RESUMEN

BACKGROUND: Enforcement programs to halt the sale of tobacco to youths have been implemented across the United States. The potential cost-effectiveness of enforcement was evaluated under a range of assumptions regarding cost and impact. METHODS: An enforcement model was constructed incorporating quarterly inspections of all tobacco vendors. The cost of discounted years of life saved was calculated using reported values regarding cost and a range of assumptions regarding the impact on youth tobacco use. RESULTS: Inspecting an estimated 543,000 tobacco outlets would cost up to $190 million annually. Costs range from $44 to $8,200 per year of life saved depending on the discount rate and assumptions regarding cost, and efficacy. To compete in cost-effectiveness with implementing smoking cessation guidelines, enforcement would have to produce a 5% reduction in adolescent smoking at a cost of no more than $250 per vendor. CONCLUSION: At this level of cost and effectiveness an enforcement program could save 10 times as many lives as the same amount spent on mammography or screening for colorectal carcinoma. A one-cent per pack cigarette tax could fully fund enforcement. Enforcement of tobacco sales laws deserves further study as one component of a multifaceted approach to tobacco use prevention.

Asunto(s)

RESUMEN

Two newly synthesized cyclopenta[a]phenanthrenes, namely the 1-methyl (VIII) and 7,11-dimethyl (VII) derivatives of the parent ketone 15,16-dihydrocyclopenta[a]phenanthren-17-one (I), have been tested for their capacity to produce skin tumors in mice. The former (VIII) is essentially inactive, whereas the latter (VII) is very potent in both repeated application and two-stage tests. X-ray crystallographic structure analyses have been carried out on seven derivatives of (I), namely its 11-methyl (II), 11,12-dimethyl (III), 11-methoxy (V), 11-ethyl (VI) and 7,11-dimethyl (VII) analogues (carcinogens), the 1-methyl derivative (VIII), and 11,12,15,16-tetrahydro-11-methyl-17-oxocyclopenta[a]phenanthrene (IV) (both non-carcinogens). The detailed molecular structures resulting from these studies have shown the effects of steric interactions and substitutions on the bay-region geometry. The methyl group on C(11) causes distortions of the molecule in the bay region. Out-of-plane distortions in the bay regions of the 11-methyl derivatives (II, III, VII) are greater than for the 11-methoxy or the 11-ethyl derivatives (V, VI). Molecules (except for III and IV) are packed in the crystals with interactions that include C = O...H interactions; this packing is in layers that are nearly parallel to each other. A hydrogen atom of the 11-methyl group appears, from computer modeling, to interact sterically with the hydrogen atom of the bay-region expoxide group in the activated diol-epoxide; this steric interaction may force one conformer of the diol-epoxide to be the predominant form, thereby accounting for the importance of a bay-region methyl group. Further computer modeling has been used to analyze possible modes of interaction of the diol-epoxides of cyclopenta[a]phenanthrenes with DNA.

Asunto(s)

RESUMEN

An initial stage in the mechanism of chemical carcinogenesis by "activated" carcinogenic polycyclic aromatic hydrocarbons is believed to involve alkylation of DNA. However, very high (atomic) resolution studies of alkylated DNA are not technically feasible at this time, and therefore the detailed, high-resolution three-dimensional structures of portions of alkylated DNA have been determined. The initial phase of this study (reported here) has involved the preparation of a series of adenosines and 2'-deoxyadenosines substituted at N6 by related aralkyls of differing carcinogenic potential. We report here the crystal structure determinations of four of these compounds: Compound 1, N6-(anthracenyl-9-methyl)adenosine; Compound 2, N6-(10-methyl-anthracenyl-9-methyl)adenosine; Compound 3, N6-[12-methyl-benz(a)anthracenyl-7-methyl]adenosine; and Compound 5, N6-(10-methylanthracenyl-9-methyl)-2'-deoxyadenosine. Results are compared with those for a previously published analysis Compound 6, N6-[12-methylbenz(a)anthracenyl-7-methyl]-2'-deoxyadenosine. Several results of structural interest have emerged. All five compounds have the syn-conformational relationship between the sugar (ribose or 2'-deoxyribose) and the base (adenine), in contrast to the anti arrangement in B-DNA and in nonalkylated nucleosides. In four of the five compounds, there is an intramolecular hydrogen bond between the 5'-hydroxyl group and adenine. However, in the fifth molecule, this hydrogen bond is not found, and yet the conformation is syn. This indicates that formation of this internal hydrogen bond is not a prerequisite for the adoption of the syn-conformation. In general, the overall conformations of all five compounds are similar, the base lying approximately perpendicular to the polycyclic aromatic ring system. The packing of molecules in the unit cell is also of interest because it consists of alternations of adenine and polycyclic aromatic ring systems in columns through the crystal, indicating that this may serve as a model for the interaction with DNA. The oxygen atom of the sugar ring points towards the hydrocarbon ring system of another molecule. It is premature at this stage of our study to speculate as to the effects of alkylation on the conformational properties of either RNA or DNA. The only comment that appears justified is that the propensity of these adducts to adopt the syn-conformation may be indicative of a preference of alkylated DNA for the Z-conformation (even if the form that is initially attacked is B-DNA).(ABSTRACT TRUNCATED AT 400 WORDS)

Asunto(s)

RESUMEN

An alkylating derivative of a hydrocarbon, 10-chloromethyl-9-chloroanthracene, gave rise to reduced numbers of chemically induced pulmonary adenomas in strain A mice enzootically infected with Sendai virus, while in the case of 7,12-dimethylbenz(a)anthracene, the opposite relationship was observed. Therefore, the presence or absence of viral infection was demonstrated to have a strong influence on carcinogenic susceptibility.

Asunto(s)

RESUMEN

Carcinogenic bromomethyl- and chloromethylanthracenes and benz(a)anthracenes were found to react rapidly in vitro with DNA under physiological conditions and to varying degrees with nucleotides and nucleosides. The compounds were assayed for production of lung adenomas in strain A mice and relative carcinogenic potencies were compared with in vitro alkylation and with in vitro solvolysis rates. Success at quantitative correlation with carcinogenic potency was not obtained with either in vitro parameter. However, comparable noncarcinogenic compounds lacked their marked in vitro reactivity with DNA. Some potential polynuclear electrophiles, including chloromethyl derivatives of acridine and benz(c)acridine, a hydroxymethyl and an acetoxymethyl derivative of benz(a)anthracene, an acetoxymethylanthracene, and an acridinylglycine ester, were found not to be carcinogenic in the lung adenoma test.

Asunto(s)

RESUMEN

The mutagenicity and cytotoxicity of 19 ICR compounds, including 6 reported previously, have been determined in the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyltransferase system. As with other physical and chemical agents, ICR 170 and 191 exhibit a phenotypic expression time of 7 to 9 days, independent of concentrations tested. Thirteen of these compounds are mutagenic. At equimolar concentrations, the compounds with the tertiary amine-type side chain (ICR 217, 340, 355, 368, 170, and 292) are more mutagenic than the compounds with the secondary amine-type side chain (ICR 449, 371, 191, and 372). All secondary amine types show a "plateau" in their concentration-dependent mutagenesis curves at 3 to 4 microM. Shortening of the side chain by one carbon (ICR 171) results in a reduced mutagenicity. Substitution of a sulfur atom for a nitrogen in the side chain (ICR 342) increases both mutagenicity and cytotoxicity. The presence of two 2-chloroethyl groups on the side chain (ICR 220) also results in greatly increased cytotoxicity and mutagenicity. When the 2-chloroethyl group of ICR 340, 372, 292, 191, or 170 is replaced by a 2-hydroxyethyl group (ICR 340-OH, 372-OH, 292-OH, 191-OH, or 170-OH), a mutagenically inactive compound results which remains toxic. Replacement of the amine linkage with an ether linkage (ICR 283) also yields a mutagenically inactive compound.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

Simple alkylating derivatives of polycyclic aromatic hydrocarbons have been found to be much more carcinogenic in the Strain A mouse than are the parent hydrocarbons. It has also been shown that the carcinogenicity of these halomethyl hydrocarbons is not a function of the first-order solvolysis rate. The acridine antitumor agent and mutagen ICR 170, 2-methoxy-6-chloro-9-[3-(ethyl-2-chloroethyl)aminopropylamino]acridine dihydrochloride, has been shown to be a potent carcinogen in the same system when administered i.v., superseding data in the literature indicating inactivity when the drug is administered i.p. Stimulation of the immune system has been shown to have a marked inhibitory effect on the carcinogenic activity of this compound.

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)

Asunto(s)