Recombinant human endostatin improves anti-tumor efficacy of paclitaxel by normalizing tumor vasculature in Lewis lung carcinoma.
OBJECTIVE
Normalization of the tumor vasculature and microenvironment by several angiogenesis inhibitors has been reported. Given that recombinant human endostatin (rh-endostatin) is also an endogenous angiogenesis inhibitor, a comprehensive evaluation of the effects of rh-endostatin on tumor vasculature and microenvironment and chemotherapy sensitivity would be favorable.


METHODS
Multiple treatment schedules of the combination of rh-endostatin and paclitaxel were tested in Lewis lung carcinoma. Further, we monitored microvascular density, tumor hypoxic fraction, and collagen covered tumor vessels at three different time points following the treatment of rh-endostatin, as well as the transcription of angiogenesis related factors (vascular endothelial growth factor-A and thrombospondin-1) and vasculature markers (regulator of G-protein signaling 5 and platelet/endothelial cell adhesion molecule-1).


RESULTS
The anti-tumor efficacy of paclitaxel was significantly improved 7 days after the treatment of rh-endostatin. Tumor microvascular density was decreased by rh-endostatin, although it became even higher 7 days after termination of rh-endostatin. Non-necrotic hypoxic fraction was significantly reduced 7 days after treatment of rh-endostatin, accompanied with increased collagen covered tumor vessels and coverage of pericytes around endothelial cells. Rh-endostatin could transiently upregulate the transcription of thrombospondin-1 and modulate the imbalance between vascular endothelial growth factor-A and thrombospondin-1.


CONCLUSIONS
Rh-endostatin could normalize the tumor vasculature and microenvironment in Lewis lung carcinoma probably via modulation of the balance between vascular endothelial growth factor-A and thrombospondin-1. During the time of vascular normalization, paclitaxel treatment was found to have maximal effect on tumor growth delay.
Huang
Guichun
G
Medical Oncology Department of Jinling Hospital, Medical School of Nanjing University, 305 ZhongShan Eastern Road, Nanjing, 210002, People's Republic of China. huangguichun@smail.nju.edu.cn
Chen
Longbang
L
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003131:Combined Modality Therapy; D017931:DNA Primers; D043169:Endostatins / Q000235:genetics / Q000627:therapeutic use*; D016228:Endothelial Growth Factors / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D017239:Paclitaxel / Q000627:therapeutic use; D020286:Pericytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019699:Thrombospondins / Q000235:genetics / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D017931:DNA Primers; D043169:Endostatins; D016228:Endothelial Growth Factors; D011994:Recombinant Proteins; D019699:Thrombospondins; D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel