Pre-clinical evaluation of 1-nitroacridine derived chemotherapeutic agent that has preferential cytotoxic activity towards prostate cancer.
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.
Tadi
Kiranmayi
K
Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595, USA.
Ashok
Badithe T
BT
Chen
Yuangen
Y
Banerjee
Debabrata
D
Wysocka-Skrzela
Barbara
B
Konopa
Jerzy
J
Darzynkiewicz
Zbigniew
Z
Tiwari
Raj K
RK
D059002:Androgen Receptor Antagonists; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D006657:Histones / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009564:Nitracrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C513812:9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D007364:Intercalating Agents; D009564:Nitracrine