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

Lung cancer is the most common cause of cancer deaths in males and females. Although small-cell lung cancer is sensitive to chemotherapy, it gradually becomes resistant due to the emergence of multidrug-resistant cells. P-glycoprotein (P-gp) encoded by the mdr1 gene is one of the key molecules in MDR. It has been shown to bind anti-cancer drugs, to be an ATPase, and to be localized in the plasma membranes of MDR cells (Hamada and Tsuruo, 1988). Expression of the mdr1 gene was found to be elevated in intrinsically drug-resistant cancers as well as in tumors that acquired drug resistance during chemotherapy (Noonan et al., 1990). Recently, even a low level of P-gp expression was reported to be useful as a marker of resistance to combination chemotherapy in ovarian and small-cell lung cancers (Holzmayer et al., 1992). Thus, the selective killing of tumor cells expressing P-gp seems very important for successful cancer therapy. We found previously that 2 monoclonal antibodies, MRK16 and MRK17, that react with the extracellular domain of P-gp, induced lysis of MDR cancer cells in vitro by inducing antibody-dependent monocyte-mediated cytotoxicity (Hamada and Tsuruo, 1986;Nishioka et al., 1992) and caused rapid regression of subcutaneously established MDR human ovarian cancers (Tsuruo et al., 1989).Many reports have shown that it is very important for successful immunotherapy of cancers to attract effector cells, such as monocytemacrophages and lymphocytes, into the site of tumor growth (Rosenberg, 1992). Much attention has been paid to transduction of cytokine genes into tumor cells not only for analysis of cytokinemediated biological effects on tumor growth, but also for clinical use as tumor vaccines. Previous works demonstrated that the transductions of cytokine genes such as IL-2, IL-4, IL-7, TNF-a, IFN-g and GM-CSF into tumor cells induced regression of tumors (Watanabe et al., 1989;Dranoff et al., 1993;Hock et al., 1993). To enhance the accumulation of killer cells, particularly monocytemacrophages, we focused on MCP-1, also known as monocyte chemotactic and activating factor (MCAF), which is a potent chemoattractant and an activator of monocytes (Furutani et al., 1989). In this study, we transfected MDR human small-cell lung cancer (H69/VP) cells with the MCP-1 gene, and examined whether MCP-1 gene transduction enhanced the therapeutic efficacy of anti-P-gp (MRK16) MAb against MDR cancers. We found that MCP-1-producing clones exhibited similar tumorigenicity and in vivo growth rates as control clones. However, systemic treatment with MRK16 was more effective in inhibiting tumorigenicity and growth of MCP-1-gene-transfected cells than that of mocktransfected cells in a nude mouse model. We also show that the MCP-1-gene-transfected cells could produce regression of bystander tumor cells in the combination with MRK16. MATERIAL AND METHODS Cell linesThe human small-cell lung cancer H69 and its etoposide (VP-16) resistant variant H69/VP were kindly supplied by Dr. N. Saijo (Tokyo, Japan). His group previously showe...

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