SKLB1002, a novel inhibitor of VEGF receptor 2 signaling, induces vascular normalization to improve systemically administered chemotherapy efficacy.
Vascular endothelial growth factor receptor (VEGFR) or vascular endothelial growth factor (VEGF) inhibitors have shown only modest clinical activity for most tumor types when used as single agents. However, present evidence indicates that these antiangiogenic drugs can cause transient "normalization" of the tumor vasculature, thereby improving the delivery of systemic chemotherapy. We examined temporal changes in tumor vascular function in response to the novel VEGFR2 inhibitor, SKLB1002. Established tumor-bearing animals were evaluated at serial time points for treatment-associated changes in tumor vascular architecture and function. As a result, blocking VEGF signaling by SKLB1002 produced a morphologically and functionally "normalized" vascular network. Consistent with our observations, a 2.2 fold increase in intratumoral doxorubicin levels was determined with SKLB1002 pretreatment compared with administration of doxorubicin alone. Finally, combined SKLB1002 and doxorubicin exhibited significant antitumor (49% of control size) and antimetastatic effects (12% of control metastatic nodules) in vivo. Our results showed SKLB1002 induced vascular normalization and enhanced anticancer drug delivery, which were associated with the observed synergistic effect in vivo.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
G
G
Shen
Y
Y
Li
T
T
Du
G
G
Shi
L
L
Dai
X
X
Chen
R
R
Zheng
W
W
Li
X
X
Su
S
S
Zhang
Y
Y
Wei
S
S
Yang
H
H
Deng
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D004317:Doxorubicin / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D005455:Fluorescent Antibody Technique; D000860:Hypoxia / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D040301:Vascular Endothelial Growth Factor Receptor-2