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J D Scribner

Publications and source records attributed to J D Scribner.

At least 19 recordsLinked to original sources
PubMed1986

Enhancement of beta-propiolactone tumorigenesis in mouse skin by pretreatment with the anti-inflammatory steroid fluocinolone acetonide.

Using a two-step carcinogenesis protocol, SENCAR mice were initiated with 25 micrograms 7,12-dimethylbenz[a] anthracene (DMBA) and were then treated twice weekly with either (a) 0.5 mg beta-propiolactone (BPL) or (b) 1 microgram fluocinolone acetonide (FA) followed in 30 min by 0.5 mg BPL. The tumor incidence for the group receiving FA prior to BPL was significantly greater than for BPL alone (P less than 0.0005). Under these experimental conditions, BPL alone showed neither promoting activity nor complete carcinogenic activity. These results were not anticipated, but the reasons for their occurrence are being explored.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Use of 2-acetamidophenanthrene and 2-acetamidofluorene in investigations of mechanisms of hepatocarcinogenesis.

Comparison studies have been undertaken on the hepatocarcinogen 2-acetamidofluorene (AAF) and its nonhepatocarcinogenic analog 2-acetamidophenanthrene (AAP). Previous studies have shown that amount of compound acutely and persistently bound to rat liver DNA is comparable for the two compounds following single injections into adult Fischer rats, but that AAP fails to initiate tumors in weanling Sprague-Dawley rats. In this work we show that the amount of bound adduct from AAF and AAP is also comparable after three weeks of feeding compound to weanling Sprague-Dawley male rats. Three of the adducts found in RNA of AAP-treated rats cochromatographed on Sephadex LH-20 with two adenosine adducts and one guanosine adduct prepared by reaction of the nucleosides with N-acetoxy-N-trifluoroacetyl-2-aminophenanthrene at neutrality. Because of the lack of initiating ability of AAP in liver, we have also investigated early biochemical alterations in liver after various regimens. Feeding of either AAF or AAP to male weanling rats, followed by three weeks of DDT feeding produced no alteration in either histochemically detected gamma-glutamyltranspeptidase or in ganglioside complement in total liver homogenate. Partial hepatectomy after feeding of either AAF or AAP resulted in the appearance of new fucoganglioside and alteration in the distribution of the major gangliosides. DDT feeding after partial hepatectomy resulted in foci of elevated gamma-glutamyltranspeptidase in AAF-fed rats but not in AAP-fed rats. These results support a previous proposal that AAP may initiate tumorigenesis in rat liver, but that the promoting regimens now in use lack the ability to cause further progression of the initiated cells. The data also suggests that ganglioside synthesis may be a more sensitive marker for early stages in carcinogenesis than are the various histochemical stains now in use.

2-Acetylaminofluorene↗
PubMed1983

Evidence for a new model of tumor progression from carcinogenesis and tumor promotion studies with 7-bromomethylbenz[a]anthracene.

7-Bromoethylbenz[a]anthracene (BrMeBA) has been shown previously to be a modest initiator of tumors in mouse skin and a powerful promoter. Evidence has also been presented that carcinomas and papillomas arising in mouse skin from a two-stage induction regimen (initiation and promotion) originate in two separate populations, rather than representing progressive stages on a single pathway. In this report, we show that 10 nmol of BrMeBA applied biweekly to female SENCAR mice initiated with 7,12-dimethylbenz[a]anthracene (DMBA) is an effective promoting dose. The question of whether BrMeBA or its solvolysis product, 7-hydroxymethylbenz[a]anthracene, is the effective promoter was tested in Charles River CD-1 mice, in which 90 nmol of BrMeBA applied weekly following a single dose of 200 nmol of DMBA induced papillomas in 17 weeks (median induction time) and carcinomas in 43 weeks after beginning of promotion. Without DMBA initiation, papillomas appeared 11 weeks later in much lower yield, while carcinomas appeared 14 weeks later. Animals treated with 7-hydroxymethylbenz[a]anthracene for 82 weeks had developed only 16 tumors in eight animals (initiated) or six tumors in five animals (uninitiated), with survivals of 18 of 30 and 19 of 30, respectively. In SENCAR mice treated with 90, 30, or 10 nmol of BrMeBA biweekly, the ratio of total carcinomas to total papillomas in initiated mice was about half that in uninitiated mice, due primarily to a large reduction in papilloma incidence in uninitiated mice. When adjusted for the number of papillomas, the risk of developing the first carcinomas at any time was dependent only on the dose of BrMeBA and not on whether DMBA was given first. An attempt to inhibit BrMeBA promotion with the antiinflammatory steroid fluocinolone acetonide resulted in inhibition of DMBA-initiated papillomas but had no effect on the carcinoma latent period of incidence. The results are explained in terms of new models of tumor progression which suggest either that promotors with the capabilities of 12-O-tetradecanoylphorbol-13-acetate can divert cells at a minimum level of initiation from progression to cancer or that initiation can create at least two populations of altered cells, one (or more) of which is less likely to progress to cancer than normal cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Metabolism and nucleic acid binding of 7-fluoro-2-acetamidofluorene in rats: oxidative defluorination and apparent dissociation from hepatocarcinogenesis of 8-(N-arylamide) guanine adducts on DNA.

The significance in hepatocarcinogenesis of various arylamine/amide adducts with nucleic acid was investigated by the use of comparison studies on several different parameters. Female Fischer and Sprague-Dawley rats are comparably sensitive to hepatocarcinogenesis by 2-acetamidofluorene (AAF), while male rats are more sensitive. 7-Fluoro-AAF is more carcinogenic in Sprague-Dawley rats than is AAF, but is strikingly so toward the liver of the female rat. Based on these observations, binding of both compounds to liver nucleic acids was determined for male and female Fischer rats at 1 and 3 days after a single injection of carcinogen, and in female Sprague-Dawley rats from 1 to 28 days after a single injection. As shown by others, no 8-(N-2-fluorenylacetamido)guanine adduct could be found in RNA or DNA of female Sprague-Dawley rats treated with AAF (nor was the corresponding 7-fluoro derivative detectable). These adducts were present, however, in comparable amounts in both male and female Fischer rats. The binding of 7-fluoro-AAF derivatives was higher than that of AAF derivatives in female Sprague-Dawley rats. Feeding of either AAF or 7-fluoro-AAF to Sprague-Dawley rats for 4 weeks before a single injection of [3H]7-fluoro-AAF resulted in reduction of the 8-(N-2-(7-fluoro)fluorenylacetamido)guanine adduct in males to undetectable levels in DNA and to 10% of control level in RNA. Non-acetylated adducts were increased in males, but decreased in females by AAF prefeeding; 7-fluoro-AAF prefeeding resulted in little change in adduct formation in females and in a major increase in non-acetylated adducts in males. AAF adducts disappeared from DNA more rapidly than did 7-fluoro-AAF adducts. Assay of the urinary metabolites from the animals in the prefeeding experiment showed that all compounds fed (including the non-hepatocarcinogens 4-acetamidobiphenyl and 2-acetamidophenanthrene) increased the proportion of N-hydroxy-7-fluoro-AAF among the metabolites. Defluorination of 7-fluoro-AAF to 7-hydroxy-AAF was also demonstrated and the ratio of 7-hydroxy-AAF to 5-hydroxy-7-fluoro-AAF was comparable to that observed for 7-hydroxy-AAF/5-hydroxy-AAF and AAF itself, suggesting that fluoro substitution does not increase activity by preventing detoxication.

2-Acetylaminofluorene↗
PubMed1981

DDT acceleration of mammary gland tumors induced in the male Sprague-Dawley rat by 2-acetamidophenanthrene.

2-Acetamidophenanthrene (AAP) yields adducts to rat liver DNA and RNA in amounts comparable to those found for the potent hepatocarcinogen 2-acetamidofluorene, but is not hepatocarcinogenic. This suggested that AAP might initiate liver tumors, but was incapable of causing their progression to a detectable state. To test this hypothesis, the protocol devised by Peraino was used, in which 21-day-old male Sprague-Dawley rats were fed 0.02% AAP in a grain diet for three weeks. this was followed by long-term feeding of 0.05% 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT). The mean latent period of all tumors (primarily mammary tumors) was reduced about six months by the DDT feeding. No tumors were found in rats treated with DDT only. Livers in all animals appeared normal at autopsy or on laparotomy, and showed barely detectable signs of toxicity upon histological examination. Thus, we have found that a once wide-spread environmental chemical acts as a tumor accelerator on a major target for human tumors. Because this finding is in the male rat, the significance of this result for breast cancer in women is uncertain.

Animals↗
PubMed1981

Determinants of nucleic acid adduct formation.

Although N-aryl- or N-acetyl-N-arylnitrenium ions are considered the reactive species in the attack of many aromatic amines or amides on biologic macromolecules, a coherent picture explaining the variety of reactions of the ultimate carcinogens from which they are derived has not been established. Self-consistent field-molecular orbital calculations were used to attempt to understand the reactions of 3 ultimate carcinogens in the aromatic amine class. The MINDO/3 calculations for the cations resulting from loss of acetate from 3-acetoxyxanthine, N-acetoxy-2-fluorenylacetamide (N-AcO-2-FAA) and N-acetoxy-4-acetamidostilbene show that these cations are unlikely to exist in a triplet state, contrary to experimental data which could be interpreted otherwise. Iterative extended Hückel theory calculations for these cations show that the reactions which suggested a triplet state may be explained on the basis of hard/soft-acid/base theory. Electrostatic potential maps combined with frontier orbital theory suggest a coherent explanation for the variety of reactions of N-AcO-2-FAA. The use of the polyelectronic perturbation theory has previously been shown to predict correctly the major product of reaction between guanosine and 5 ultimate carcinogens. I have shown here that the unmodified theory (using Hückel molecular orbital theory) further predicts the major product of reaction between DNA and N-hydroxy-2-naphthyl-amine, but that it predicts secondary products incorrectly.

2-Acetylaminofluorene↗
PubMed1980

A comparison of the DNA binding, cytotoxicity and repair synthesis induced in human fibroblasts by reactive derivatives of aromatic amide carcinogens.

The cytotoxicity of three structurally-related direct-acting carcinogens, N-acetoxy-2-acetylaminofluorene, N-acetoxy-2-acetylaminophenanthrene and N-acetoxy-4-acetylaminobiphenyl, was compared in normal cells and in excision repair deficient xeroderma pigmentosum cells (XP12BE). All three proved significantly more cytotoxic to the XP cells than to the normal cells. At equicytoxic levels, substantially more residues were initially bound to the DNA of the normal cells than to the XP cells, suggesting that the former are able to remove a large percentage of the DNA bound residues before these can result in cell death. The ability of these cell strains to remove bound residues from DNA, to incorporate thymidine into parental strands of DNA during repair replication, and to recover from potentially lethal damage if held in the non-replicating, density-inhibited G0 state was compared as a function of dose and time. The XP12BE cells proved virtually incapable of excision repair of DNA damage induced by these carcinogens and of recovery. In contrast, normal cells recovered from the potentially lethal effects of these three compounds and did so at a rate comparable to their rate of removal of bound residues and of repair synthesis. In the excision-deficient XP12BE cells, DNA adducts induced by N-acetoxy-2-acetylaminophenanthrene proved 3- to 6-fold more cytotoxic than adducts induced by the other two carcinogens.

Acetoxyacetylaminofluorene↗
PubMed1980

Comparative carcinogenicities of 4-N-pyrrolidinylazobenzene, its 4'-ethyl derivative, N-methyl-5-phenylazoindoline, and N,N-dimethyl-4-aminoazobenzene in the rat.

Ashby et al. (Carcinogenesis 1:1-7, 1980) have reported that 4-N-pyrrolidinylazobenzene is a powerful toxin and transforming agent in BHK cells. They have also proposed a scheme for the prediction of carcinogenic activity which is based on structural analysis of this and other compounds, including N-methyl-5-phenylazoindoline, tested in their BHK system. Contrary to their prediction, we found that 4-N-pyrrolidinylazobenzene and N-methyl-5-phenylazoindoline were not carcinogenic when fed to adult rats under conditions where N,N-dimethyl-4-aminoazobenzene induced a high incidence of hepatic carcinomas. 4'-Ethyl substitution of the pyrrolidine derivative yielded a weak carcinogen. These data suggest that complex structure-activity analyses for carcinogenic activity in this class of compounds are premature in the absence of data on whole animals. The transformation of BHK cells appears to require further validation as a predictor of the carcinogenic activity of chemicals for animals.

Animals↗
PubMed1980

The influence of molecular size and partition coefficients on the predictability of tumor initiation in mouse skin from mutagenicity in Salmonella typhimurium.

Initiation of tumors in mouse skin is well correlated with mutagenesis in hamster V79 cells (correlation coefficient r = 0.88), but is poorly correlated with bacterial mutagenicity in the Ames assay (r = 0.58). Efforts to understand the difference in the degrees of correlation led to the observation that if the bacterial mutagenicity data are combined with a molecular size or partition factor, the correlation of initiating activity with this combined parameter approaches that found with the hamster cell mutagenesis. The improvement in correlation (r = 0.84) leads to the suggestion that when a broad size range of compounds is considered a most important factor in accounting for the poor correlation initially observed may be a difference between mammalian and bacterial cells in permeability or target access.

Animals↗
PubMed1979

Mechanisms of action of carcinogenic aromatic amines: an investigation using mutagenesis in bacteria.

The mutagenicities of groups of N-acetoxy-N-arylacetamides, nitroarenes, arylamides and arylamines were determined in the Salmonella typhimurium tester stains TA98, TA1538, TA100, TA1535 and TA1537. Three broad classes of mutagenic activity were found, interpreted as follows: class A, including 2-naphthylamine, produced essentially only base-pair substitution without induction of error-prone repair; class B, including 4-aminobiphenyl, caused consideration induction of error-prone repair, accompanied by a lower level of frame shifting; class C, including N-acetoxy-2-acetamidofluorene, produced high levels of frame shifting, with some induction of error-prone repair. Correlation of these results with known reactions of certain aromatic amine derivatives with nucleosides and nucleic acids, and with molecular orbital calculations, suggests that the effect of class A is produced by small aromatic groups attached to extranuclear heteroatoms in DNA bases, the effect of class B is caused by large aromatic groups attached to extranuclear heteroatoms or by arylamines attached to C-8 of guanine, while the effect of class C is caused by arylamides attached to C-8 of guanine, probably rotating into the helix, as proposed by others. The data also suggest that the N-acetoxy-N-arylacetamides are generally useful models for ultimate metabolites derived in vivo, even if the in vivo metabolites do not carry an acetyl group. Finally, there is a rough correlation between the sum of reversions induced in TA98 and TA100 by the N-acetoxy-N-arylacetamides and their previously determined local carcinogenicities. There is a poor correlation between mutagenicity in any one tester strain and carcinogenicity.

Amines↗
PubMed1979

Reactions of the carcinogen N-acetoxy-4-acetamidostilbene with nucleosides.

The carcinogen N-acetoxy-4-acetamidostilbene (N-AcO-AAS) yields multiple products in reactions with guanosine, adenosine or cytidine in aqueous acetone. The major product from the reaction with cytidine is a deamination product, 1-(4-acetamidophenyl)-1-(3-uridyl)-2-hydrosy-2-phenylethane. Three minor products were unstable and were characterized only by their UV spectra and pK values. Adenosine yielded two major products, one of them 1-(4-acetamidophenyl)-1-(N6-adenoxyl)-2-hydroxy-2-phenylethane, and the second 3-(beta-D-ribosyl)-7-phenyl-8-(4-acetamidophenyl)-7,8 dihydroimidazo [2,1-i] purine. The major adduct with guanosine is 1-(4-acetamidophenyl)-1-(1-guanosyl)-2-hydroxy-2-phenylethane. One minor adduct also appears to be a guanosine-N-1 derivative, while two other minor adducts yield 1-(4-acetamidophenyl)-2-phenyl-1, 2-ethanediol on acid hydrolysis, and thus appear to be O6-derivatives. None of the guanine adducts isolated had the properties of N-7, C-8 or N2 adducts. In this respect, N-Aco-AAS appears to behave more like a classical alkylating agent than like previously studied N-acetoxy-N-arylacetamides, although the target organs of 4-acetamidostilbene are the same as those of other N-arylacetamides.

Adenosine↗
PubMed1979

Reactions of the carcinogen N-acetoxy-4-acetamidostilbene with polynucleotides in vitro.

N-Acetoxy-4-acetamidostilbene (N-AcO-AAS) has been shown to react with mononucleosides to give numerous alkylation products [1]. In this work, homopolynucleotides, RNA and DNA were treated with N-[beta-14 C]-AcO-AAS, washed, degraded with S1 nuclease and acid phosphatase, and chromatographed on Sephadex LH-20. RNA prepared in vitro with 14C on cytosine, adenine or guanine was treated with non-radioactive N-AcO-AAS, then digested and chromatographed similarly. By this means, many of the adducts rising from nucleoside reactions were shown to result from treatment of nucleic acids with the same carcinogen, as well as a number of products which have not been matched to products of monomer alkylation. Labeled 1-(4-acetamidophenyl)-2-phenyl-1, 2-ethanediol was detected in the digest of RNA treated with radioactive N-AcO-AAS, suggesting that phosphate alkylation had taken place.

Chemical Phenomena↗
PubMed1979

Identification of some products from the reaction of trans-4-aminostilbene metabolites and nucleic acids in vivo.

Esters of N-hydroxy-N-acetylaminostilbene react with guanosine, adenosine and cytidine in vitro and yield a number of different reaction products, some of which have been recently identified. We have now demonstrated that Urd-N3,alpha-beta,OH-AABB, Guo-N1,alpha-beta,OH-AABB, AdoN1,alpha-N6,beta-AABB and a Guo-O6 derivative are also formed in vivo, when the precarcinogen trans-4-dimethylaminostilbene is orally administered to female Wistar rats. However, these reaction products constitute only a small fraction of the adducts formed with liver rRNA. N-Acetylaminobibenzyl-alpha,beta-threo-diol is released from liver RNA upon hydrolysis. Comparison of the adduct pattern resulting from the reaction of N-acetoxy-N-acetylaminostilbene with yeast RNA in vitro and that obtained from in vivo rat liver RNA reveals not only quantitative but also qualitative differences. This indicates that reactive metabolites other than hydroxamic acidesters may contribute to the in vivo binding.

Adenosine↗