Preclinical toxicological examination of a putative prostate cancer-specific 4-methyl-1-nitroacridine derivative in rodents

التفاصيل البيبلوغرافية
العنوان: Preclinical toxicological examination of a putative prostate cancer-specific 4-methyl-1-nitroacridine derivative in rodents
المؤلفون: Raj K. Tiwari, Yuangen Chen, Jerzy Konopa, V. P. S. Garikapaty, Badithe T. Ashok, Qiang Huang, Debabrata Banerjee, Kiranmayi Tadi
المصدر: Anti-Cancer Drugs. 18:87-94
بيانات النشر: Ovid Technologies (Wolters Kluwer Health), 2007.
سنة النشر: 2007
مصطلحات موضوعية: Male, Cancer Research, medicine.medical_specialty, Pharmacology, Kidney, Median lethal dose, Lethal Dose 50, Mice, Prostate cancer, DU145, Internal medicine, Animals, Nitracrine, Medicine, Pharmacology (medical), Mice, Inbred BALB C, Hematology, business.industry, Lethal dose, Nucleic Acid Hybridization, Prostatic Neoplasms, Cancer, Combination chemotherapy, DNA, Neoplasm, medicine.disease, Rats, Blood, Liver, Oncology, Injections, Intravenous, Toxicity, business, Injections, Intraperitoneal
الوصف: 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 LD 50 (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, LD 50 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.
تدمد: 0959-4973
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::accfd1c661bbf776b78aa8ee39b09166Test
https://doi.org/10.1097/01.cad.0000236316.04199.20Test
رقم الانضمام: edsair.doi.dedup.....accfd1c661bbf776b78aa8ee39b09166
قاعدة البيانات: OpenAIRE