Hartley, J.A., Spanswick, V.J., Brooks, N., Clingen, P.H., McHugh, P.J., Hochhauser, D., Pedley, R.B., Kelland, L.R., Alley, M.C., Schultz, R., Hollingshead, M.G., Schweikart, K.M., Tomaszewski, J.E., Sausville, E.A., Gregson, S.J., Howard, P.W. and Thurston, D.E. (2004) SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity. Cancer research, 64 (18). pp. 6693-6699. 10.1158/0008-5472.CAN-03-2941.
Full text not available from this repository.
SJG-136 (NSC 694501) is a rationally designed pyrrolobenzodiazepine dimer that binds in the minor groove of DNA. It spans 6 bp with a preference for binding to purine-GATC-pyrimidine sequences. The agent has potent activity in the National Cancer Institute (NCI) anticancer drug screen with 50% net growth inhibition conferred by 0.14 to 320 nmol/L (7.4 nmol/L mean). Sensitive cell lines exhibit total growth inhibition and 50% lethality after treatment with as little as 0.83 and 7.1 nmol/L SJG-136, respectively. COMPARE and molecular target analysis of SJG-136 data versus that of >60,000 compounds tested in the NCI 60 cell line screen shows that, although the agent has similarity to other DNA binding agents, the pattern of activity for SJG-136 does not fit within the clusters of any known agents, suggesting that SJG-136 possesses a distinct mechanism of action. Testing in the NCI standard hollow fiber assay produced prominent growth inhibition in 20 of 24 i.p. and 7 of 24 s.c. test combinations with 5 of 12 cell lines exhibiting cell kill. In addition, SJG-136 produced antitumor activity in mice bearing CH1 and CH1cisR xenografts, a cisplatin-resistant human ovarian tumor model, and also in mice bearing LS174T xenografts, a human colon tumor model. SJG-136 produces DNA interstrand cross-links between two N-2 guanine positions on opposite strands and separated by 2 bp. In human tumor cell lines, the cross-links form rapidly and persist compared with those produced by conventional cross-linking agents such as nitrogen mustards. In mice bearing the LS174T human colon xenograft, DNA interstrand cross-links can be detected in tumor cells using a modification of the single cell gel electrophoresis (comet) assay after administration of a therapeutic dose. Cross-links in the tumor increase with dose and are clearly detectable at 1 hour after i.v. administration. The level of cross-linking persists over a 24-hour period in this tumor in contrast to cross-links produced by conventional cross-linking agents observed over the same time period.
|Departments, units and centres:||Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry|
|Journal or Publication Title:||Cancer research|
|Deposited By:||Library Staff|
|Deposited On:||08 Mar 2012 11:09|
|Last Modified:||08 Mar 2012 11:09|
Item downloaded times since 08 Mar 2012 11:09.
View statistics for "SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity."
Repository Staff Only: Item control page
School of Pharmacy Staff Only: Edit a copy to replace this item