Selective inhibition of thymidine transport at low doses of the alkylating agents triethyleneiminobenzoquinone (Trenimon)

The alkylating antitumor agent triethyleneiminobenzoquinone (Trenimon) causes a rapid decrease in the incorporation of labeled thymidine into the DNA of Yoshida or Ehrlich ascites tumor cells. The effect is expressed 4 h after administration of 6 × 10⁻⁸ moles/kg of the drug to mice bearing Yoshida ascites tumors or of 6 × 10⁻⁷ moles/kg to Ehrlich ascites tumor-bearing animals, respectively. The reduced incorporation of labeled thymidine which is observed under these conditions is not due to an inhibition of DNA synthesis. DNA synthesis was measured by an isotope dilution assay after pulse-labeling with ³H-thymidine and by monitoring the increase in the total amount of DNA of the cell populations. The data demonstrate that DNA synthesis is not affected during the first 8 h after exposure to the drug. This conclusion is supported by cell kinetic measurements which indicate that the alkylating agent does not interfere with the progression of cells into the S phase, but exerts a block at the G 2 stage of the cell cycle. The reduced incorporation of thymidine into DNA is explained by a decreased transport of the nucleoside into the cells.     

Reduction in the frequency of N-methyl-N-nitrosourea-induced somatic mutations in Tradescantia by pretreatment with low doses of alkylating agents

Treatment of Tradescantia cuttings with sub-mutagenic doses of N-methyl-N-nitrosourea (MNU), N-ethyl-N-nitrosourea and methyl methanesulphonate before challenging doses of MNU reduced the frequency of somatic mutations in stamen hairs as compared with the effect of challenging dose alone. The highest response was about a 50% reduction in the mutagenic effect of the challenge dose.     

Tumour induction by low molecular weight alkylating agents

Low molecular weight alkylating carcinogens, such as nitroso compounds, alkylate guanine of DNA to 7-alkylguanine, but the amount of this product correlates poorly with tumour induction. Loveless postulated that a minor product of alkylation, O-(6)-alkylguanine, may be responsible for mutagenesis and carcinogenesis. He showed that methyl methanesulphonate (MMS) does not produce O-(6)-methylguanine from deoxyguanosine, and in the present study it failed to induce thymic lymphomas or pulmonary adenomas in inbred Swiss mice. Loveless gave evidence that ethyl methanesulphonate (EMS), methylnitrosourea (MNU) and ethylnitrosourea (ENU) did produce O-(6)-alkylguanine, and all three induced pulmonary adenomas in the present study. It has also been shown that both of the alkylnitrosoureas induced thymic lymphomas but ethyl methanesulphonate did not.     

Membrane mechanisms of the effect of alkylating cytostatic agents

The data bearing witness to realization of the cytostatic activity of alkylating agents by means of interaction with cell membrane receptors was obtained. Alkylating agents block receptors of the polyphosphoinositol system. It is shown that chloralkylamines inhibiting sites coincide with M-++cholinomimetics and alpha-adrenergic receptors, inhibitors of H-histamine receptors, cyclo- and lypoxigenase inhibitors. Such likeness is determined by identical structures of the molecule active part, and quantum-chemical calculations.     

Genotoxic studies in populations occupationally exposed to low doses of physical and chemical agents in Republic Croatia

In Croata Republic personnel occupationally exposed to radiation is examined with a method of chromosomal aberrations every 5 years, by the law. A population exposed to chemical factors is examined with a method of sister chromatid exchange as well as with micronucleus test. In the paper it is discussed a significance of various methods of examination of low doses of clastogenic and aneugenic factors on human genome.     

The influence of gamma-irradiation in low doses on the rate of dominant lethal mutations in drosophila melanogaster

The dose-rate effect of acute and chronic irradiation in the dose of 0.2 Gy in Drosophila melanogaster repair (mei-41, mus209 [Russian character: see text] mus309) and free radicals detoxication (sod) mutant strains was investigated. Was shown the lack of dose rate effect on the rate of dominant lethal mutations in mei-41, mus209 and sod. However in mus309, that has defect in the main Drosophila pathway of the DNA double strand breack repair, the increase of the mutation rate after chronic irradiation was observed (inverse dose-rate effect). The obtained results suggest the main role of DNA double strand breack repair in dose-rate effect formation in Drosophila.     

The influence of the nucleotide excision-repair system on mutagenesis in Salmonella typhimurium LT2 after exposure to low doses of monofunctional alkylating agents.

The role of nucleotide excision repair in the mutagenicity of the monofunctional alkylating agents N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), methyl methanesulfonate (MMS), N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG), and N-ethyl-N-nitrosourea (ENU) in Salmonella typhimurium was examined. The mutagenic potential of the mutagenic agents used increased in the following order: MMS less than ENU less than ENNG less than MNNG. The results obtained confirm the involvement of nucleotide excision repair in the removal of mutagenic lesions from the DNA of S. typhimurium cells exposed to high doses of methylating as well as ethylating agents. At the low doses of all the alkylating agents used, the nucleotide excision repair-proficient strain was mutagenized more efficiently than the uvrB mutant. This phenomenon, a consequence of competition between nucleotide excision-repair enzymes and constitutive O6-methylguanine-DNA methyltransferase, is discussed.     

The reaction of alkylating agents with bacteriophage R17. Biological effects of phosphotriester formation

The extent of biological inactivation and of the degradation of the RNA after reaction of bacteriophage R17 with ethyl methanesulphonate, isopropyl methanesulphonate and N-ethyl-N-nitrosourea was studied. Formation of breaks in the RNA chain probably results from hydrolysis of phosphotriesters formed in the alkylation reactions. Near neutral pH the ethyl and isopropyl phosphotriesters are sufficiently stable for the kinetics of the hydrolysis reaction to be followed. Results indicate that the rate of hydrolysis increases rapidly as the pH is raised. The evidence shows that a phosphotriester group does not itself constitute a lethal lesion. The extent of phosphotriester formation by the different agents is discussed in terms of reaction mechanism.     

Neutron dose effect relationships at low doses

Summary Stimulated by recent observations of non-linearity in the dose effect relationship for the transformation of mammalian cells in vitro by fission neutron irradiation and the reverse dose rate effect in this system, the data for mutation induction in the stamen hairs ofTradescantia occidentalis has been re-examined. The non-linear dose effect relationships suggested in the original reports are confirmed both by the dose effect relationships themselves and by an examination of the statistics of the results. This non-linearity also appears to be present in the more recent observations of other workers. It is suggested that the non-linearity in the system may be due to a sub-population of cells in a particularly sensitive phase of the cell cycle at the time of irradiation. There is a possibility that the data also indicate a qualitative difference in the underlying biophysical actions of neutron and photon radiations.Dedicated to Prof. W. Jacobi on the occasion of his 60th birthday     

Evaluation of genetic risks of alkylating agents: tissue doses in the mouse from air contaminated with ethylene oxide

The degree of alkylation of proteins was used to determined tissue doses D_t i.e. the concentration of free alkylating agent, integrated over time, in resting male mice exposed for 1–2 h to air containing 1–35 ppm ethylene oxide (EO). The exposure doses were thus 0.03–2% of LD₅₀. The results agree with an absorption of all EO in alveolar ventilation, a rapid distribution to all organs, and a rapid detoxication and excertion (biological half-life about 9 min).D_t is proportional to the exposure dose within the range studied. In most organs, including the testes, the D_t is about 0.5 μM · h per ppm · h of expsoure. The degree of alkylation of DNA agreed with expectation from the doses determined.Expressing genetic risks of environmental chemicals in the frame of reference of radiation hazard will facilitate comparison and summations of risks of various origins. On the basis of dose-effect curves of EO and X-rays in barely, a tissue dose of EO in man of $\text{i}\text{m}\text{M}$ · h may be provisionally set equal to 80 rad of low LET radiation. Allowing for the difference in alveolar ventilation between mouse and man, this would mean that epoxide operators working at 5 ppm EO 40 h/week receive a weeky gonad dose of EO amounting to about 4 “rad-equivalenst”. Various data show that this risk estimate is realistic.