A novel strategy of cancer gene therapy by transcriptional targeting of an allogeneic histocompatibility transgene.
BACKGROUND
A drawback of cancer gene therapy is the failure of toxic gene introduction into a proportion of the tumor cells, resulting in re-progression of the disease. Cancer cell-specificity of the gene introduction has also been problematic.


METHODS
Previously defined promoter/enhancer DNA of Q5 tumor antigen gene was used for the purpose of transcriptional targeting. A replication defective adenovirus carrying H-2D(d) cDNA placed downstream of the Q5 promoter/enhancer (Ad/Q5-H-2D(d)) was constructed and administered systemically to C57Bl/6 (H-2(b)) mice bearing pre-established hepatic metastasis of the syngeneic M5076 tumor.


RESULTS
5 of the 10 mice showed complete regression of the tumor. Combination of the therapy with low dose cyclophosphamide (CY) administration augmented the therapeutic effect. The effect was brought about by tumor cell-specific allograft rejection reactions and by tumor antigen-specific reactions induced as "bystander effect" by the former reactions.


CONCLUSIONS
The results provide an experimental basis of a highly efficient novel strategy of cancer gene therapy.
Kuwada
Eri
E
Medinet Medical Institute, Medinet Co., Ltd., 2-2-8 Tamagawadai, Setagayaku, Tokyo 158-0096, Japan.
Noguchi
Katsuo
K
Seo
Naohiro
N
Yamashiro
Hiromichi
H
Egawa
Kohji
K
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D018076:DNA, Complementary / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006084:Graft Rejection; D006183:H-2 Antigens / Q000235:genetics* / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D014158:Transcription, Genetic; D019076:Transgenes / Q000502:physiology*; D014184:Transplantation, Homologous; D014779:Virus Replication
D018906:Antineoplastic Agents, Alkylating; D018076:DNA, Complementary; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D003520:Cyclophosphamide