Combined therapy of multidrug-resistant human lung cancer with anti-P-glycoprotein antibody and monocyte chemoattractant protein-1 gene transduction: the possibility of immunological overcoming of multidrug resistance.
We determined whether transduction of the monocyte chemoattractant protein-1 (MCP-1) gene into MDR human lung cancer cells affected their tumorigenicity and sensitivity to antibody-dependent cellular cytotoxicity (ADCC) reaction mediated by the anti-P-glycoprotein (P-gp) monoclonal antibody MRK16. The human MCP-1 gene inserted into an expression vector (BCMGSNeo) was transfected into MDR human small-cell lung cancer (H69/VP) cells. Monocyte chemotactic activity was found in culture supernatants collected from MCP-1-transfected H69/VP cells, but not in supernatants of parent and mock-transfected cells. In an in vitro experiment, recombinant MCP-1 did not affect monocyte-mediated ADCC against H69/VP cells when added to the monocyte culture in either the activation or the effector phase at sufficient concentrations to attract and activate monocytes. Tumorigenicity and growth rates of MCP-1-producing H69/VP cells in nude mice were similar to those of parental cells and mock-transfected cells. However, systemic treatment with MRK16 was more effective in inhibiting the formation of tumors by MCP-1-gene-transfected cells than by mock-transfected cells. Systemic treatment with MRK16 also inhibited the growth of a mixture (1:1) of MCP-1-producing cells and mock-transfected cells. These results suggest that combination therapy with MRK16 and MCP-1 gene transduction may be a useful immunological strategy to inhibit the growth of human MDR cancer cells expressing P-gp.
Nishioka
Y
Y
Third Department of Internal Medicine, The University of Tokushima School of Medicine, Tokushima City, Japan.
Yano
S
S
Fujiki
F
F
Mukaida
N
N
Matsushima
K
K
Tsuruo
T
T
Sone
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018932:Chemokine CCL2 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D012333:RNA, Messenger