Antiangiogenesis targeting tumor microenvironment synergizes glucuronide prodrug antitumor activity.
OBJECTIVE
This study is aimed at investigating the in vivo antitumor activity of a novel cell-impermeable glucuronide prodrug, 9-aminocamptothecin glucuronide (9ACG), and elucidating the synergistically antitumor effects of antiangiogenesis therapy by targeting the tumor microenvironment.


METHODS
We analyzed the antitumor effects of 9ACG alone or combined with antiangiogenic monoclonal antibody DC101 on human tumor xenografts by measuring tumor growth and mouse survival in BALB/c nu/nu nude and NOD/SCID mice. The drug delivery, immune response, and angiogenesis status in treated tumors were assessed by high performance liquid chromatography, immunohistochemistry, and immunofluorescence assays.


RESULTS
We developed a nontoxic and cell-impermeable glucuronide prodrug, 9ACG, which can only be activated by extracellular beta-glucuronidase to become severely toxic. 9ACG possesses potent antitumor activity against human tumor xenografts in BALB/c nu/nu nude mice but not for tumors implanted in NOD/SCID mice deficient in macrophages and neutrophils, suggesting that these cells play an important role in activating 9ACG in the tumor microenvironment. Most importantly, antiangiogenic monoclonal antibody DC101 potentiated single-dose 9ACG antitumor activity and prolonged survival of mice bearing resistant human colon tumor xenografts by providing strong beta-glucuronidase activity and prodrug delivery through enhancing inflammatory cell infiltration and normalizing tumor vessels in the tumor microenvironment. We also show that inflammatory cells (neutrophils) were highly infiltrated in advanced human colon cancer tissues compared with normal counterparts.


CONCLUSIONS
Our study provides in vivo evidence that 9ACG has potential for prodrug monotherapy or in combination with antiangiognesis treatment for tumors with infiltration of macrophage or neutrophil inflammatory cells.
Juan
Ting-Yi
TY
Divisions of Urology, Graduate Institute of Life Sciences, Institute of Biomedical Sciences, Academia Sinica, National Yang-Ming University,Taipei,Taiwan.
Roffler
Steve R
SR
Hou
Hsien-San
HS
Huang
Shih-Ming
SM
Chen
Kai-Chuan
KC
Leu
Yu-Lin
YL
Prijovich
Zeljko M
ZM
Yu
Cheng-Ping
CP
Wu
Chang-Chieh
CC
Sun
Guang-Huan
GH
Cha
Tai-Lung
TL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D020719:Glucuronides / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
C461385:9-aminocamptothecin glucuronide; D000911:Antibodies, Monoclonal; C511761:DC101 monoclonal antibody; D020719:Glucuronides; D011355:Prodrugs; D040301:Vascular Endothelial Growth Factor Receptor-2; D002166:Camptothecin