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PubMed1999

Unique alterations of thyroid function parameters after i.v. administration of alkylating drugs (cyclophosphamide and ifosfamide).

Alkylating drugs (cyclophosphamide and ifosfamide) have been in clinical use for the treatment of malignant diseases in the past. They are most useful anticancer agents and cyclophosphamide is also widely used for its immunosuppressive properties. However the effect of alkylating drugs on thyroid hormone parameters have not been evaluated so far. Three groups of patients were prospectively evaluated: Group I: 15 patients with Wegener's granulomatosis and 4 patients with severe scleritis received a single dose cyclophosphamide (15 mg/kg bw/day) and 250 mg prednisone i.v. Group II: 9 patients with malignant lymphomas were treated according to the IMVP 16-protocol. Patients received daily ifosfamide 1000 mg/m2 from day 0 to 4 and vepesid from day 0 to 2. Patients did not receive corticosteroids additionally. Group III: 6 patients with a relapse of malignant lymphomas received ifosfamide 1.500 mg/m2/day from day 0 to 4 i.v. and dexamethasone 40 mg/m2 as well as ara-c and etoposid. All patients received mesna to prevent hemorrhagic cystitis and odansetran or metoclopramide as antiemetic drugs. Alkylating drugs were given as a one hour infusion. Thyroid hormone parameters were determined before and on day 1, 2, 3, 4 after drug administration. We observed a significant increase in T4 and fT4 concentrations and a concomitant fall in TSH in either group one day after the administration of alkylating drugs. The effect was most pronounced in group III: T4 increased from 113 +/- 8 nmol/L to 175 +/- 8 (normal: 58-154) and fT4 from 14.0 +/- 0.8 to 24.8 +/- 2.5 pmol/L (normal 10-25). TSH dropped from 1.27 +/- 0.16 to 0.33 +/- 0.07 mU/L (normal 0.3-4). All changes were significant: p < 0.001. Two of the six patients displayed biochemical hyperthyroidism. Also reverse T3 increased significantly. Two days after drug administration a gradual normalization occurred. However, T3, Tg, TBG, Transthyretin and albumin levels did not change throughout the study period. One patient with coexisting hypothyroidism, who received his last thyroxine substitution therapy one day before the administration of cyclophosphamide (as in group I), also demonstrated an increase in T4, fT4 and rT3 and a fall in TSH concentrations. I.v. administrations of cyclophosphamide and ifosfamide induce a transient increase in T4 and fT4 concentrations and a concomitant fall of TSH in the presence of normal Tg, T3 and thyroid binding protein concentrations. These data suggest, that the changes are not due to a release of thyroid hormones from the thyroid itself, but is likewise related to a release of thyroxine from cellular pools such as the liver.

Adult↗
PubMed2004

Solid-phase synthesis of chiral 3,4-diazaphospholanes and their application to catalytic asymmetric allylic alkylation.

Functionalized chiral diazaphospholanes ligate to a variety of transition metals, yielding chiral, catalytically active, metal complexes. Previous work has established that amino acid derivatization of the carboxyl groups of (R,R)-N,N'-phthaloyl-2,3-(2-carboxyphenyl)-phenyl-3,4-diazaphospholane (1) yields phosphines that are excellent ligands for palladium-catalyzed asymmetric allylic alkylation reactions. Alanine functionalization is particularly effective for allylic alkylation of 1,3-dimethylallyl acetate. Standard Merrifield resins and amino acid coupling methods are used to synthesize the bead-attached phosphine having the topology bead-linker-LAla-(R,R)-1-LAla-OMe, as a 1:1 mixture of linkage isomers. Use of this supported phosphine in Pd-catalyzed asymmetric allylic alkylation yields 92% enantiomeric excess, matching prior solution-phase results. A 20-member collection of amino acid-functionalized phosphines on beads with the topology bead-linker-AA(2)-AA(1)-1-AA(1)-AA(2) was synthesized by using parallel solid-state methods and screened for efficacy in allylic alkylation. Resulting enantioselectivities indicate that the AA(1) position has the strongest effect on the reaction. Catalyst activities can vary widely with the nature of the phosphine ligand and the reaction conditions. Meaningful analysis of intrinsic catalytic activities awaits identification of the structure and abundance of the active catalyst.

Alkylation↗
PubMed2005

The antimalarial drug artemisinin alkylates heme in infected mice.

Heme alkylation by the antimalarial drug artemisinin is reported in vivo, within infected mice that have been treated at pharmacologically relevant doses. Adducts resulting from the alkylation of heme by the drug were characterized in the spleen of treated mice, and their glucuroconjugated derivatives were present in the urine. Because these heme-artemisinin adducts were not observed in noninfected mice, this report confirms that the alkylating activity of this antimalarial drug is related to the presence of the parasite in infected animals. The identification of heme-artemisinin adducts in mice should be considered as the signature of the alkylation capacity of artemisinin in vivo.

Alkylation↗
PubMed2003

A general strategy for target-promoted alkylation in biological systems.

Selective alkylation of a chosen sequence of DNA typically relies on ligand-directed delivery of a compound that expresses an intrinsic reactivity. A significant and biologically relevant enhancement in specificity is theoretically possible if such an intrinsic reactivity could be replaced by a latent activity induced solely by the target of interest, but examples of this are rare and not easily emulated. A simple strategy for target-promoted alkylation is now illustrated by an intramolecular adduct formed by an oligonucleotide-quinone methide conjugate. This adduct persists in the absence of a complementary sequence of DNA for at least 8 days, yet remarkably is able to alkylate target DNA upon duplex hybridization. Neither formation of the intramolecular self-adduct nor transfer of the quinone methide to its target is significantly quenched by 450-fold excess 2-mercaptoethanol. Similarly, noncomplementary DNA is neither subject to alkylation by the self-adduct nor able to effect its consumption. Reversible trapping of the nascent quinone methide through an intramolecular reaction thus appears efficient enough to inhibit competing intermolecular reaction. Only complementary base pairing induces a conformational change necessary to promote intermolecular transfer of the quinone methide. Generalization of this approach based on reversible intramolecular trapping of a reactive intermediate by a ligand with multiple recognition subdomains has the potential for wide-ranging applications in targeting nucleic acids and proteins.

Alkylation↗
PubMed1994

Disulfide linkages in the in vitro refolded intermediates of recombinant human macrophage-colony-stimulating factor: analysis of the sulfhydryl alkylation of free cysteine residues by fast-atom bombardment mass spectrometry.

Fast-atom bombardment mass spectrometry was used to follow the time course of disulfide bond formation during in vitro refolding of recombinant human macrophage-colony-stimulating factor. The content of iodoacetamide-alkylated half-cystines in proteolytic peptides of trapped refolding intermediates collected at 0, 6, 17, 24, and 72 hr was determined under reducing conditions. Size-exclusion high-performance liquid chromatography analyses of the collected alkylated samples indicate that aggregated monomer proceeded through a nonaggregated monomer to an intermediate dimer and finally to the fully folded and active dimer. Underalkylation was first detected by fast-atom bombardment mass spectrometry in 17-hr samples at Cys157 and Cys159 and this corresponded to the first sample containing dimer. Analyses of intermediates from subsequent time points indicated a decrease in alkylated sulfhydryls, and at 72 hr no alkylated peptide was detected. Early samples containing only monomer showed no evidence of disulfide bonds, and the occurrence of disulfide shuffling at the monomer stage could be ruled out under the highly reducing conditions used for refolding. Biological activity was not detectable in early samples but increased to 3.6% after 24 hr of refolding and to 86% of maximum at the 72-hr time point.

Alkylation↗
PubMed1998

Topoisomerase II-mediated site-directed alkylation of DNA by psorospermin and its use in mapping other topoisomerase II poison binding sites.

Psorospermin is a plant natural product that shows significant in vivo activity against P388 mouse leukemia. The molecular basis for this selectivity is unknown, although psorospermin has been demonstrated to intercalate into DNA and alkylate N7 of guanine. Significantly, the alkylation reactivity of psorospermin at specific sites on DNA increased 25-fold in the presence of topoisomerase II. In addition, psorospermin trapped the topoisomerase II-cleaved complex formation at the same site. These results imply that the efficacy of psorospermin is related to its interaction with the topoisomerase II-DNA complex. Because thermal treatment of (N7 guanine)-DNA adducts leads to DNA strand breakage, we were able to determine the site of alkylation of psorospermin within the topoisomerase II gate site and infer that intercalation takes place at the gate site between base pairs at the +1 and +2 positions. These results provide not only additional mechanistic information on the mode of action of the anticancer agent psorospermin but also structural insights into the design of an additional class of topoisomerase II poisons. Because the alkylation site for psorospermin in the presence of topoisomerase II can be assigned unambiguously and the intercalation site inferred, this drug is a useful probe for other topoisomerase poisons where the sites for interaction are less well defined.

Alkylation↗
PubMed1998

Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes.

Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT-/- MLH1(+/+) mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT-/- MLH1(-/-) mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Phorbol ester abrogates up-regulation of DNA polymerase beta by DNA-alkylating agents in Chinese hamster ovary cells.

Mammalian DNA polymerase beta (beta-pol), a DNA repair polymerase, is known to be constitutively expressed in cultured cells, but treatment of cells with the DNA-alkylating agents MNNG or methyl methanesulfonate has been shown to up-regulate beta-pol mRNA level. To further characterize this response, we prepared a panel of monoclonal antibodies and used one of them to quantify beta-pol in whole cell extracts by immunoblotting. We found that treatment of Chinese hamster ovary cells with either DNA-alkylating agent up-regulated the beta-pol protein level 5-10-fold. This induction appeared to be secondary to DNA alkylation, as induction was not observed with a genetically altered cell line overexpressing the DNA repair enzyme O6-methylguanine-methyltransferase. We also found that 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of wild type Chinese hamster ovary cells increased expression of beta-pol protein (approximately 10-fold). Any interrelationship between this TPA response and the DNA-alkylation response was studied by treatment with combinations of MNNG and TPA. The beta-pol up-regulation observed with MNNG treatment was abrogated by TPA, and conversely the up-regulation observed with TPA treatment was abrogated by MNNG.

Alkylating Agents↗
PubMed2004

Fludarabine in comparison to alkylator-based regimen as induction therapy for chronic lymphocytic leukemia: a systematic review and meta-analysis.

The superiority of Fludarabine over conventional therapy as primary induction therapy for patients with chronic lymphocytic leukemia (CLL) has been shown in several studies but no studies have yet reported a pooled estimate of the treatment effect. We performed a systematic review of evidence from 5 randomized controlled trials involving approximately 1300 patients with CLL, comparing Fludarabine with several alkylator-based combination regimens in the primary treatment of CLL. Complete response rate was significantly higher for Fludarabine compared to alkylator-based chemotherapy (RR 1.87, 95% CI 1.10-3.19, P=0.02), while overall response, though superior, did not reach statistical significance (RR 1.22, 95% CI=0.88-1.69, P=0.24). Overall survival was similar for Fludarabine and alkylator-based therapy (the pooled log hazard ratio of death, HR=-0.05, 95% CI=-0.36-0.26, P=0.75). Infection rate was significantly higher (RR 1.58, 95% CI=1.10-2.27, P=0.01), but there was no significant difference in the incidence of thrombocytopenia, neutropenia and anemia. Therefore, this meta-analysis supports the findings that Fludarabine as an induction agent for patients with CLL yields a better clinical response with acceptable toxicity when compared with alkylator-based combination therapy, but without a survival benefit by 5-6 years of follow up.

Alkylating Agents↗
PubMedDate not supplied

Alkylation of DNA and carcinogenicity of N-nitroso compounds.

The possible mode of action of two classes of highly organ- and species-specific carcinogenic N-nitroso compounds, namely the N-nitrosamines and N-nitrosamides, is outlined in this review. Chemical or enzymatic conversion of these agents into active alkylating species is a prerequisite for their biological activity. Although these species are capable of reacting with all cellular macromolecules, there is good evidence that their ability to attack DNA is related to their carcinogenicity. This paper reviews the reasons and experimental support for the hypothesis that it is specifically alkylation of DNA at the O6 position of guanine that initiates malignant transformation, an important factor being the presence of an enzyme system capable of eliminating O6-alkylguanine from DNA. No such repair reaction appears to exist for this or other alkylation products when they are present in RNA. The activity of this system is enhanced by chronic administration of alkylating agents, and the role that this may play in carcinogenesis is discussed.

Alkylation↗
PubMed1991

Cell specific DNA alkylation in target and non-target organs of N-nitrosobis(2-oxopropyl)amine-induced carcinogenesis in hamster and rat.

Tissue-specific formation and short-term persistence of alkylated DNA bases have been studied immunocytochemically in Syrian hamsters and rats killed 3-48 h after a single s.c. or oral dose of N-nitrosobis(2-oxopropyl)amine (BOP). Antisera specific for O6-(m)ethylguanine and for 7-(m)ethylguanine were used. Strong nuclear staining, indicative of a high level of DNA alkylation, was observed at all time points in the intra- and interlobular duct cells and in the centroacinar cells of the hamster pancreas, the main target organ of BOP-induced carcinogenesis. Acinar cells were weakly stained for up to 24 h. In the liver, nuclear staining was strong in all cell types, and more pronounced in the periportal than in the central venous area. Both O6-alkylguanine and 7-alkylguanine preferentially disappeared from the centrilobular area of the liver which is in agreement with the high O6-methyltransferase activity of liver and the unusually high levels of 7-methylguanine DNA glycosylase activity in hamster tissues. Strong staining was observed throughout the experiment in the tubular cells of the renal cortex and in bronchiolar Clara and alveolar type II cells of the lung. The staining intensity of the cells of the thyroid follicles and of the columnar epithelial cells of the colon was moderate. In the rat, nuclear staining was strong in the nasal cavity (Bowman glands), the epithelium lining the thyroid follicles, the lung, liver and in the fibroblasts of the ureter intima and adventitia. The epithelial cell nuclei of the colon and ureter were moderately stained. In the pancreas, staining was weak in acinar, duct and islet cells; no acinar staining remained at 48 h. In the liver, nuclear staining was strong all over the lobule. O6-Alkylguanine was preferentially removed from the centrilobular area. The renal tubular cells were only weakly stained. From the present study we can conclude that--with the exception of hamster kidney and rat liver--high levels of DNA alkylation and stability of the alkylated products were related to a high tumor incidence.

Alkylation↗
PubMed1981

Effects of selenium on 1,2-dimethylhydrazine metabolism and DNA alkylation.

Sodium selenite (Se) decreases the incidence of colon tumors induced in rats by 1,2-dimethylhydrazine (DMH). In order to determine the basis for this inhibition, we studied the effects of Se on DMH metabolism, DNA alkylation and the rate of cell turnover of the target tissue. The effects of Se pretreatment (4 p.p.m. in the drinking water, for 2, 4 or 6 weeks) on DMH metabolism were monitored in male Sprague-Dawley rats by measuring expired 14CO2 and azo[14C]methane over a 12 h period after a.c. injection of [14C]DMH (20 mg/kg body weight). Compared to control rats, which received only [14C]DMH, Se pretreatment caused an increase in exhaled azomethane (31--69%) and a corresponding decrease in 14CO2 (4--33%) as the length of treatment increased from 2 to 6 weeks. The extent of DNA alkylation (measured as N-7 and O6-methylguanine formation) after Se pretreatment was reduced 20--27% in liver and was increased 40--43% in colon. Metabolic incorporation of [14C] from [14C]DMH into adenine and guanine (presumably via C1 pathways) was reduced 69--72% in colon DNA of Se-treated rats and [3H]thymidine incorporation was reduced 61--65%. This may have been due to decreased cell turnover. A similar response was not observed in the liver. The data suggest that Se decreases hepatic DMH metabolism, and that this may be compensated by an increase in extrahepatic metabolism and alkylation. Although colon alkylation is increased by Se pretreatment, fewer tumors result. This may be due to a decrease in DNA synthesis in this tissue.

1,2-Dimethylhydrazine↗
PubMed1982

Induction of morphological differentiation in cultured mouse neuroblastoma cells by alkylating agents.

A series of N-alkyl-N-nitrosoureas, which produce both alkylation and carbamoylation, was found to induce neurite formation in mouse neuroblastoma N-18 cells just as does N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Related compounds, which produce only carbamoylation or nitroguanidination, did not induce morphological differentiation, while methyl methanesulfonate (MMS) and dimethyl sulfate, which produce only alkylation, did. MNNG, methyl nitrosourea and MMS were more effective in the induction of differentiation than their corresponding ethyl derivatives. These data suggested that alkylation contributed to the induction of morphological differentiation in N-18 cells.

Alkylating Agents↗
PubMed1987

Immunological quantitation of O4-ethylthymidine in alkylated DNA: repair of minor miscoding base in human cells.

Rabbit antisera specific for O4-ethyldeoxythymidine (O4-EtdThd) were developed and used in competitive and non-competitive immunoassays for the quantitation of the miscoding promutagenic adduct O4-EtdThd in DNA. High titer antiserum TB3 (affinity constant, 8.1 X 10(8)) gave 50% inhibition of the tracer antigen-antibody binding with 0.26 pmol of O4-EtdThd in radioimmunoassay and negligible inhibition with unmodified DNA components. In competitive enzyme-linked immunosorbent assay (ELISA), using ENU-poly(dT) instead of hapten-protein conjugate as antigen, inhibition of antigen-antibody binding was proportional to both, the concentration of ethylnitrosourea (ENU) and alkylated DNA. The sensitivity of detection of O4-EtdThd in DNA was enhanced to fmol of O4-EtdThd and ng amounts of alkylated DNA by using avidin-biotin linked immunoreagents in non-competitive ELISA and immunoslot blot assays. An O4-EtdThd concentration-dependent binding of specific antibody, detecting 0.12 fmol of the modified base, was observed with DNA alkylated in vitro with ENU at an O4-EtdThd/Thd molar ratio of 2.6 X 10(-6). The immunological quantitation of O4-EtdThd in ENU-treated human skin fibroblast and kidney epithelial cells indicates a gradual removal of the modified base as a function of post-treatment time in culture. In both cell types about 50% of the initial damage was repaired during a 72-h period. Earlier studies using human organ extracts ruled out the participation of an alkyltransferase or glycosylase enzyme for the repair of O4-alkylthymine. None the less, the kinetics data presented indicate that normal human cells in culture are proficient for the repair of critical pyrimidine alkylation adduct that may be associated with cellular oncogenic transformation of susceptible mammalian cells.

Alkylation↗
PubMed1977

Alkylation of rat liver DNA by dimethylnitrosamine: effect of dosage on O6-methylguanine levels.

Alkylation of liver DNA was studied following administration to Sprague-Dawley rats of doses of dimethylnitrosamine (DMN) varying from 0.25 to 20 mg/kg body weight. Measurements were made of the amounts of O6-methylguanine and 7-methylguanine present in liver DNA at 4 and 24 hours after treatment with the carcinogen. There was a linear relationship between 7-methylguanine levels and dose of the nitrosamine at both of these times. In contrast, the corresponding levels of O6-methylguanine were not directly proportional to dosage but were less than expected, particularly at low doses below 2.5 mg/kg. This discrepancy was significant at 4 hours, but was even more marked at 24 hours. Only doses above 4 mg/kg at the 4-hour time point gave rise to a 0.11 ratio of alkylation of guanine at the O6-position to that at the 7-position. This ratio was that expected for the initial interaction of the alkylating species derived from DMN with DNA. Evidence was obtained to support the hypothesis that these results were due to an enzymatic removal of O6-methylguanine from liver DNA, which occurred much more efficiently at lower initial levels of alkylation. Repeated daily injections of DMN up to 11 days alos gave rise to O6-methylguanine levels that were not proportional to dosage but were relatively greater at higher dose levels. The significance of these findings in the induction of liver cancer by feeding or repeated injection of DMN was explored.

Alkylating Agents↗
PubMed1992

Enhancement of alkylating agent activity by SR-4233 in the FSaIIC murine fibrosarcoma.

BACKGROUND: The most commonly used antineoplastic drugs are more cytotoxic toward normally oxygenated tumor cells than toward hypoxic tumor cells. PURPOSE AND METHODS: To examine the ability of SR-4233, a new cytotoxic agent, to overcome the resistance of hypoxic tumor cells to antitumor alkylating agents, we tested the cytotoxic effect of SR-4233 alone and in combination with varying doses of cisplatin (CDDP), cyclophosphamide (CPM), carmustine (BCNU), or melphalan (L-PAM) on tumor cells and bone marrow cells isolated from C3H/FeJ mice bearing the FSaIIC fibrosarcoma. RESULTS: When SR-4233 alone was given, tumor cell killing was limited. When SR-4233 was administered just before single-dose treatment with CDDP, CPM, BCNU, or L-PAM, however, marked dose enhancement leading to increased cytotoxic effects on tumor cells and on bone marrow cells was observed. Similar experiments with tumor cell subpopulations, selected by Hoechst 33342 dye diffusion, confirmed that while cytotoxicity to both bright (oxygenated) and dim (hypoxic) cells was increased by combining each alkylating agent with SR-4233, the enhancement of the effect was relatively greater in the subpopulation of dim cells. The delay in the growth of tumors in animals treated with the combination of SR-4233 and CDDP, CPM, or L-PAM was 1.6-fold to 5.3-fold greater than that in animals treated with each alkylating agent alone. CONCLUSION: Our results suggest that SR-4233 may have the potential to improve the clinical efficacy of commonly used antitumor alkylating agents.

Alkylating Agents↗
PubMed1996

Analysis of DNA alkylation damage and repair in mammalian cells by the comet assay.

The single cell gel electrophoresis (SCGE) or comet assay, which measures DNA strand breaks in individual cells, was used to analyse DNA damage and repair induced by the SN1-type alkylating carcinogens N-ethyl-N'-nitro-N-nitrosoguanidine and N-ethyl-N-nitrosourea in CHO cells. The comet assay was comparable in sensitivity to the alkaline elution assay. The alkyl-adducts detected as DNA single-strand breaks (ssb) by this technique were completely repaired within 24 h after treatment. These data indicate that long-lived lesions, such as alkylphosphotriesters, are not converted into ssb under the standard SCGE alkaline conditions (pH 13.5). The lesions revealed by the comet assay are mainly apurinic/apyrimidinic (AP) sites and breaks formed as intermediates in the base excision repair process of N-alkylpurines. When SCGE was performed at pH 12.5 instead of pH 13.5 a lower level of ssb was detected and these breaks were completely resealed within 2 h after treatment. These data suggest that different subsets of lesions are detected under different pH conditions. The SCGE combined with inclusion within the cells of endonuclease III revealed that a high portion of AP sites induced by alkylation damage were not converted into ssb by alkali. The level of endonuclease III-sensitive sites decreased as a function of the repair time and by 24 h after treatment no sites were left on the DNA. The use of this modified SCGE assay allows the estimation of the total amount of unrepaired AP sites present on DNA. Alkylation-induced ssb as detected by the comet assay should be regarded as an indicator of repair rate and balance more than a measure of actual DNA damage.

Alkylation↗
PubMed2004

In vivo kinetics of micronuclei induction by bifunctional alkylating antineoplastics.

The aim of the present study was to determine in vivo the kinetics of micronucleated polychromatic erythrocyte (MN-PCE) induction in mice, as an approach for studying the mechanism of micronuclei induction by mitomycin C, cis-diamine dichloroplatinum, busulfan and bis-chloroethylnitrosourea, bifuctional alkylating antineoplastic agents having different patterns of crosslink induction. The kinetics of MN-PCE induction was established by scoring the frequency of MN-PCE in 2000 PCE in peripheral blood, for periods of 8 or 10 h after acute treatment and up to 80 h, with different doses of the agent. The kinetics of MN-PCE induction and particularly the times of maximal induction by different bifunctional alkylating agents were compared with the kinetics previously obtained for ethylnitrosourea, methylnitrosourea and 6-mercaptopurine, agents that cause MN-PCE mainly in the first, second and third divisions after exposure, respectively. The results obtained in the present study allow us to conclude that: (i) bifunctional alkylating agents have very different efficiencies of genotoxic and cytotoxic action; (ii) all assayed bifunctional alkylating agents induced micronuclei during the first cell division, owing to the mistaken repair of primary lesions, e.g. excision; (iii) busulfan and bis-chloroethylnitrosourea showed an additional late mechanism of micronuclei induction, which is expressed at the third division and seems to be related to the mismatch repair process.

Animals↗