The novel sequence-specific DNA cross-linking agent SJG-136 (NSC 694501) has potent and selective in vitro cytotoxicity in human B-cell chronic lymphocytic leukemia cells with evidence of a p53-independent mechanism of cell kill.

Abstract

SJG-136 (NSC 694501) is a novel DNA cross-linking agent that binds in a sequence-selective manner in the minor groove of the DNA helix. It is structurally novel compared with other clinically used DNA cross-linking agents and has exhibited a unique multilog differential pattern of activity in the NCI 60-cell line screen (i.e., is COMPARE negative to other cross-linking agents). Given this profile, we undertook a preclinical evaluation of SJG-136 in primary tumor cells derived from 34 B-cell chronic lymphocytic leukemia (B-CLL) patients. SJG-136 induced apoptosis in all of the B-CLL samples tested with a mean LD50 value (the concentration of drug required to kill 50% of the cells) of 9.06 nmol/L. Its cytotoxicity was undiminished in B-CLL cells derived from patients treated previously, those with unmutated VH genes, and those with p53 mutations (P=0.17; P=0.63; P=0.42, respectively). SJG-136-induced apoptosis was associated with the activation of caspase-3 that could be partially abrogated by the caspase-9 inhibitor Z-LEHD-FMK. Furthermore, SJG-136 did not trigger the phosphorylation of p53 or the up-regulation of GADD45 expression in B-CLL cells whereas the cross-linking agent chlorambucil elicited both of these effects. This suggests that SJG-136 cross-linking adducts are not subject to p53-mediated DNA excision repair mechanisms in B-CLL cells. Taken together, these data demonstrate a novel mechanism of action for SJG-136 that appears to circumvent the effects of poor prognostic markers. This unique cytotoxicity profile warrants further investigation and supports the evaluation of this agent in Phase I clinical trials for patients with B-CLL.

• Authors: Christopher J Pepper, Rachel M Hambly, Christopher D Fegan, Patrick Delavault, David E Thurston
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 18 Pg. 6750-5 (Sep 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15374993 (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)
• Benzodiazepinones
• Cross-Linking Reagents
• Pyrroles
• Tumor Suppressor Protein p53
• Benzodiazepines
• CASP3 protein, human
• Caspase 3
• Caspases
• Vidarabine
• fludarabine

Topics

• Apoptosis (drug effects)
• B-Lymphocytes (cytology, drug effects, pathology)
• Benzodiazepines (pharmacology)
• Benzodiazepinones (pharmacology)
• Case-Control Studies
• Caspase 3
• Caspases (metabolism)
• Cross-Linking Reagents (pharmacology)
• DNA Damage
• DNA Repair
• Enzyme Activation
• Humans
• K562 Cells
• Leukemia, Lymphocytic, Chronic, B-Cell (blood, drug therapy, genetics, pathology)
• Pyrroles (pharmacology)
• T-Lymphocytes (cytology, drug effects, pathology)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (physiology)
• Vidarabine (analogs & derivatives, pharmacology)