Pre-clinical evaluation of 1-nitroacridine derived chemotherapeutic agent that has preferential cytotoxic activity towards prostate cancer

被引:19
|
作者
Tadi, Kiranmayi [1 ]
Ashok, Badithe T. [1 ]
Chen, Yuangen [1 ]
Banerjee, Debabrata [2 ]
Wysocka-Skrzela, Barbara [3 ]
Konopa, Jerzy [3 ]
Darzynkiewicz, Zbigniew [4 ]
Tiwari, Rai K. [1 ]
机构
[1] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA
[2] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Med & Pharmacol, New Brunswick, NJ USA
[3] Gdansk Univ Technol, Dept Pharmaceut Technol & Biochem, Gdansk, Poland
[4] Gdansk Univ Technol, Dept Pathol, Valhalla, NY USA
关键词
chemotherapy; xenografts; 1-nitroacridine derivative; systemic treatment; DNA double strand breaks; gamma H2AX;
D O I
10.4161/cbt.6.10.4790
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Chemotherapy in prostate cancer (CaP) even as an adjunct has not been a success. In this communication, we report the pre-clinical efficacy of a nitroacridine derivative, C-1748 (9 [2'-hydroxyethylamino]-,4-methyl-1-nitroacridine) in CaP cell culture and human xenograft animal models. C-1748, a DNA intercalating agent has been derived from its precursor C-857 that was a potent anti-cancer drug, but failed clinical development due to "high" systemic toxicities. Chemical modifications such as the introduction of a "methyl" group imparted novel properties, the most interesting of which is the difference in the IC50 values between LnCaP (22.5 nM), a CaP cell line and HL-60, a leukemia cell line (> 100 nM). Using gamma H2AX as an intervention marker of DNA double strand breaks, we concluded that C-1748 is more efficacious in CaP cells than in HL-60 cells. In hormone dependent cells, the androgen receptor (AR) was identified as an additional target of C-1748. In xenograft studies, administration of C-1748 intra-peritoneally inhibited tumor growth by 80-90% with minimal toxicity. These studies identify C-1748 as a novel acridine drug that has a high therapeutic index and low cytotoxicity on myelocytic cells with potential for clinical development.
引用
收藏
页码:1632 / 1637
页数:6
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