Effective gene therapy for medullary thyroid carcinoma using recombinant adenovirus inducing tumor-specific expression of interleukin-12.
No satisfactory treatment of metastatic medullary thyroid carcinoma (MTC) is available. Cell-specific gene therapy offers a new approach. We have constructed a recombinant replication-defective adenoviral vector expressing murine interleukin-12 (mIL-12), driven by a modified CALC-I promoter (TCP). This vector (AdTCPmIL-12) includes two separate cassettes encoding mIL-12 p35 or p40 subunit controlled by TCP inserted in the E1 region of adenovirus type 5. In vitro and in vivo reporter gene expression using TCP revealed its cell-specific activity. AdTCPmIL-12-infected rat MTC (rMTC) cells produced high amounts of functional mIL-12 cells in vitro, while other cell lines infected with AdTCPmIL-12 did not. AdTCPmIL-12-transduced rMTC cells completely lost their tumorigenicity in syngenic WAG/Rij rats. Direct injection of 1 x 10(9) plaque forming units of AdTCPmIL-12 into subcutaneous rMTC tumors in WAG/Rij rats caused tumor regression in over 60% of animals within 20 days. Rats cured of tumors did not develop tumors after re-injection of naive rMTC cells, demonstrating lasting immunity. Treatment with AdTCPmIL-12 of one tumor resulted in regression of an established tumor at a distant site. Moreover, intratumoral or intravenous injection of AdTCPmIL-12 did not induce evident toxicity. These results indicate AdTCPmIL-12 can contribute to effective and less toxic gene therapy of MTC.
Yamazaki
M
M
Thyroid Study Unit, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Zhang
R
R
Straus
F H
FH
Messina
M
M
Robinson
B G
BG
Hashizume
K
K
DeGroot
L J
LJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002116:Calcitonin / Q000235:genetics; D018276:Carcinoma, Medullary / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D011919:Rats, Inbred Strains; D013964:Thyroid Neoplasms / Q000628:therapy*; D014407:Tumor Cells, Cultured
D018664:Interleukin-12; D002116:Calcitonin