Journal Article

<i>In Vitro</i> Exposure of Precision-Cut Lung Slices to 2-(4-Amino-3-Methylphenyl)-5-Fluorobenzothiazole Lysylamide Dihydrochloride (NSC 710305, Phortress) Increases Inflammatory Cytokine Content and Tissue Damage

Holger P. Behrsing, Michael J. Furniss, Myrtle Davis, Joseph E. Tomaszewski and Ralph E. Parchment

in Toxicological Sciences

Volume 131, issue 2, pages 470-479
Published in print February 2013 | ISSN: 1096-6080
Published online November 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs319
In Vitro Exposure of Precision-Cut Lung Slices to 2-(4-Amino-3-Methylphenyl)-5-Fluorobenzothiazole Lysylamide Dihydrochloride (NSC 710305, Phortress) Increases Inflammatory Cytokine Content and Tissue Damage

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The anticancer drug (2-[4-amino-3-methylphenyl]-5-fluorobenzothiazole lysylamide dihydrochloride) (NSC 710305, Phortress) is a metabolically activated prodrug that causes DNA adduct formation and subsequent toxicity. Preclinically, it was found that hepatic, bone marrow, and pulmonary toxicity presented challenges to developing this drug. An ex vivo precision-cut lung slice (PCLS) model was used to search for concentration dependent effects of NSC 710305 (10, 25, 50, and 100µM) on cytokine content, protein content, and immuno/histological endpoints. Preparation and culture of PCLS caused an initial spike in proinflammatory cytokine expression and therefore treatment with NSC 710305 was delayed until 48h after initiating the slice cultures to avoid confounding the response to slicing with any drug response. PCLSs were evaluated after 24, 48, and 72h exposures to NSC 710305. Reversibility of toxicity due to the 72-h treatment was evaluated after a 24-h recovery period. NSC 710305 caused a concentration-dependent cytokine response, and only the toxicity caused by a 72-h exposure to 25µM reversed during the 24-h recovery period. Immuno/histological examination and quantitation of tissue protein levels indicated that tissue destruction, ED-1 (activated macrophage) staining, and protein levels were associated with the levels of proinflammatory cytokines in the tissue. In conclusion, the concentration- and time-dependent inflammatory response of PCLS to NSC 710305 preceded relevant tissue damage by a few days. The no-observable adverse effect level (NOAEL) for 24, 48, and 72h exposures was established as 10µM NSC 710305.

Keywords: NSC 710305; Phortress; PCLS; lung slices; cytokines; lung injury; inflammation; in vitro; pulmonary toxicity.

Journal Article.  6018 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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