title: Tumor necrosis factor induces doxorubicin resistance to lung cancer cells in vitro.
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.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: T W
authors.initials: TW
authors.lastname: Prewitt
authors.forename: W
authors.initials: W
authors.lastname: Matthews
authors.forename: G
authors.initials: G
authors.lastname: Chaudhri
authors.forename: H W
authors.initials: HW
authors.lastname: Pogrebniak
authors.forename: H I
authors.initials: HI
authors.lastname: Pass
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D016685:Mitomycin / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D016685:Mitomycin; D004317:Doxorubicin; D002945:Cisplatin