Inductions of oxidative DNA damage and mesothelioma by crocidolite, with special reference to the presence of iron inside and outside of asbestos fiber

Inductions of oxidative DNA damage (oh⁸dG) in vitro and peritonealmesothelioma in rats (F344, female) were compared between crocidolite(CR) and de-ironized crocidolite [DCR, washed by HCl and ethylenediaminetetraacetic acid (EDTA)] to verify the hypothesis that reactiveoxygen species contribute to carcinogenesis, focusing on therole of iron present inside or outside of the CR. The yieldof oh⁸dG was 14.6 oh⁸dG/10⁵ in CR and 30.2 in DCR under simpleincubation with DNA. In the incubation systems added severalchemicals and H₂O₂, OCR induced higher levels of oh⁸dG thanCR. Especially, the addition of Fe₂O₃ and H₂O₂ to OCR increasedoh⁸dG in DNA depending on the Fe₂O₃ concentration, however,this tendency was not observed in the same system of CR. Surprisingly,7 out of 10 rats died within 2 days after the injection of 10mg of Fe₂O₃ following the DCR injection (5 mg/rat), showingnecroses of hepatocytes from the surface of each lobe whereCR and Fe₂O₃ particles had been deposited together. There wasno death in other groups of rats. One year after the i.p. injectionof CR (5 mg/rat, single injection), mesotheliomas were foundin all rats administered OCR and Fe (2 mg/rat, once a week,for 35 weeks), in 4 rats of OCR alone (n = 10), in 5 rats ofCR alone (n = 10) and in none of the rats administered Fe₂O₃alone (n = 10). Therefore, present results indicate that theinduction of oxidative DNA damage changed even when the sametype of asbestos was washed by chemical treatment, and Fe₂O₃promoted the development of mesothelioma which was induced byOCR.     

Is there any place for a wait-and-see policy in stage I0 follicular lymphoma?: A study of 43 consecutive patients in a single center

BACKGROUND:: A wait-and-see policy (WS) does not appear to modify the long-termprognosis of advanced-stage follicular lymphomas (FL), whileirradiation of limited stages some times causes complicationsand does not avert distant relapses. Consequently, we decidedto test WS in a selected su bset of the localized FL, i.e.,patients in complete remission (CR) after the initial lymphnode biopsy (stage I₀). PATIENTS AND METHODS:: Forty-three previously untreated patients were diagnosed withstage I₀ FL and 26 of them were included in the WS. Their medianage was 60.3 years; 19 were male and 24 female. All histologicalslides were reviewed and confirmed the diagnosis of FL. Medianfollowup was 6.3 years (y). RESULTS:: Thirteen of the 26 untreated patients are still relapse-free,while six relapsed locally only (median: 4.2 years after diagnosis),and reattained CR with radiotherapy. Seven patients relapsedat distant sites (median: 1 year after diagnosis). No localizedrelapses were observed in the treated group, but there were7 distant relapses. CONCLUSIONS:: The use of use in stage I₀ FL did not appear to modify the prognosisof these patients. Furthermore, we observed two distinct patternsof relapse (local and distant) that are difficult to differentiateat onset. follicular lymphoma, limited stages, wait-and-see policy     

单肺通气方式对食管癌患者围手术期炎性细胞因子和氧自由基的影响

目的： 探讨单肺通气（OLV）方式对食管癌患者围手术期炎性细胞因子和氧自由基的影响。方法：拟行食管癌根治术患者40例,随机分为长时间组(Ⅰ组)和间断双肺通气组(Ⅱ组),每组20例。两组患者分别在麻醉诱导后(T₁)、OLV 45min(T₂)、90min(T₃)及术后2 h(T₄)采取外周静脉血,分别测定血清肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-6、IL-8、丙二醛（MDA）浓度及超氧化物歧化酶（SOD）活性。结果：两组患者的TNF-α、IL-6和IL-8于T2时均明显上升（P<0.05）,Ⅱ组T₃、T₄时TNF-α、IL-6和IL-8均明显低于Ⅰ组（P<0.05）。两组患者的MDA于T₃、T₄时显著升高（P<0.05）,且Ⅱ组在T₃、T₄时显著低于Ⅰ组（P<0.05）;两组患者的SOD于T₃、T₄时显著降低（P<0.05）,且Ⅱ组在T₃、T₄时显著高于Ⅰ组（P<0.05）。结论：单肺通气期间间断双肺通气可减轻对肺组织的损伤。     

DNA and protein adducts as indicators of in vivo methylation by nitrosatable drugs

Exposure to methylating carcinogens may be monitored by measuringboth the formation of S-methylcysteine in haemoglobin and theurinary excretion of N-7-methylguanine (7-MeG), which is derivedin part from methylated nucleic acids. Female rats were exposedto methylmethanesulphonate, methylnitrosourea and to three drugs,aminopyrine, cimetidine and pyrilamine, which are potentialmethylating agents if nitrosation occurs in vivo. Because S-methylcysteinein haemoglobin and urinary 7-MeG occur naturally, the experimentswere carried out with stable isotope-labelled analogues whichcontained trideutero (d₃)-methyl groups. Gas chromatography-massspectrometry was used for the quantitative determination ofd₃-labelled adducts after their separation from the biologicalmatrix and chemical derivatization. Transfer of the intact d₃-methylgroup to cysteine and guanine was detected after intragastricadministration of d₃-methyl-methanesulphonate (50 mg/kg), d₃-N-methyl-N-nitrosourea(50 mg/kg), and d6-aminopyrine (AP) and sodium nitrite (both100 mg/kg). AP alone gave no detectable d₃-methyl adducts. Co-administrationof nitrite and d₆-pyrilamine or d₃-cimetidine yielded no d₃-7-MeG,although N-nitroso-d₃-cimetidine alkylated DNA in vitro in adose-dependent fashion. For AP and nitrite combinations urinaryexcretion of d₃-7-MeG was linearly related to the dose of nitriteand was essentially complete within 5 days. For d₃-methylmethane-sulphonate(50 mg/kg) the ratio of haemoglobin d₃-S-methyl-cysteine tourinary d₃-7-MeG was considerably (>9-fold) higher than foreither d₃-N-methyl-N-nitrosourea or AP/ nitrite (100 mg/kg)mixture. This is in accord with the S_N2 nature of the weak carcinogenmethylmethanesulphonate compared with the S_N1 nature of thereactive methylating agent derived from either one of the N-methyl-N-nitrosocompounds.     

Sister chromatid exchanges in Chinese hamster V79 cells treated with the trivalent chromium compounds chromic chloride and chromic oxide

The induction of sister chromatid exchanges (SCEs) in Chinesehamster V79 cells exposed to soluble CrCl₃ and insoluble Cr₂O₃,compounds of trivalent chromium (Cr³⁺), was determined. Theirability to induce SCEs was compared with those of three hexavalentchromium (Cr⁶⁺) compounds: K₂CrO₄, Na₂CrO₄ and Na₂Cr₂O₇. Boththe delay in progression through the cell cycle induced by Cr³⁺compounds and the SCE frequencies in the delayed cells werealso evaluated. The exposure for 28 h to CrCl₃ and Cr₂O₃ atconcentrations of 9.7–39 µg and of 34–136fig of Cr³⁺ per ml, respectively, induced a statistically significant(p < 0.001) dose-dependent increase in SCEs up to 1.9–fold(CrCl₃ and 4-fold (Cr₂Cl₃) over control levels. Compared withthe effective concentrations of Cr⁶⁺ compounds, which producedup to 4-fold increase of SCEs, inducing concentrations of CrCl₃and Cr₂O₃ were 300- and 1000-fold higher in terms of chromium.By prolongation of treatment time up to 48 h, a progressivedose- and time-related enhancement in SCE frequencies inducedby Cr³⁺ compounds in delayed cells was observed. Lower concentrationsof Cr₂O₃, without effect after 28 h of treatment, induced anincrease of SCEs by prolongation of exposure time.     

热疗联合TACE治疗中晚期肝癌的临床观察

目的评价热疗联合动脉灌注栓塞术(TACE)治疗中晚期肝癌的临床疗效及毒副反应。方法选取中晚期肝癌患者80例,随机分成两组,每组40例。A组采用局部区域热疗联合TACE,B组仅行TACE。两组病例均在TACE 1~2疗程后进行临床疗效及毒副反应的评价。结果A组病例中卡氏评分提高占80%（32/40）;B组病例中卡氏评分提高占47.5%（19/40）（P＜0.05)。A组与B组病例的临床近期疗效分别为：CR 0%、0%;PR72.5%、45%;SD 20%、37.5%;PD7.5%、17.5%（P＜0.05）,且不增加毒副反应。A组病例的T细胞亚群和NK细胞的活性均明显高于治疗前,而B组的T细胞亚群和NK细胞的活性均低于治疗前（P＜0.05）。结论热疗联合TACE治疗中晚期肝癌可提高介入治疗肝癌的近期疗效,减轻毒副作用,且对患者的免疫功能有保护作用,值得临床推广运用。     

Effect of cell proliferation on initiation of aflatoxin B1-induced enzyme altered hepatic foci in rats and hamsters

Rat is susceptible whereas hamster is resistant to aflatoxinB₁ (AFB₁) hepatocarcinogenesis. Effect of cell proliferationon AFB₁ -induced glutathione S-transferase placental form (GST-P)positive foci has been examined in these two species after asingle i.p. dose of AFB₁ and phenobarbital (PB) as a promoterin a 3 week period. Bromodeoxyuridine incorporation as a measureof cell proliferation and GST-P hepatic foci were analyzed byimmunohistochemical methods. Hepatic cell proliferation wasmaximum at 24 h after either partial hepatectomy (PH) or CCl₄(4 mmol/ kg) pretreatment of rats whereas cell proliferationwas maximum at 48 h after PH or CCl₄ (1 mmol/kg) treatment ofhamsters. Enhanced number of GST-P positive hepatic minifoci(two to nine cells) and foci (>100 µ) and focal areawere observed in rats with either AFB₁ (0.5 mg/kg) given 24h after PH or AFB₁ (0.5 or 2.5 mg/kg) given 48 h after CCl₄dosing. In hamsters, 1 or 2 mg AFB₁ treatment produced onlyGST-P positive single hepatocytes without presence of any minifociwhereas 3 or 6 mg AFB1 produced minifoci consisting only ofdoublets. Pretreatment with CCl₄ 48 or 72 h before 1 mg AFB₁dose level increased GST-P positive single cells and minifociseveral fold. PH 24 or 48 h before 1 or 2 mg AFB₁ dose levelincreased minifoci. However, increase in minifoci was higherin PH hamsters at 48 h compared with those at 24 h. These resultsindicate that even though maximum initiation occurs in bothspeices when AFB₁ is administered at the peak of DNA synthesis,rats are more responsive than hamsters to cellular proliferationin the initiation phase of AFB₁ induced hepatocarcinogenesis.     

Synthesis and mutagenicity of 3, 3'-dihalogenated benzidines

3, 3'- Difluorobenzidine (F₂ Bz), and 3, 3'- dibromobenzidine(Br₂Bz) were synthesized and compared with 3, 3'-dichloro-benzidine(C1₂ Bz) for ability to revert Salmonella typhimurium. The relativemutagenicities in all systems are CI₂Bz = Br₂Bz > F₂Bz >Bz. F₂Bz, CI₂Bz, and Br₂Bz are direct-acting mutagens towardsS. typhimurium strain TA98. The acetylase-deficient derivativeTA98/1, 8-DNP₆ displays no resistance to induction of mutagenesisby these compounds, in the absence of mammalian activation.With addition of hamster hepatic S-9 activation the mutagenicityof these compounds increases greatly. TA98/1, 8-DNP₆ shows someresistance to this mutagenicity. Multiple Mechanisms must existfor the genotoxicity of 3, 3'-dihalogenated benzidines.     

Malignant transformation of mouse BALB/c3T3 cells induced by NaNO2

The addition of sodium nitrite (NaNO₂; 5–20 mM) for 72h to mouse BALB/c3T3 cells resulted in the induction of transformedfoci (type III foci) in a dose-dependent manner. The cells isolatedfrom the NaNO₂-induced transformed foci produced progressivelygrowing tumors when inoculated into nude mice subcutaneouslyat an inoculum size of 1 x 10⁶ cells per site. In contrast,the original untreated cells did not take even at an inoculumsize of 1 x 10⁶ cells per site. The possibility that NaNO₂ mightreact with cellular or medium components to make carcinogenicN-nitrosamines and that these might induce cell transformationwas examined and almost excluded. Thus, nitrite itself seemsto have a cell transforming activity. Recent evidence suggeststhat NO₂^– is produced by the activated macrophage of mammals.We also detected NO₂^– production in culture media in themouse macrophage-like cell Line J774–A1 after lipopolysaccharide(LPS) treatment, and also in the human promyeloleukemia cellline HL60 after differentiation into macrophage-like cells by12-O-tetradecanoyl phorbol-13-acetate and further activationby LPS.     

Differential binding of chromium(VI) and chromium(III) complexes to salmon sperm nuclei and nuclear DNA and isolated calf thymus DNA

The binding of CrCl₃.6H₂O, Cr(NO₃)₃.9H₂O, [Cr(L-His)₂] (NO₃)₃.H₂O,[Cr(L-Cys)(L-His)].3.5H₂O, [Cr(L-His)(D-Pen)].H₂O, Na[Cr(L-Cys)₂].2H₂O,K₂[Cr(GS)₂].3H₂O, Na₂-CrO₄.4H₂O, and Na₂Cr₂O₇.2H₂O to salmonsperm nuclei and nuclear DNA was determined. The Cr(III)-aminoacid complexes and Cr(VI) exhibited significantly lower Cr-nucleiand Cr-DNA binding levels relative to the inorganic complexesCrCl₃.6H₂O and Cr(NO₃)₃.9H₂O. The binding of CrCl₃.6H₂O, Cr(NO₃)₃.9H₂Oand Na₂Cr₂O₇.2H₂O to salmon sperm nuclei and nuclear DNA inthe presence of rat lung cytosol was determined under the sameconditions. For those complexes studied in both buffer and cytosol,the Cr-DNA binding levels for Cr(III) complexes were higherin buffer than in cytosol, while a relatively higher bindinglevel was observed for Cr(VI) in cytosol than in buffer. Slightlylower nuclear protein levels were present in Cr(VI) incubationsthan in Cr(III) incubations with nuclei both in the presenceand the absence of cytosol. The relative binding of CrCl₃.6H₂O,Cr(NO₃)₃.9H₂O, [Cr(L-His)₂](NO)₃.H₂O, [Cr(L-Cys) (L-His)].3.5H₂O,[Cr(L-His)(D-Pen)].H₂O, Na[Cr(L-Cys)₂].2H₂O and Na₂CrO₄.4H₂Oto isolated calf thymus DNA in buffer was also determined. Positivelycharged, labile inorganic Cr(III) complexes, CrCl₃.6H₂O andCr(NO₃)₃.9H₂O, exhibited higher binding to DNA than [Cr(L-His)(D-Pen)].H₂O, and no binding to DNA was observed with Cr(VI)and the other neutral, positively and negatively charged, inertCr(III)-amino acid complexes. Although labile aquo chromium(III)complexesare quite reactive with DNA, the reactivity of chromium(III),formed upon intracellular reduction of carcinogenic chromium(VI),toward DNA will be diminished by complexation with cellularproteins, peptides and amino acids.     

Fluoro-substituted N-nitrosamines. 3. Microsomal metabolism of N-nitrosodibutylamine and of fluorinated analogs

In vitro metabolism of N-nitrosodibutylamine (NDBA) and of threefluorinated analogs, N-nitroso-4, 4, 4-trifluorobutyl-butylamine(NDBA-F₃), N-nitroso-bis(4, 4,4-trifluorobutyl)-amine (NDBA-F₆)and N-nitroso-bis(2, 2, 3, 3, 4, 4, 4-hepta-fluorobutyl)amine(NDBA-F₁₄) was investigated with rat liver microsomes. To elucidatedifferences in metabolism caused by fluorination, aldehydes,nitrite and unchanged nitrosamines were determined. NDBA, NDBA-F₃and NDBA-F₆ were dealkylated and to a smaller extent also denitrosated.Dealkylation at the fluorinated butyl groups was reduced incomparison to the unfluorinated butyl groups. NDBA-F₁₄ was practicallyunmetabolized by microsomal enzymes in vitro.     

Fluoro-substituted N-nitrosamines. 2. Metabolism of N-nitrosodiethylamine and of fluorinated analogs in liver microsomal fractions

In vitro metabolism of N-nitrosodiethylamine (NDEA) and of itstwo fluorinated analogs N-nitroso-2,2,2-trifluoroethyl-ethylamine(NDEA-F₃) and N-nitroso-bis(2,2,2-trifluoro-ethyl)amine (NDEA-F₆)was comparatively investigated using rat liver microsomes andS-9 fraction. Aldehydes, nitrite and unchanged nitrosamineswere determined. Additionally the mutagenicity was measuredin a Salmonella/mammalian microsome assay. NDEA and NDEA-F₃were deethylated and, to a smaller extent, denitrosated. Dealkylationof NDEA-F₃ at the fluorinated ethyl group, however, was stronglyinhibited. NDEA-F₆ was practically not metabolized under thein vitro conditions used. In contrast to NDEA, the mutagenicityof NDEA-F₃ was at best marginal; NDEA-F₆ was not mutagenic.The results show that substitution of fluorine in ß-positionof NDEA strongly influences -C-hydroxylation and denitrosation.     

Autologous bone marrow transplantation for acute myeloblastic leukemia in Europe: further evidence of the role of marrow purging by mafosfamide. European Co-operative Group for Bone Marrow Transplantation (EBMT).

Fifty-nine European teams have reported 919 autografts for the consolidation of acute myelocytic leukemia (AML) up to December 31, 1989. The distribution for autologous bone marrow transplantation (ABMT) was 671 in first complete remission (CR1) and 196 in CR2. Pretransplantation regimes were: total-body irradiation (TBI), 456; busulfan plus cyclophosphamide (BU-CY) 174; marrow purging with mafosfamide, 269 (corresponding to 26% of all patients in CR1 and 41% in CR2). Patients autografted in CR1 with no high risk factor (standard risk) had a leukemia-free survival (LFS) and relapse rate at 7 years of 48 +/- 2 and 41 +/- 3%, respectively. Of all the prognostic factors studied, only secondary leukemia was correlated with a poorer LFS (19 +/- 9% at 1 year) and a higher relapse rate (76 +/- 11%) (p less than 0.0001). For patients autografted in CR2, the LFS and relapse rate were 34 +/- 4 and 54 +/- 5%. With the restriction of a shorter follow-up, the results achieved with the BU-CY combinations (LFS and relapse rate at 3 years, CR1 47 +/- 6 and 45 +/- 7%; CR2, 37 +/- 9 and 50 +/- 10%) did not differ from those with TBI or other chemotherapy combinations. LFS and relapse rates were correlated with several pretransplant intervals: in CR1, patients reaching CR more rapidly (less than or equal to 40 days) had a better LFS (53 +/- 3 versus 42 +/- 3%; p = 0.03) and a lower relapse rate (46 +/- 3 versus 57 +/- 3%; p = 0.03). In patients autografted less than 3 months, 3-6 months and more than 6 months after CR, the LFS was 26 +/- 5, 49 +/- 3, and 55 +/- 4%, respectively, and the relapse rates 63 +/- 5, 38 +/- 3, and 36 +/- 4% (p less than 0.0001 for both). In CR2, patients autografted more than 18 months after the initial diagnosis had a better LFS (42 +/- 5 versus 24 +/- 5%; p less than 0.001) and a lower relapse rate (45 +/- 6 versus 65 +/- 6%; p less than 0.001). For those autografted less than 3 months, 3-6 months and more than 6 months after CR, the probability of LFS was 30 +/- 5, 30 +/- 7, and 50 +/- 9% (p = 0.06), respectively and the relapse rates 63 +/- 6, 50 +/- 8, and 36 +/- 8% (p = 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)     

Fluoro-substituted N-nitrosamines. 4. Comparative genotoxic activities of N-nitrosodibutylamine and three fluorinated analogues in two bacterial systems

N-Nitrosodibutylamine (NDBA) and three fluorinated analogues(N-nitroso (4,4,4-trifluorobutyl)butyl-amine, F₃NDBA; N-nitrosobis(4,4,4-trifluorobutyl)amine, F₆NDBA; and N-nitrosobis (2,2,3,3,4,4,4-heptafluorobutyl) amine, F₁₄NDBA) were comparatively investigatedfor biological activity in two bacterial systems. Opposite ordersof magnitude were obtained for their potency in the two tests.For inducing his⁺ reversion in auxotrophic strains of Salmonellatyphimurium the sequence was F₃NDBA > F₆NDBA > NDBA andfor inducing lethal DNA damage in repair deficient strains ofEscherichia coli WP2 it was NDBA > F₆NDBA F₃NDBA. F₁₄NDBAwas not active in either test system.     

Evidence for a 2,3-epoxide as an intermediate in the microsomal metabolism of 6-nitrobenzo[a]pyrene

The rat liver microsomal metabolism of 3-deutero-6-nitro-benzo[a]pyrene([3-²H]6-NO₂-BaP) was studied. The metabolites were separatedby h.p.l.c. The 500 MHz ¹H n.m.r. spectral analysis of the metabolitesindicated that the 3-hydroxy-6-NO₂-BaP and 6-NO₂-BaP-3,9-hydroquinoneeach retained 33% of the deuterium label at the C-2 position.It is proposed that the migration of deuterium occurs via anNIH shift mechanism. These results indicate that a 2,3-epoxideis a common intermediate.     

Genetic differences in enzymes associated with peroxisome proliferation and hydrogen peroxide metabolism in inbred mouse strains

Enzyme activities relating to H₂O₂ production (peroxisomal acyl-CoAoxidase) and degradation (catalase and glutathione peroxidase)were measured in the livers of male mice of the inbred strainsC57BL/6J (C57) and C3H/HeJ (C3H) and their F₁ hybrid, B6C3F₁.Groups of the three genotypes were maintained on either a basaldiet or one containing 0.1% of the peroxisome-proliferatingagent, nafenopin, for six weeks. In both control and nafenopin-exposedgroups, the C57 strain displayed higher acyl-CoA oxidase activitylevels than the C3H mice, whereas the activity levels of catalaseand gluthione peroxidase were not different for the two inbredstrains. The groups of similarly fed B6C3F₁ hybrids had intermediatevalues for acyl-CoA oxidase. Several other parameters relatingto peroxisome proliferation did not differ among the three genotypes.Acyl-CoA oxidase levels in cultured hepatocytes from C57 micewere greater than those in hepatocytes obtained from the C3Hstrain during two days in culture and this difference was maintainedfor 4 days by nafenopin exposure. Acyl-CoA oxidase is centralto the hypothetical H₂O₂ mechanism of peroxisome proliferator-inducedand, therefore, the genetic difference documented here may leadto a useful approach in testing this hypothesis.     

Deuterium isotope effect on metabolism of N-nitrosodimethylamine in vivo in rat

The maximal rates of metabolic oxidation of N-nitrosodimethylamine(NDMA) and N-nitrosodimethylamine-d₆ (NDMA-d₆) in viva (V^H andV^D, respectively) have been measured by following ¹⁴CO₂ exhalationin rats after intraperitoneal injection of the two ¹⁴C-labelledcarcinogens at high doses (20 or 40 mg/kg). Complete deuterationof NDMA reduced only slightly the maximal rate of metabolismwhen the two substrates were administered separately (V^H/V^D1.2). However, much larger(4-fold) deuterium isotope effectswere observed when mixtures of NDMA with NDMA-d₆ were injected.These results are tentatively interpreted as evidence that C-Hbond cleavage is not a rate-limiting feature of overall metabolism,but that the complex between NDMA and the principal enzyme(s)metabolizing it in vivo freely equilibrates with unbound substrate.Single, large, intrapentoneal doses of NDMA and NDMA-d₆ produceda similar alkylation of rat liver DNA and also of kidney DNA.However, a small oral dose (54 µg/kg) of NDMA-d₆ produced1/3 less alkylation of liver DNA and 3 times as much alkylalionof kidney DNA as did an equimolar dose of NDMA. The reductionin alkylation of liver DNA correlates well with, and possiblyexplains, the decreased ability of NDMA-d₆ to induce liver tumorsin rats. The associated increase in the alkylation of kidneyDNA suggests that this change is due to a decrease in the amountof nitrosamine removed from the portal blood on the first passthrough the liver.     

Cancer chemoprevention by aliphatic selenocyanates: effect of chain length on inhibition of mammary tumors and DMBA adducts

The objective of this study was to examine the anticarcino-genicactivity of a series of aliphatic selenocyanates with increasinglength of the carbon side chain, CH₃–(CH₂)_n–SeCN,in which n = 0, 2, 4 or 6. Their ability to prevent mammarycancer was evaluated during the initiation phase using the rat7,12-dimethyl-benz[a]anthracene (DMBA) model. Each compoundwas added to the diet at a final concentration of 2 p.p.m. Seand was given from 2 weeks before to 1 week after DMBA administration.Analysis of the tumor data suggested the following order ofchemopreventive potency for this series of aliphatic selenocyanates:heptyl     

Activation of K-ras in aflatoxin B1-induced lung tumors from AC3F1 (A/JxC3H/HeJ) mice

In addition to being a potent hepatocarcinogen, aflatoxin B₁(AFB₁) is a pulmonary carcinogen in experimental animals andepidemiological studies have shown an association between AFB₁exposure and lung cancer in humans. Since point mutations atcodons 12, 13 and 61 of the K-ras protooncogene are often implicatedin chemically induced mouse lung tumors and in human lung adeno-carcinomas,we undertook an investigation of the role of K-ras activationin AFB₁-induced pulmonary carcino-genesis. Female AC3F1 (A/JxC3H/HeJ)mice were treated with AFB₁ (150 mg/kg i.p., divided into 24doses over 8 weeks), and 6–14 months after the completionof dosing mice were killed and pulmonary adenomas and carcinomasremoved. Of the 76 AFB₁-induced lung tumors analyzed by singlestrand conformation polymorphism (SSCP) and direct sequencing,75 possessed K-ras codon 12 mutations (46 GTT, 14 GAT, 13 TGTand 2 TTT; normal, GGT) and one had a GGC