title: Sensitization of tumor target cells to cytolysis by murine macrophage cytolytic factor by drugs inhibiting DNA, RNA, and protein synthesis.
abstract: The mechanism(s) with which tumor target cells actively resist the lethal lesion induced by murine macrophage cytolytic factory (CF) has been probed by drug-induced sensitization of these cells. We have examined whether drug-induced sensitization is attributable to the action of these drugs on cellular DNA, RNA, or protein synthetic rates. The murine mammary adenocarcinoma cell line EMT-6 pretreated with a dose range of actinomycin-D (.03-3.0 micrograms/ml) for 4 hr was inhibited from 66 to 98% in DNA synthesis rate, from 81 to 93% in RNA synthesis rate, and from 38 to 52% in protein synthesis rate. The maximum sensitization toward lysis by CF was achieved with a drug dose of 1.0 micrograms/ml. The lack of correlation between the drug-induced effects on sensitization and effects on these metabolic rates was evident from the correlation coefficients for the percentage of maximum sensitization of the target toward CF-induced lysis, and the percent of inhibition of DNA, RNA, and protein synthesis. These were 0.11, -0.11, -0.44, respectively. Similarly, target cells treated with a dose range of cycloheximide (0.3-30 micrograms/ml) were inhibited from 81 to 95% in DNA synthesis rate, 68 to 81% in RNA synthesis rate, and 82 to 93% in protein synthesis rate. However, at none of the drug levels employed was significant sensitization of the target cell to CF-induced lysis observed. This was reflected in the correlation coefficients of -0.55, -0.28, and -0.34 for DNA, RNA, and protein synthetic rates, respectively. The essential role of cellular microtubule-dependent events early in the lytic mechanism was demonstrated by exposing colchicone-treated targets to CF. While colchicone could markedly inhibit lysis if introduced before CF, this inhibitory effect was not detected if the drug were withheld for 4 hr after CF exposure. The importance of the repair mechanism(s) early in the cellular response to lesion formation was demonstrated by altering the schedule for CF and actinomycin D administration to the target. If actinomycin D treatment was withheld from the targets for as little as 3 hr following introduction of CF, the lytic mechanism had already bypassed the drug-sensitive steps, manifest in markedly decreased susceptibility to lysis. Collectively, the data show that the ability of the EMT-6 target cells to resist CF-induced lysis does not depend solely on the ability of the cells to synthesize DNA, RNA, or protein.
authors.forename: J M
authors.initials: JM
authors.lastname: Souchek
authors.forename: M E
authors.initials: ME
authors.lastname: Leroux
authors.forename: J
authors.initials: J
authors.lastname: Klostergaard
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003603:Cytotoxins / Q000633:toxicity*; D003609:Dactinomycin / Q000494:pharmacology; D066298:In Vitro Techniques; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D015846:Monokines; D009696:Nucleic Acids / Q000096:biosynthesis; D014176:Protein Biosynthesis; D011506:Proteins / Q000633:toxicity*
chemical_list: D003603:Cytotoxins; D015846:Monokines; D009696:Nucleic Acids; D011506:Proteins; D003609:Dactinomycin; D003513:Cycloheximide; D003078:Colchicine