PubMed · 14151253
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F E KNOCK. 1964. NEWER ANTICANCER AGENTS.. https://doi.org/10.1016/s0025-7125(16)33478-2
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In the present work, we evaluated (p < 0.05) the participation of base excision repair (BER) and nucleotide excision repair (NER) mechanisms in repairing DNA lesions induced by N-nitrosodiethylamine (NDEA) at 1.5 ng/mL-36.5 microg/mL, through cell survival, in different single and double Escherichia coli DNA repair mutants (uvrA, uvrB, uvrC, fpg, nth, xthA, fpg/nth, uvrA/fpg, fpg/xthA, mutY, and fpg/mutY), using pre-incubation periods of 90 min. Mutant strains BH20 (fpg) and AB1886 (uvrA) showed microsomal enzyme (S9 mix) independent NDEA cytotoxicity. Cytotoxicity was also detected at lowest NDEA concentrations, in the presence of S9 mix, with strains BH980 (mutY) and BH990 (fpg/mutY). NDEA cytotoxicity, without S9 mix, was detected for mutant strains AB1884 (uvrC) and AB1885 (uvrB). Through SOS chromotest with 90 min of pre-incubation for uvrA and nth strains, only NER was shown to be required for repairing NDEA-induced lesions with or without metabolic activation. PQ37 and PQ66 strains, both uvrA mutants, showed different levels of NDEA sensitivity. The findings suggest that, under the used conditions, and at low concentrations, NDEA-induced lesions require both repair pathways.
A new class of potent electrophilic "R(+)" alkylating agents has been developed using weakly nucleophilic carborane anions as leaving groups. These reagents, R(CHB(11)Me(5)X(6)) (R = Me, Et, and i-Pr; X = Cl, Br), are prepared via metathesis reactions with conventional alkylating agents such as alkyl triflates, using the high oxophilicity of silylium ion-like species, Et(3)Si(carborane), as the driving force to obtain increased alkyl electrophilicity. The crystal structure of the isopropyl reagent, i-Pr(CHB(11)Me(5)Br(6)), has been determined, revealing covalence in the alkyl-carborane bonding. This contrasts with the free i-Pr(+) carbocation observed when the anion is less coordinating (e.g. Sb(2)F(11)(-)) or with tertiary alkyl centers, as in [tert-butyl][carborane] salts. In solution, the reagents exist as equilibrating isomers with the alkyl group at the 7-11 or 12 halide positions of the CB(11) icosahedral carborane anion. These alkylating agents are so electrophilic that they (a) react with alkanes at or below room temperature via hydride extraction to produce carbenium ions, (b) alkylate benzene without a Friedel-Crafts catalyst to give arenium ions, and (c) alkylate electron-deficient phosphorus compounds that are otherwise inert to conventional alkylating agents such as methyl triflate.
Impaired DNA repair may fuel up malignant transformation of breast cells due to the accumulation of spontaneous mutations in target genes and increasing susceptibility to exogenous carcinogens. Moreover, the effectiveness of DNA repair may contribute to failure of chemotherapy and resistance of breast cancer cells to drugs and radiation. The breast cancer susceptibility genes BRCA1 and BRCA2 are involved in DNA repair. To evaluate further the role of DNA repair in breast cancer we determined: (1) the kinetics of removal of DNA damage induced by hydrogen peroxide and the anticancer drug doxorubicin, and (2) the level of basal, oxidative and alkylative DNA damage before and during/after chemotherapy in the peripheral blood lymphocytes of breast cancer patients and healthy individuals. The level of DNA damage and the kinetics of DNA repair were evaluated by alkaline single cell gel electrophoresis (comet assay). Oxidative and alkylative DNA damage were assayed with the use of DNA repair enzymes endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (Fpg), recognizing oxidized DNA bases and 3-methyladenine-DNA glycosylase II (AlkA) recognizing alkylated bases. We observed slower kinetics of DNA repair after treatment with hydrogen peroxide and doxorubicin in lymphocytes of breast cancer patients compared to control individuals. The level of basal, oxidative and alkylative DNA damage was higher in breast cancer patients than in the control and the difference was more pronounced when patients after chemotherapy were engaged, but usually the level of DNA damage in these patients was too high to be measured with our system. Our results indicate that peripheral blood lymphocytes of breast cancer patients have more damaged DNA and display decreased DNA repair efficacy. Therefore, these features can be considered as risk markers for breast cancer, but the question whether they are the cause or a consequence of the illness remains open. Nevertheless, our results suggest that research on the mutagen sensitivity and efficacy of DNA repair could impact the development of new diagnostic and screening strategies as well as indicate new targets to prevent and cure cancer. Moreover, the comet assay may be applied to evaluate the suitability of a particular mode of chemotherapy to a particular cancer patient.