Abstract |
SJG-136 is a novel pyrrolobenzodiazepine dimer analogue that acts as a minor-groove interstrand DNA cross-linking agent. The present study investigated the impact of ABCB1 (mdr-1) expression on the activity of SJG-136 using both in vitro and in vivo systems. SJG-136 was highly potent in the colon cancer cell lines HCT-116, HT-29 and SW620 (IC50 0.1-0.3 nM). However, HCT-8 and HCT-15 cells expressing significant levels of mdr-1 were less sensitive (IC50 2.3 and 3.7 nM, respectively) using a SRB assay. The cytotoxicity was increased in HCT-15 and A2780(AD) in presence of 5 microg/ml verapamil. Mdr-1 mRNA expression was determined by qRT-PCR and correlated to SJG-136 IC50s (r2=0.86, P=0.0001). Isogenic 3T3 cells expressing mdr-1 cDNA (3T3 pHamdr-1) were less sensitive to SJG-136 than the parental 3T3 cells (IC50 208 and 6.3 nM, respectively). Finally, SJG-136 (120 microg/kg/d dx5) was highly active against A2780 xenografts (SGD=275) but not A2780(AD) xenografts (SGD=67).
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Authors | S M Guichard, J S Macpherson, D E Thurston, D I Jodrell |
Journal | European journal of cancer (Oxford, England : 1990)
(Eur J Cancer)
Vol. 41
Issue 12
Pg. 1811-8
(Aug 2005)
ISSN: 0959-8049 [Print] England |
PMID | 16046116
(Publication Type: Journal Article)
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Chemical References |
- 1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione)
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Benzodiazepinones
- Drug Combinations
- Pyrroles
- RNA, Messenger
- Verapamil
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(metabolism)
- Animals
- Antineoplastic Agents
(metabolism, therapeutic use)
- Benzodiazepinones
(metabolism, therapeutic use)
- Cell Line, Tumor
- Colonic Neoplasms
(drug therapy, metabolism)
- Drug Combinations
- Humans
- Immunoblotting
- Inhibitory Concentration 50
- Mice
- Mice, Inbred C57BL
- Pyrroles
(metabolism, therapeutic use)
- RNA, Messenger
(metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
(methods)
- Transplantation, Heterologous
- Verapamil
(pharmacology)
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