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J Thorac Cardiovasc Surg 1994;107:43-49
© 1994 Mosby, Inc.

GENERAL THORACIC SURGERY

Tumor necrosis factor induces doxorubicin resistance to lung cancer cells in vitro

Bethesda, Md.

From the Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md.

Address for reprints: Harvey I. Pass, MD, Head, Thoracic Oncology Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 2B07, 9000 Rockville Pike, Bethesda, MD 20892.

Abstract

Tumor necrosis factor can alter the cell cycle of tumor cells and protect hematopoietic stem cells from cell cycle–specific chemotherapy, but the ability of tumor necrosis factor to protect cancer cells from chemotherapy by manipulation of the cell cycle is unknown. Twenty-four–hour exposure of A549 human lung cancer cells to tumor necrosis factor shifted cells from S phase to G₀/G₁ phase as determined by analysis of isolated cell nuclei with an FACScan Cell Sorter. This effect was not seen in cells exposed to interleukin-1 or interleukin-6. Growth assays demonstrated that tumor necrosis factor slowed the doubling time of A549 cells, confirming that tumor necrosis factor caused G₀/G₁ arrest in these cells. Pretreatment with tumor necrosis factor rendered cells resistant to subsequent 1-hour exposure to doxorubicin, a chemotherapeutic agent active against S phase cells. Tumor necrosis factor did not protect cells against either cisplatin or mitomycin C, drugs not specific for S phase. Measurement of intracellular drug levels indicated that pretreatment with tumor necrosis factor did not affect doxorubicin uptake or efflux. These findings suggest that cells producing tumor necrosis factor within a tumor may render surrounding malignant cells resistant to cell cycle–specific chemotherapy, and this mechanism may explain failure of sequential immunotherapy-chemotherapy protocols. (J THORAC CARDIOVASC SURG 1994;107:43-9)

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