PMID- 23143926
OWN - NLM
STAT- MEDLINE
DCOM- 20130812
LR  - 20211021
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 131
IP  - 2
DP  - 2013 Feb
TI  - 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.
PG  - 470-9
LID - 10.1093/toxsci/kfs319 [doi]
AB  - 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 100 
      microM) 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 48 
      h after initiating the slice cultures to avoid confounding the response to 
      slicing with any drug response. PCLSs were evaluated after 24, 48, and 72 h 
      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 25 microM 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 72 h exposures was established as 10 
      microM NSC 710305.
FAU - Behrsing, Holger P
AU  - Behrsing HP
AD  - Laboratory of Investigative & Screening Toxicology, LHTP, SAIC-Frederick, Inc., 
      Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, 
      USA. behrsingh@mail.nih.gov
FAU - Furniss, Michael J
AU  - Furniss MJ
FAU - Davis, Myrtle
AU  - Davis M
FAU - Tomaszewski, Joseph E
AU  - Tomaszewski JE
FAU - Parchment, Ralph E
AU  - Parchment RE
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20121109
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (2,6-diaminohexanoic acid (4-(5-fluorobenzothiazol-2-yl)-2-methylphenyl)amide)
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Thiazoles)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Animals
MH  - Cytokines/*metabolism
MH  - In Vitro Techniques
MH  - Inflammation Mediators/*metabolism
MH  - Lung/*drug effects/pathology
MH  - Lysine/*analogs & derivatives/toxicity
MH  - Male
MH  - Rats
MH  - Rats, Inbred F344
MH  - Thiazoles/*toxicity
PMC - PMC3551430
EDAT- 2012/11/13 06:00
MHDA- 2013/08/13 06:00
PMCR- 2014/02/01
CRDT- 2012/11/13 06:00
PHST- 2012/11/13 06:00 [entrez]
PHST- 2012/11/13 06:00 [pubmed]
PHST- 2013/08/13 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - kfs319 [pii]
AID - 10.1093/toxsci/kfs319 [doi]
PST - ppublish
SO  - Toxicol Sci. 2013 Feb;131(2):470-9. doi: 10.1093/toxsci/kfs319. Epub 2012 Nov 9.