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.

Abstract

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.