phenanthrenes and Lymphoma

The ability of 6(5H)-phenanthridinone (Phen), a new potent poly(ADP-ribose)polymerase (PARP) inhibitor, to potentiate the effect of ionizing radiation on tumour cells was evaluated. RDM4 murine lymphoma cells were irradiated using a 60Co panoramic source and then examined for their growth, cell cycle distribution and apoptosis. Phen (100 microM) was found to inhibit more than 90% of the PARP activity in control and irradiated cells. Cell proliferation was assessed using Alamar Blue, a new fluorometric assay. Phen was found to sharply increase the radiation-induced inhibition of cell proliferation. Indeed, at 2.5 Gy the relative cell number of Phen-treated cells was 60% below control levels. At the same radiation dose, the G2M arrest was also significantly reinforced by the addition of Phen. Furthermore, this PARP inhibitor was shown to significantly increase the amount of DNA fragmentation as revealed by the DNA migration pattern in agarose gel electrophoresis. Comparable results were obtained with 3-aminobenzamide, another PARP inhibitor, but at concentrations 200-fold higher. Taken together, these results indicate the potential interest of Phen as a valuable pharmacological probe for investigating the role of PARP in cellular responses to radiation. They also suggest a possible use of Phen as an adjuvant in radiotherapy.

Topics: Animals; Apoptosis; Cell Cycle; DNA Damage; Enzyme Inhibitors; Lymphoma; Mice; Mice, Inbred AKR; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Tumor Cells, Cultured

By catalyzing posttranslational modifications of nuclear proteins, poly(ADP-ribose) polymerase (PARP) controls their functions and therefore constitutes an enzyme of crucial importance in tumor development. In this study, we have investigated the action of 6(5H)-phenanthridinone, an isoquinoline derivative and one of the most potent PARP inhibitors described so far, on RDM4 murine lymphoma cells in culture. We also examined whether this compound could act synergistically with an antineoplastic drug in tumor-cell destruction. Our results demonstrate that a marked inhibition of PARP activity can be obtained in whole cells after a short incubation, and that this compound, when associated with an alkylating agent, dichloro-2,2' N-methyldiethylamine (chloromethine), leads to a marked drop in the RDM4 proliferation, indicative of a synergy between the two compounds.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Lymphoma; Mechlorethamine; Mice; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Tumor Cells, Cultured

Eight nitropolycyclic aromatic hydrocarbons (PAHs), including 1- and 4-nitropyrene, 1,3-, 1,6- and 1,8-dinitropyrene, 7-nitrobenz[a]anthracene, 6-nitrochrysene and 6-nitrobenzo-[a]pyrene and their parent PAHs were tested fro tumorigenicity in the newborn mouse model by i.p. administration at 1, 8, and 15 days after birth. Both pyrene and 1-nitropyrene induced similar incidences of hepatic tumors in males, yielding a 12-15% and a 21-28% tumor incidence at total doses of 700 and 2800 nmol per mouse, respectively. Liver tumors did not occur in females and the 3-10% lung tumor yield in both sexes was similar to that found in solvent-treated controls. The presumed proximate carcinogen, 1-nitrosopyrene, administered at 700 nmol per mouse, caused liver tumors in 45% of the males and in 9% of the females. 4-Nitropyrene was more tumorigenic than pyrene or 1-nitropyrene; at a dose of 2800 nmol, it induced liver tumors in 83% of the males and 7% of the females, with a lung tumor yield of 38 and 31%, respectively. Female mice treated with 200 nmol of 1,3-, 1,6- or 1,8-dinitropyrene did not develop liver tumors but the hepatic tumor incidence in males was 20, 32 and 16%, respectively, which was significantly greater than that found in mice treated with pyrene. In male mice administered 2800 nmol of benz[a]anthracene, the hepatic tumor incidence was 79%, while treatment with 7-nitrobenz[a]anthracene showed an incidence of only 28%. Similarly, 560 nmol of benzo[a]pyrene caused a 49% liver tumor yield in males while those given 6-nitrobenzo[a]pyrene had a 28% incidence. Treatment with benzo[a]pyrene also induced a 35 and 48% lung tumor incidence in males and females while the comparable values in 6-nitrobenzo[a]pyrene-treated mice were 14 and 2%. Chrysene administered at 2800 nmol per mouse induced hepatic and lung tumors in 41% and 21% of the males, respectively; at the 700-nmol dose, it induced only liver tumors in 29% of the males and in none of the females. In contrast, treatment with 6-nitrochrysene at 700 nmol per mouse resulted in a 76 and 23% hepatic tumor incidence in males and females, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Animals, Newborn; Benz(a)Anthracenes; Benzo(a)pyrene; Biotransformation; Carcinogens; Chrysenes; Female; Liver Neoplasms, Experimental; Lung Neoplasms; Lymphoma; Male; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Nitro Compounds; Phenanthrenes; Pregnancy; Pyrenes; Structure-Activity Relationship

Topics: Adenoma; Animals; Animals, Newborn; Carcinogens; Chrysenes; Female; Liver Neoplasms; Lung Neoplasms; Lymphoma; Male; Mice; Neoplasms, Experimental; Phenanthrenes; Pregnancy; Structure-Activity Relationship

Topics: Administration, Oral; Administration, Topical; Animals; Female; Liver Neoplasms; Lung Neoplasms; Lymphoma; Male; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasms, Experimental; Papilloma; Phenanthrenes; Sex Factors; Skin Neoplasms

Topics: Animals; Animals, Newborn; Benzo(a)pyrene; Benzopyrenes; Carcinogens; Carcinoma, Hepatocellular; Liver Neoplasms; Lung Neoplasms; Lymphoma; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Mice; Neoplasms; Neoplasms, Experimental; Phenanthrenes; Research; Toxicology