Suppression of tumor growth by viral vector-mediated gene transfer of N-terminal truncated platelet factor 4.
Platelet factor four (PF4), an inhibitor of endothelial cell proliferation in vitro, inhibits angiogenesis and tumor growth in vivo in experimental animals. The present study was designed to determine whether gene therapy-mediated expression of a form of PF4 lacking 16 amino acids of N-terminus from tumor cells could inhibit angiogenesis and tumor growth in vivo. Two replication-defective recombinant retroviral vectors were constructed. One encodes human PF4 (rRV-PF4) and the other encodes the N-truncated peptide (rRVp17-70). These vectors were then used to transduce KB cells, a human head and neck squamous carcinoma cell line. Expression of PF4 and p17-70 transgenes was confirmed by Western blot analysis. In vitro, both rRV-PF4 and rRVp17-70 were able to inhibit selectively the proliferation of human umbilical vascular endothelial cells (HUVEC) but not KB cells. In vivo activity was assessed by injecting 10(7) KB cells subcutaneously into nude mice and by monitoring subsequent tumor growth, xenograft vascular histochemistry, and animal survival. Viral vector-mediated cDNA transfer of PF4 and p17-70 resulted in inhibiting solid tumors through an anti-angiogenic action in vivo. Our data indicate that targeting tumor angiogenesis using viral-mediated gene transfer of full-length and N-terminal truncated PF4 represents a promising strategy for cancer gene therapy.
Li
Yanhan
Y
National Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, People's Republic of China.
Jin
Yixin
Y
Chen
Huishu
H
Jie
Gu
G
Tobelem
Gerard
G
Caen
Jacques P
JP
Han
Zhong Chao
ZC
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation / Q000473:pathology; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010978:Platelet Factor 4 / Q000235:genetics* / Q000627:therapeutic use*; D012190:Retroviridae / Q000235:genetics*; D015996:Survival Rate
D010978:Platelet Factor 4