A candidate for cancer gene therapy: MIP-1 alpha gene transfer to an adenocarcinoma cell line reduced tumorigenicity and induced protective immunity in immunocompetent mice.
OBJECTIVE
To evaluate the possibility of cancer gene therapy by the gene delivery of chemokine, the effects of human macrophage inflammatory protein 1 alpha (hu-MIP-1 alpha), murine-macrophage inflammatory protein 1 alpha (mu-MIP-1 alpha), and human-interleukin 8 (hu-IL-8) on tumor progression and immunization were studied.


METHODS
Cachexia-inducing and highly tumorigenic adenocarcinoma cells (cell line colon 26, clone 20) were transfected with either a control plasmid, hu-MIP-1 alpha, mu-MIP-1 alpha, or hu-IL-8 expression vector. The production of hu-MIP-1 alpha reached > 1.5 ng/ml in vitro when transfectant cells were cultured at a cell density of 2 x 10(5) cells in 7 ml for 3 days. Immunocompetent BALB/c mice were inoculated into the footpad with the tumor cells, and then primary tumor growth, morphological analyses, and tumor immunogenicity were studied.


RESULTS
The secretion of hu-MIP-1 alpha, mu-MIP-1 alpha, and hu-IL-8 did not affect the growth rate in vitro. Reduced tumorigenicities in vivo were observed in transfected cells with hu-MIP-1 alpha and mu-MIP-1 alpha. Morphologic observation of the site of inoculation of cells transfected with hu-MIP-1 alpha showed infiltration of macrophages and neutrophils on the 5th day after the inoculation. Mice that had rejected cells transfected with hu-MIP-1 alpha gene were immune to a subsequent challenge with the parental cells.


CONCLUSIONS
The rejection of the cells depends on cytolysis and generates potent and long lasting antitumor immunity. These data suggest that tumor cells transfected with the MIP-1 alpha gene might be useful as an effective therapy for the treatment of certain tumors.
Nakashima
E
E
Hospital Pharmacy, Kanazawa University, Japan.
Oya
A
A
Kubota
Y
Y
Kanada
N
N
Matsushita
R
R
Takeda
K
K
Ichimura
F
F
Kuno
K
K
Mukaida
N
N
Hirose
K
K
Nakanishi
I
I
Ujiie
T
T
Matsushima
K
K
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D002100:Cachexia; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007121:Immunocompetence; D016209:Interleukin-8 / Q000235:genetics; D008175:Lung Neoplasms / Q000556:secondary; D019402:Macrophage Inflammatory Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D011994:Recombinant Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011994:Recombinant Proteins