NK012 and SN-38 released from NK012 had been observed until 192h. On the other hand, SN-38 converted from CPT-11 was detected only 1h postinjection. Fluorescence from NK012 was detected up to 48h, whereas that from CPT-11 almost disappeared by 24h postinjection. NK012 appeared to exert potent antitumour activity against intractable stroma-rich orthotopic pancreatic tumour xenografts due to its sufficient accumulation followed by the effective sustained release of SN-38 from NK012.
Saito
Yohei
Y
Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
Yasunaga
Masahiro
M
Kuroda
Jun-Ichiro
J
Koga
Yoshikatsu
Y
Matsumura
Yasuhiro
Y
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059004:Topoisomerase I Inhibitors; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D008823:Micelles; D059004:Topoisomerase I Inhibitors; D003841:Deoxycytidine; D000077146:Irinotecan; D002166:Camptothecin; D000093542:Gemcitabine