Chronic gene delivery of interferon-inducible protein 10 through replication-competent retrovirus vectors suppresses tumor growth.
Sustained maintenance of therapeutic levels of angiostatic proteins in tumor tissues continues to represent a major challenge to antiangiogenesis therapy of cancer. In this study, we tested the hypothesis of utilizing gene transfer via replication-competent retroviral (RCR) vectors for chronic protein delivery. We now show that bioactive human interferon-inducible protein-10 (IP10) can be secreted from a variety of mammalian cells upon transduction with RCR vectors carrying the human IP10 gene. The production of IP10 from RCR-transduced cells could be maintained for at least three months in culture. The level and duration of IP10 expression in vivo was sufficient to inhibit growth of subcutaneous (s.c.) tumors as well as metastatic lesions in mice. This tumor inhibition was correlated to a marked reduction in tumor vascularization and mitotic activity. By conducting immunohistological studies, we have been able to show that IP10 vector-affected tumors evidenced elevated levels of IL-12p35 mRNA, with no sign of changes in the local inflammatory response, however, as determined by macrophage infiltration and the expression of proinflammatory cytokines. We are addressing the feasibility of using RCR vector-based gene therapy as a more convenient alternative tool to chronically deliver antiangiogenic proteins for cancer therapy.
Sun
Yuansheng
Y
Division of Medical Biotechnology, Paul-Ehrlich-Institut, 63225 Langen, Germany.
Finger
Carsten
C
Alvarez-Vallina
Luis
L
Cichutek
Klaus
K
Buchholz
Christian J
CJ
D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000627:therapeutic use*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000473:pathology; D002460:Cell Line; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism*; D005354:Fibrosarcoma / Q000473:pathology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007668:Kidney / Q000166:cytology; D009052:Leukemia Virus, Murine / Q000235:genetics; D008545:Melanoma / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D020533:Angiogenesis Inhibitors; D054357:Chemokine CXCL10; D019743:Chemokines, CXC