A clinical report of bone regeneration in maxillofacial surgery using bonelike synthetic bone graft.

The objective of this study is to evaluate the osteoconductivity and bioactivity of the Bonelike graft in repairing surgical cystic bone defects. Bonelike is implanted in 11 patients, aged between 24 and 53 years with a mean age of 36 years, consisting of 5 men and 6 women. According to the standard follow up protocols, radiological examinations are performed and Bonelike/bone retrieved samples have been analyzed histologically using non-decalcified sections obtained perpendicular to bone length axis. Radiographic examination and histological results clearly demonstrate an extensive new bone formation apposed on Bonelike granules with a significant degree of maturation. These clinical applications in maxillary bone defects indicate perfect bone bonding between new bone formed and Bonelike granules, along with partial surface biodegradation. This quick and effective osteoconductive response from Bonelike may reduce the time needed to reconstruct the bone defected area of patients.

Secondary nitroalkanes: induction of DNA repair in rat hepatocytes, activation by aryl sulfotransferase and hepatocarcinogenicity of 2-nitrobutane and 3-nitropentane in male F344 rats.

The secondary nitroalkanes, 2-nitropropane, 2-nitrobutane, 3-nitropentane, 2-nitroheptane, nitrocyclopentane and nitrocyclohexane, as well as the primary nitroalkanes, 1-nitropropane, 1-nitrobutane, 1-nitropentane and 1-nitroheptane, were examined for their ability to induce DNA repair in rat hepatocytes and to serve as substrates for activation by partially purified rat liver aryl sulfotransferase in vitro. All of the secondary, but none of the primary nitroalkanes examined, induced significant DNA repair in rat hepatocytes. Also, the nitronates of all of the secondary nitroalkanes, but none of the primary nitroalkanes, served as substrates for the aryl sulfotransferase-catalysed production of 8-aminoguanosine and 8-oxoguanosine from guanosine in vitro. In a carcinogenicity assay using male F344 rats, the secondary nitroalkanes, 2-nitrobutane and 3-nitropentane, produced a highly significant incidence of hepatocarcinoma with metastases to the lungs, whereas the primary nitroalkane, 1-nitrobutane, was not carcinogenic. While a low incidence of hepatocarcinoma was also produced by cyclopentanone oxime, the results were not statistically significant. Since the secondary nitroalkane, 2-nitropropane, in contrast to the primary nitroalkane, 1-nitropropane, was also previously shown to be hepatocarcinogenic in rats, it is probable that secondary nitroalkanes constitute a hitherto unrecognized class of chemical carcinogens.

Evaluation of secondary nitroalkanes, their nitronates, primary nitroalkanes, nitrocarbinols, and other aliphatic nitro compounds in the Ames Salmonella assay.

The secondary nitroalkanes 2-nitropropane, 2-nitrobutane, 3-nitropentane and nitrocyclopentane, as well as their anionic forms (nitronates); the primary nitroalkanes 1-nitropropane, 1-nitrobutane, and 1-nitropentane and their respective nitronates; the nitrocarbinols 2-nitro-1-propanol, 2-nitro-1-butanol, 3-nitro-2-butanol, and 3-nitro-2-pentanol and their respective nitronates; 2-methyl-2-nitropropane, and 2-nitroso-2-nitropropane were tested in the Ames Salmonella assay using strains TA98, TA100 and TA102. Nitronates of the secondary nitroalkanes 2-nitropropane, 2-nitrobutane, 3-nitropentane, and nitrocyclopentane were significantly mutagenic in Salmonella strains TA100 and TA102 at 10-80 mumoles/plate, but the parent compounds were mutagenic at only a single dose level or were not mutagenic at all in the same dose range. The primary nitroalkanes and the nitrocarbinols were not mutagenic, or only marginally so, at the concentrations tested. The nitronates of the primary nitroalkanes and the nitrocarbinols reprotonated too rapidly under the conditions of the assay for adequate evaluation of mutagenicity. 2-Methyl-2-nitropropane was not mutagenic in strains TA100 and TA102; 2-nitroso-2-nitropropane was also not mutagenic in strains TA100 and TA102, but induced an equivocal mutagenic response in TA98. The positive Salmonella mutation data for the nitronates of the secondary nitroalkanes studied correlate very well with the very slow rate of reprotonation of secondary nitroalkane nitronates at pH 7.7 (Conaway et al. (1991) Cancer Res., 51, 3143), and provide further evidence that nitronates of secondary nitroalkanes, rather than the neutral parent forms with which they may be in equilibrium, are the more proximate mutagenic species.

Comparison of oxidative damage to rat liver DNA and RNA by primary nitroalkanes, secondary nitroalkanes, cyclopentanone oxime, and related compounds.

The hepatocarcinogen 2-nitropropane causes oxidative damage to liver DNA and RNA after administration to rats; increases in 8-hydroxydeoxyguanosine and formation of an unknown moiety (DX1) in DNA, plus increases in 8-hydroxyguanosine and the appearance of two unidentified peaks (RX1 and RX2) in RNA were observed by high-performance liquid chromatography of nucleosides from 2-nitropropane-treated rats using electrochemical detection (E. S. Fiala et al, Cancer Res., 49:5518-5522, 1989). In the present study, damage to Sprague-Dawley rat liver RNA and DNA was assessed to determine whether the characteristic pattern of oxidative nucleic acid damage caused by 2-nitropropane also occurred after i.p. administration of primary nitroalkanes, other secondary nitroalkanes, 2-methyl-2-nitropropane (a tertiary nitroalkane), and cyclopentanone oxime. All of the secondary nitroalkanes and cyclopentanone oxime significantly increased levels of 8-hydroxyguanine in both DNA and RNA and caused the appearance of DX1, RX1 and RX2. The primary nitroalkanes and the tertiary nitroalkane 2-methyl-2-nitropropane did not cause a similar pattern of nucleic acid damage. The rates of reprotonation of nitronates of the secondary nitroalkanes to the respective un-ionized neutral forms at pH 7.7 were more than 20-fold less than the rates of reprotonation of primary nitroalkane nitronates, suggesting that the anionic nitronates, rather than neutral compounds, are more immediately responsible for the DNA and RNA damage observed in vivo. Since 8-hydroxyguanine is a miscoding lesion in DNA, these results suggest the possibility, still to be rigorously tested, that hepatocarcinogenicity may be associated not only with 2-nitropropane but also with other secondary nitroalkanes as well as with those ketoximes that are capable of being converted to secondary nitroalkanes in vivo.

Sex and organ differences in oxidative DNA and RNA damage due to treatment of Sprague-Dawley rats with acetoxime or 2-nitropropane.

The hepatocarcinogens 2-nitropropane and acetoxime have previously been found to induce a specific and qualitatively identical pattern of base damage in rat liver DNA and RNA, including the induction of increased levels of 8-hydroxyguanine. Because both 2-nitropropane and acetoxime are weaker carcinogens in female rats than male rats, we examined the ability of these chemicals to induce this pattern of damage in liver and kidney nucleic acids of male and female Sprague-Dawley rats 6 and 18 h after administration. Significantly lower levels of 8-hydroxydeoxyguanosine, 8-hydroxyguanosine and other presumed modified nucleosides discernible by high-performance liquid chromatography with electrochemical detection were found in liver nucleic acids of female rats at both time points. In addition, minimal alteration of nucleic acids was observed in the kidney, which is not a target organ for the carcinogenicity of either 2-nitropropane (2-NP) or acetoxime (ACO). These results support the hypothesis that the specific DNA alterations observed are relevant to the hepatocarcinogenicity of 2-NP and ACO.

Oxidative DNA and RNA damage in rat liver due to acetoxime: similarity to effects of 2-nitropropane.

Acetoxime (ACO) and 2-nitropropane (2-NP), both industrially important chemicals and known hepatocarcinogens in rats, induced increased levels of 8-hydroxy-guanine in liver DNA and RNA of male Sprague-Dawley and F344 rats after either oral or i.p. administration. Both compounds also produced qualitatively the same patterns of other apparent modifications of liver DNA and RNA nucleosides, discernible by HPLC with electrochemical detection. Six hours after administration, the effects of 2-NP on liver nucleic acids were more pronounced in F344 rats than in Sprague-Dawley rats, suggesting that 2-NP may prove to be a stronger carcinogen in the F344 strain. The effects of ACO, a weaker carcinogen than 2-NP, were less than those of the nitroalkane in both rat strains. These results suggest that the hepatocarcinogenicity of ACO, like that of 2-NP, may depend on increased generation of reactive oxygen species capable of producing DNA and RNA base damage in rat liver. In addition, the data support the hypothesis that the hepatocarcinogenicity of ACO depends on its partial in vivo N-oxidation to 2-NP.