Nitroacridines are potent
DNA-binding and
cytotoxic agents in
cancer cells, but could not be developed clinically due to high systemic toxicities. We are developing a 1-nitroacridine derivative,
9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine (C-1748), as an effective chemotherapeutic agent for
prostate cancer.
C-1748 demonstrates high antitumor efficacy against human
prostate cancer xenografts with markedly low mutagenicity and toxicity in dogs compared with its parent 9-(2'-hydroxyethylamino)-1-nitroacridine (C-857). A surprising feature of
C-1748 is the 40-fold difference in 50% inhibitory concentration between DU145
prostate cancer and HL-60
leukemia cells. In this study, we report the preclinical toxicity study of a single acute dose of
C-1748 in Copenhagen rats and BALB/c mice, intraperitoneally and intravenously for 24 h and 7 days. The effect of
C-1748 on hematology, cardiac and liver
enzymes, and renal
electrolytes was assessed by blood and serum analysis. The LD50 (lethal dose, 50%) for
C-1748 was 9 and 13.42 mg/kg compared with 2.2 and 3 mg/kg for
C-857 intraperitoneally and intravenously, respectively, in mice. In Copenhagen rats, LD50 was 15 and 14.4 mg/kg intraperitoneally and intravenously, respectively, compared to 4 and 1.3 mg/kg for
C-857. No changes in blood cell counts were observed, which were in the normal range for rodents. No changes were observed in clinical chemistries of
enzymes such as
aspartate aminotransferase,
alkaline phosphatase and
creatine phosphokinase, which were within the normal range of values. No genome alterations were seen in
prostate cancer cell lines by comparative genomic hybridization together with a lack of systemic toxicity, making it a unique
cancer cell-type-specific
drug that needs further clinical evaluation for toxicity and synergy in
combination chemotherapy regimens.