title: Targeted antivascular therapy with the apolipoprotein(a) kringle V, rhLK8, inhibits the growth and metastasis of human prostate cancer in an orthotopic nude mouse model.
abstract: Antivascular therapy has emerged as a rational strategy to improve the treatment of androgen-independent prostate cancer owing to the necessity of establishing a vascular network for the growth and progression of the primary and metastatic tumor. We determined whether recombinant human apolipoprotein(a) kringle V, rhLK8, produces therapeutic efficacy in an orthotopic human prostate cancer animal model. Fifty thousand androgen-independent human prostate cancer cells (PC-3MM2) were injected into the prostate of nude mice. After 3 days, these mice were randomized to receive the vehicle solution (intraperitoneally [i.p.], daily), paclitaxel (8 mg/kg i.p., weekly), rhLK8 (50 mg/kg i.p., daily), or a combination of paclitaxel and rhLK8 for 4 weeks. Treatment with paclitaxel or rhLK8 alone did not show significant therapeutic effects on tumor incidence or on tumor size compared with the control group. The combination of rhLK8 and paclitaxel significantly reduced tumor size and incidence of lymph node metastasis. Significant reduction in microvessel density and cellular proliferation and induction of apoptosis of tumor cells, and tumor-associated endothelial cells, were also achieved. Similarly, PC-3MM2 tumors growing in the tibia showed significant suppression of tumor growth and lymph node metastasis by the combination treatment with rhLK8 and paclitaxel. The integrity of the bone was significantly preserved, and apoptosis of tumor cells and tumor-associated endothelial cells was increased. In conclusion, these results suggest that targeting the tumor microenvironment with the antivascular effect of rhLK8 combined with conventional cytotoxic chemotherapy could be a new and effective approach in the treatment of androgen-independent prostate cancer and their metastases.
authors.affiliation: Cancer Biology Team, Mogam Biotechnology Research Institute, Yongin, Republic of Korea.
authors.forename: Ho-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Yu
authors.forename: John N
authors.initials: JN
authors.lastname: Papadopoulos
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Kim
authors.forename: Junqin
authors.initials: J
authors.lastname: He
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Park
authors.forename: Yeup
authors.initials: Y
authors.lastname: Yoon
authors.forename: Jang-Seong
authors.initials: JS
authors.lastname: Kim
authors.forename: Sun Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001054:Apolipoproteins A / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D018082:Kringles; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D001054:Apolipoproteins A; C574732:LK8 peptide; D010446:Peptide Fragments; D011994:Recombinant Proteins; D017239:Paclitaxel