Ribozyme targeting of the growth factor pleiotrophin in established tumors: a gene therapy approach.
The growth and metastasis of solid tumors relies on the activities of polypeptide growth factors to recruit stromal tissue and expand the tumor mass. Pleiotrophin (PTN) is a secreted growth factor with angiogenic activity that has been found to contribute to the growth and metastasis of tumors including melanoma. Here, we present a gene therapy approach of targeting PTN in established tumors using ribozymes. Tetracycline-regulated ribozyme expression vectors were used to deplete conditionally PTN mRNA from melanoma xenograft tumors in vivo. We found that tetracycline-mediated initiation of ribozyme expression in established tumors reduced further tumor growth. Next, we generated synthetic anti-PTN ribozymes that inhibit PTN-dependent colony formation of cells in soft agar. Intraperitoneal administration of these synthetic ribozymes into nude mice inhibited growth of PTN-positive, subcutaneous melanoma. Furthermore, PTN released from the tumors into the circulation of mice was reduced after ribozyme treatment. These data show that ribozyme targeting of rate-limiting tumor growth factors could provide an efficient tool for cancer therapy and that the efficacy may be reflected in the reduction of the serum levels of the targeted protein, PTN.
Malerczyk
C
C
Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20057, USA.
Schulte
A M
AM
Czubayko
F
F
Bellon
L
L
Macejak
D
D
Riegel
A T
AT
Wellstein
A
A
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000098:blood supply / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D016337:RNA, Catalytic; D012333:RNA, Messenger / Q000235:genetics*; D012878:Skin Neoplasms / Q000098:blood supply / Q000628:therapy*; D013752:Tetracycline / Q000627:therapeutic use; D014162:Transfection / Q000379:methods
D002352:Carrier Proteins; D016207:Cytokines; D016337:RNA, Catalytic; D012333:RNA, Messenger; C066845:pleiotrophin; D013752:Tetracycline