dinitrobenzenes and Necrosis

2,4,6-Trinitrotoluene (TNT) is one of the most prevalent high explosives in the environment. 2,4-Dinitrotoluene (2,4-DNT) and 2,6-dinitrotoluene (2,6-DNT) are the most common isoforms of dinitrotoluene. The goal of this study was to determine the acute toxic effects of TNT, 2,4-DNT, and 2,6-DNT in adult male bullfrogs. The LD(50) for TNT was 1,060 mg/kg BW while the LD(50 )for 2,4-DNT and 2,6-DNT was 1,098 mg/kg BW. All three compounds elicited similar symptoms of toxicity including changes of skin color, body weight, development of seizures, liver and kidney necrosis, and lung cyanosis. Relative organ weights did not show significant change.

Topics: Animals; Body Weight; Cyanosis; Dinitrobenzenes; Dose-Response Relationship, Drug; Explosive Agents; Kidney; Lethal Dose 50; Liver; Longevity; Lung; Male; Necrosis; Rana catesbeiana; Seizures; Skin Pigmentation; Trinitrotoluene

CpG oligodeoxynucleotides (CpG-ODNs) fail to elicit antitumor immunity after intravenous administration presumably due to their rapid renal clearance and low tumor accumulation. To address this issue, we tested the hypothesis that endogenous IgG can be used as systemic drug carriers to improve the pharmacokinetics, tumor accumulation, and antitumor activity of intravenously administered CpG-ODNs. To this end, tritium-labeled CpG-ODNs conjugated with one or two dinitrophenyl (DNP) haptens (DNP- and DNP(2)-[(3)H]-CpG-ODN) were intravenously dosed into DNP-immunized Balb/c mice bearing subcutaneous CT26 colorectal tumors. Serum and tissue samples for pharmacokinetic and biodistribution profiling were collected at predetermined timepoints and analyzed by liquid scintillation. In antitumor efficacy studies, DNP-immunized, CT26 tumor-bearing mice were intravenously dosed with PBS, CpG-ODN, or DNP-CpG-ODN every five days. Tumor volumes and macroscopic and histological examination of resected solid tumors were used to quantitatively and qualitatively assess tumor growth inhibition. Relative to [(3)H]-CpG-ODN, dinitrophenylated [(3)H]-CpG-ODNs displayed substantial increases in systemic exposure (900-1650 fold) and half-life (100-300 fold), marked decreases in systemic clearance (750-1500 fold) and volume of tissue distribution (13-37 fold), as well as substantial and sustained tumor accumulation (approximately 30% vs. <2% injected dose/g). Antitumor efficacy studies demonstrated that DNP-CpG-ODN inhibited tumor growth by up to 60% relative to PBS control whereas CpG-ODN treatment had no apparent effect. Macroscopic and histological examination of harvested tumors at various timepoints revealed the presence of regions of necrotic tissue only in tumors from mice treated with DNP-CpG-ODN. Collectively, these results show the potential of endogenous IgG to mediate the systemic delivery of CpG-ODN to solid tumors and to enhance their antitumor activity following intravenous administration.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chemistry, Pharmaceutical; Colorectal Neoplasms; Dinitrobenzenes; Drug Carriers; Half-Life; Haptens; Immunization; Immunoglobulin G; Injections, Intravenous; Metabolic Clearance Rate; Mice; Mice, Inbred BALB C; Necrosis; Oligodeoxyribonucleotides; Time Factors; Tissue Distribution

We used 32P-postlabelling to compare DNA binding between the potent hepatocarcinogen 2,6-dinitrotoluene and its noncarcinogenic analog 2,6-diaminotoluene. The two compounds were compared to determine whether differences in DNA binding could partly explain the differences in their carcinogenicity. Fischer-344 rats were administered 1.2 mmol/kg of a compound by single i.p. injection and examined for DNA adduct formation in the liver. Four adducts were detected following administration of 2,6-dinitrotoluene, with a total adduct yield of 13.5 adducted nucleotides per 10(7) nucleotides. Qualitatively identical adducts were also detected after treatment with the derivative 2-amino-6-nitrotoluene. Adduct yields from 2,6-dinitrotoluene were 30 times greater than from 2-amino-6-nitrotoluene. No adducts were observed following treatment with 2,6-diaminotoluene. 2,6-Dinitrotoluene and 2,6-diaminotoluene were also compared for qualitative differences in hepatotoxicity. 2,6-Dinitrotoluene produced extensive hemorrhagic necrosis in the liver, whereas no evidence of hepatocellular necrosis was detected following administration of the latter. The differences between the two compounds in both DNA binding and cytotoxicity were consistent with the differences in their carcinogenicity.

Topics: Animals; Carcinogens; Chromatography, Ion Exchange; Dinitrobenzenes; DNA; Liver; Male; Necrosis; Phenylenediamines; Phosphorus Radioisotopes; Rats; Rats, Inbred F344