Feasibility of tailored, selective and effective anticancer chemotherapy by direct injection of docetaxel-loaded immunoliposomes into Her2/neu positive gastric tumor xenografts.
We assessed the effects of direct injection of docetaxel-loaded immuno-(trastuzumab)-liposomes (IDL) on a xenograft mouse tumor model to determine potential clinical applications of intratumoral tailored chemotherapy against Her2/neu-overexpressing gastric cancer. The NCI-N87 Her2/neu overexpressing gastric cancer cell line xenograft mouse model was treated with IDL or docetaxel-loaded liposomes (DL). The ratio of the tumor volume of the treatment:control was determined. In addition, docetaxel pharmacokinetics in tumors were measured using high-performance liquid chromatography, and the cell viability and cell cycle distribution of Her2/neu positive cells were determined by flow cytometric analysis. The IDL group showed a significantly higher distribution of docetaxel in the N87 xenograft tumor tissues and superior antitumor efficacy compared to crude administration of docetaxel and/or trastuzumab and DL. The number of viable Her2/neu positive cells decreased following treatment with either free trastuzumab or IDL. On day 7 after treatment, a decrease in the G0/G1 phase of the cell cycle was observed in the DL and IDL groups compared to the control group. No local adverse effects were observed. These results suggest that intratumoral administration of IDL maintains a high concentration of docetaxel within the tumor leading to a safe and effective regional cancer therapeutic strategy. In addition to the inherent cytotoxic effect of trastuzumab, conjugation of trastuzumab to a liposome further enhanced the retention of docetaxel within the tumors. These data suggest that immuno-liposome mediated delivery of drugs is a promising new therapeutic option for patients with advanced gastric cancer that overexpress Her2/neu.
Division of Gastrointestinal Surgery and Surgical Oncology, Department of Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon-shi, Ehime 791-0295, Japan. yayuji@m.ehime-u.ac.jp
Yuji
Y
Yamamoto
Motohira
M
Yoshida
Mitsunori
M
Sato
Koichi
K
Sato
Satoshi
S
Kikuchi
Hiroki
H
Sugishita
Jun
J
Kuwabara
Yusuke
Y
Matsuno
You
Y
Kojima
Masamitsu
M
Morimoto
Atsushi
A
Horiuchi
Yuji
Y
Watanabe
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D000077143:Docetaxel; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000276:immunology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D043823:Taxoids / Q000008:administration & dosage*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; D018796:Immunoconjugates; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab