Improvement of carcinoembryonic antigen-specific prodrug gene therapy for experimental colon cancer.
BACKGROUND
Improvement of tumor-specific gene expression is very important for achieving successful effects in prodrug gene therapy for advanced cancer with metastatic lesions. We used the Cre/loxP system for enhancing carcinoembryonic antigen (CEA)-specific prodrug gene therapy of cytosine (CD)/5-fluorocytosine (5-FC) for the treatment of a colon cancer model accompanied with liver metastases.


METHODS
Orthotopic colon cancer models were developed. Seven days later, adenovirus vector (3 x 10(9) pfu)was injected into the abdominal cavity, and 5-FC was administered for the next 10 days.


RESULTS
In these models, the double administration of AxCEANCre expressing Cre recombinase under the control of the CEA promoter, and AxCALNLCD expressing the CD gene under the control of the CAG promoter by the Cre-mediated switching system, completely inhibited liver metastases, and significantly reduced primary tumor volume compared to the administration of Mock or AxCEACD (P <.001). The survival periods of the mice treated with AxCEANCre and AxCALNLCD were longer than mice treated with Mock or AxCEACD, and longer than the mice treated with AxCACD (P <.05).


CONCLUSIONS
The enhanced CEA-specific prodrug gene therapy using the Cre/loxP system was useful for the treatment of advanced colon cancer with liver metastases, implicating clinical application.
Ueda
Kentaro
K
Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8510, Japan.
Iwahashi
Makoto
M
Nakamori
Mikihito
M
Nakamura
Masaki
M
Matsuura
Ichiro
I
Ojima
Toshiyasu
T
Yamaue
Hiroki
H
D000256:Adenoviridae; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003596:Cytosine / Q000494:pharmacology* / Q000627:therapeutic use; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D019426:Integrases / Q000235:genetics*; D007763:Lac Operon; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary; D009700:Nucleoside Deaminases / Q000235:genetics*; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; D002272:Carcinoembryonic Antigen; D011355:Prodrugs; D014764:Viral Proteins; D003596:Cytosine; D005437:Flucytosine; C045073:Cre recombinase; D019426:Integrases; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase