Pre-clinical evaluation of 1-nitroacridine derived chemotherapeutic agent that has preferential cytotoxic activity towards prostate cancer.
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| Abstract |
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 IC(50) values between LnCaP (22.5 nM), a CaP cell line and HL-60, a leukemia cell line (>100 nM). Using gammaH2AX 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.
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| Authors | Kiranmayi Tadi, Badithe T Ashok, Yuangen Chen, Debabrata Banerjee, Barbara Wysocka-Skrzela, Jerzy Konopa, Zbigniew Darzynkiewicz, Raj K Tiwari |
| Journal | Cancer biology & therapy (Cancer Biol Ther) Vol. 6 Issue 10 Pg. 1632-7 (Oct 2007) ISSN: 1555-8576 [Electronic] United States |
| PMID | 17921700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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