ABSTRACT
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.
Subject(s)
Blood/drug effects , Kidney/drug effects , Liver/drug effects , Nitracrine/analogs & derivatives , Animals , DNA, Neoplasm/drug effects , Injections, Intraperitoneal , Injections, Intravenous , Lethal Dose 50 , Liver/enzymology , Male , Mice , Mice, Inbred BALB C , Nitracrine/administration & dosage , Nitracrine/therapeutic use , Nitracrine/toxicity , Nucleic Acid Hybridization , Prostatic Neoplasms/drug therapy , RatsABSTRACT
The effect of Ledakrin (an acridine derivative with antineoplastic action), free or liposome-bound, on the bioelectric activity of frog skin was studied by the method of Ussing and it was shown that this activity (being a function of sodium transport) depended on the chemical composition of the liposomes as well as on the calcium content of the experimental medium. Two conclusions have been drawn: 1) the first phase of the response triggered by Ledakrin is due to its action on the cell membrane, 2) the second phase depends on an intracellular mechanism due, probably, to Ledakrin effect on the cytoskeleton.
Subject(s)
Aminoacridines/pharmacology , Nitracrine/pharmacology , Skin/ultrastructure , Sodium/metabolism , Action Potentials/drug effects , Animals , Biological Transport/drug effects , Cell Membrane/physiology , Culture Techniques , Epithelium/ultrastructure , Liposomes/administration & dosage , Liposomes/pharmacology , Nitracrine/administration & dosage , Pharmaceutical Vehicles , Rana temporariaABSTRACT
In rats receiving intraperitoneally Ledacrine in toxic doses the free fatty acids (FFA) and glycerol serum levels and the amount of fatty acids and glycerol released from the epididymal tissue of the rats were determined during one-hour incubation in vitro. It was found that Ledacrine in toxic doses stimulated the process of lipolysis as evidenced by raised serum FFA and glycerol levels and increased amount of FFA and glycerol released from the epididymal adipose tissue in vitro in relation to the values in control rats. The results of investigations of acid-base equilibrium parameters indicated that Ledacrine in toxic doses caused in rats metabolic acidosis associated with respiratory acidosis.
