Influence of P-glycoprotein expression on in vitro cytotoxicity and in vivo antitumour activity of the novel pyrrolobenzodiazepine dimer SJG-136.

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).

• 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)

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

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)