"目录号: HY-14573
Cell Cycle/DNA Damage-
SJG-136是一种新型合理的DNA小沟间交联剂，具有有效的广谱抗肿瘤活性。
DNA Alkylator/Crosslinker
相关产品
Mitomycin C-Oxaliplatin-Temozolomide-Streptozocin-Carboplatin-Cyclophosphamide-Calicheamicin-Melphalan-Busulfan-Palifosfamide-Carmustine-RITA-Fotemustine-Lomustine-Satraplatin-
生物活性
Description
SJG-136 is a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity.IC50 value: 0.83 nM (TGI)Target: DNA cross-linkingin vitro: The dimeric pyrrolobenzodiazepine SJG-136 has potent in vitro antiproliferative activity associated with binding in the minor groove of DNA and formation of covalent interstrand DNA cross-links. [1] 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. Cell lines sensitive to SJG-136 exhibited an LC50 with as little as 7.1 nM and total growth inhibition (TGI) with as little as 0.83 nM.[2] SJG-136 selectively cross-links guanine residues located on opposite strands of DNA, and exhibits potent in vitro cytotoxicity. SJG-136 is active over a wide dosage range in athymic mouse xenografts. [3]in vivo: SJG-136 half-life, clearance and volume of distribution values were 9 min, 190 ml/min/m2, and 1780 ml/m2, respectively. SJG-136 did not accumulate in plasma during treatment with 25 μg/kg/day for 5 days. Treatment with SJG-136 produced the anticipated DNA interstrand cross-links, as well as DNA strand breaks, in rat PBMCs. Oxidative metabolism of SJG-136 in rat liver microsomes was catalyzed by CYP3A isoforms and produced a previously unreported monomeric metabolite. [1]
Clinical Trial
NCT00103220
National Cancer Institute (NCI)
Unspecified Adult Solid Tumor, Protocol Specific
November 2004
Phase 1
NCT01200797
National Cancer Institute (NCI)
Recurrent Fallopian Tube Cancer-Recurrent Ovarian Epithelial Cancer-Recurrent Primary Peritoneal Cavity Cancer
July 2010
Phase 2
NCT00301769
National Cancer Institute (NCI)
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities-Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)-Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)-Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)-Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)-Blastic Phase Chronic Myelogenous Leukemia-de Novo Myelodysplastic Syndromes-Previously Treated Myelodysplastic Syndromes-Recurrent Adult Acute Lymphoblastic Leukemia-Recurrent Adult Acute Myeloid Leukemia-Refractory Chronic Lymphocyt
December 2005
Phase 1
NCT00121290
National Cancer Institute (NCI)
Unspecified Adult Solid Tumor, Protocol Specific
February 2005
Phase 1
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References
[1].Reid JM, et al. Pharmacokinetics, pharmacodynamics and metabolism of the dimeric pyrrolobenzodiazepine SJG-136 in rats. Cancer Chemother Pharmacol. 2011 Sep;68(3):777-86.
[2].Hartley JA, et al. 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 Res. 2004 Sep 15;64(18):6693-6699.
[3].Alley MC, et al. SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 2: efficacy evaluations. Cancer Res. 2004 Sep 15;64(18):6700-6706