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
In: Cancer research (Baltimore), Jg. 64 (2004), Heft 18, S. 6693-6699
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academicJournal
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Zugriff:
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 CHlcisR 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.
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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
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Autor/in / Beteiligte Person: | HARTLEY, John A ; SPANSWICK, Victoria J ; HOLLINGSHEAD, Melinda G ; SCHWEIKART, Karen M ; TOMASZEWSKI, Joseph E ; SAUSVILLE, Edward A ; GREGSON, Stephen J ; HOWARD, Philip W ; THURSTON, David E ; BROOKS, Natalie ; CLINGEN, Peter H ; MCHUGH, Peter J ; HOCHHAUSER, Daniel ; PEDLEY, R. Barbara ; KELLAND, Lloyd R ; ALLEY, Michael C ; SCHULTZ, Robert |
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Zeitschrift: | Cancer research (Baltimore), Jg. 64 (2004), Heft 18, S. 6693-6699 |
Veröffentlichung: | Philadelphia, PA: American Association for Cancer Research, 2004 |
Medientyp: | academicJournal |
Umfang: | print, 41 ref |
ISSN: | 0008-5472 (print) |
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