Biomedical subjects

H Nikjoo

Publications and source records attributed to H Nikjoo.

44 records · Page 3Linked to original sources

PubMed1994

Modelling of DNA breaks and the formation of chromosome aberrations.

We present results of some calculations that convert double-strand breaks to dicentrics by means of a repair-misrepair model. The method uses Monte Carlo techniques to determine the positions of the double-strand breaks and to determine the dicentric yields for comparison with those obtained experimentally in human lymphocytes following irradiation in G0. The model is able to describe the linear-quadratic curves of dicentric yield following low LET irradiation, but underpredicts by a factor of about 1.5-2.0 the high LET neutron curves. The effects of including corrections for interphase death are demonstrated. The reasons for the discrepancy at high LET are discussed and suggestions for an improvement to the fit are made.

Chromosome Aberrations↗

PubMed1991

Energy deposition in small cylindrical targets by monoenergetic electrons.

Calculations of energy deposition in cylindrical target volumes of diameter and height 1-100 nm, including those similar to the dimensions of biological molecules and structures such as DNA, nucleosomes and chromatin fibre, have been made. The calculations used the Monte Carlo track structure program MOCA8B for electrons of initial energy 0.1-100 keV. Details of the calculation are presented, as well as a selection of results. The frequency distributions of energy deposition events per gray per target, placed at random in a homogeneous aqueous medium, are given for uniform irradiation with monoenergetic electrons of various energies. The frequency distributions have been used to predict the initial biophysical parameters such as relative effectiveness for initial damage. These suggest that the final biological effects which depend on complex local damage may show substantial variations in biological effectiveness for different low linear energy transfer radiations, whereas those that depend on simple local damage may not.

Chromatin↗

PubMed1991

Track structure analysis illustrating the prominent role of low-energy electrons in radiobiological effects of low-LET radiations.

Monte Carlo track structure methods have been used to illustrate the importance of low-energy electrons produced by low-LET radiations. It is shown that these low-energy secondary electrons contribute substantially to the dose in all low-LET irradiations and are particularly efficient at producing highly localized clusters of atomic damage which may be responsible for a major part of the biological effectiveness of low-LET radiations. The data generated by Monte Carlo track structure techniques and by earlier semi-analytical methods based on the LET concept have been compared in terms of cumulative and differential fractions of total dose absorbed as a function of electron energy. The data show that low-energy secondary electrons account for up to nearly 50% of the total dose imparted to a medium when irradiated with electrons or photons.

Electrons↗

PubMed1989

Track structure analysis of ultrasoft X-rays compared to high- and low-LET radiations.

Monte-Carlo track structure simulations of ultrasoft X-rays, and of selected low- and high-LET radiations for comparison, have been used to obtain statistically valid frequency distributions of energy deposition in small subcellular targets which resemble the dimensions of short segments of DNA, nucleosomes and short segments of chromatin fibre. It is found that in all cases large numbers (approximately 10(3] of direct energy deposition events occur in these targets in a single mammalian cell irradiated with 1 Gy of any of these radiations. In almost all cases the numbers of energy depositions of substantial size (say, approximately greater than 100 eV in a DNA segment, approximately greater than 300 eV in a nucleosome or approximately greater than 800 eV in a segment of chromatin fibre) are also quite large, being approximately 10 to 100 per cell per Gy. It seems clear therefore that the direct effects of radiation on macromolecules must be considered in assessing the biological effects of any ionizing radiations on mammalian cells. The calculations also show that high-LET radiations can produce uniquely large energy depositions in the targets, such as are virtually unachievable by any of the other radiations; this allows the possibility of unique biochemical and cellular damage by high-LET radiations. At any realistic dose for mammalian cells, virtually all the energy depositions in these targets, from all the radiations, are due to single independent tracks; the multi-track component is negligibly small. The absolute numbers of energy depositions of approximately greater than 100 eV in DNA segments in a cell are similar to experimentally measured numbers of DNA double-strand breaks, but both these sets of numbers are one or two orders of magnitude larger than the numbers of lethal events produced in mammalian cells. The frequency of threshold energy of approximately 120 eV in a DNA segment correlates reasonably well with the relative biological effectiveness of ultrasoft X-rays and low-LET radiations for relatively radioresistant cells, but a lower threshold energy may be required for other, more sensitive, cells.

Alpha Particles↗

PubMed1989

Calculation of initial yields of single- and double-strand breaks in cell nuclei from electrons, protons and alpha particles.

A model of the DNA and electron and ion track structure computer codes are used to model damage in the DNA by direct action. This damage is converted into single-strand breaks using the method described by Charlton and Humm (1988) in which a minimum energy deposited in a critical volume of the DNA is correlated with the production of single-strand breaks. It is then assumed that if these single-strand breaks lie on opposite strands and are separated by less than a few base pairs they produce double-strand breaks. Absolute yields of both single- and double-strand breaks expressed in breaks/Gy-dalton are calculated and compared to measured yields. Good agreement is obtained for single-strand breaks while the calculated yields for double-strand breaks are greater than those measured.

Alpha Particles↗

PubMed1989

Energy deposition in small cylindrical targets by ultrasoft x-rays.

A Monte Carlo technique has been employed to calculate the energy deposition events in small cylindrical targets (less than or equal to 100 nm), including sizes which represent the DNA duplex, nucleosome and chromatin fibre, by simulated electron tracks from C (278 eV), A1 (1487 eV) and Ti (4509 eV) characteristic ultrasoft x-rays in water. Detailed examples of input data tables for the generation of electron tracks produced from the x-ray photon interactions are presented. Frequencies of energy deposition events per gray for target sizes from 1 to 100 nm are given and comparisons have been made with radiations of different qualities.

Chromatin↗

PubMed1987

Physical mechanism for inactivation of metallo-enzymes by characteristic X-rays: analysis of the data of Jawad and Watt.

Table 1 summarizes the mean numbers of events and interactions of various types which we calculate to occur per single dihydro-orotic dehydrogenase enzyme when irradiated in solution with D37 = 99 Gy of 8.04 keV X-rays under the experimental conditions of Jawad and Watt (1986). There are clearly many orders or magnitude too few direct interactions of X-ray photons, or electrons, with the enzymes for these processes to be responsible for the mean of one inactivating event per enzyme which must occur at the D37 dose. Jawad and Watt (1986) concluded that the enzyme inactivation was predominantly due to direct interaction of an X-ray photon with a non-metal atom of the enzyme, but our analysis shows that this is not possible by five orders of magnitude. Of the possible mechanisms (a)-(d), the only one which remains feasible in this experimental system is the indirect action of radiolysis products from the solution (d). Diffusion distances of the order of 0.1 micron may be quite adequate for such inactivation. The situation would be very different for enzymes or other molecules within mammalian cells where diffusion distances are very much smaller (probably of the order of a few nanometres). Our analysis leaves unexplained the fairly small (20 per cent) change in effectiveness reported by Jawad and Watt (1986) for X-ray energy above, as compared to below, the K-absorption edge of Fe. The experimental observation is directly dependent on the accuracy of the dosimetry at these two energies; we have made no attempt to evaluate this.

Dihydroorotate Oxidase↗

PubMedDate not supplied

The mysteries of telomere structure and recognition: could radioprobing help?

PURPOSE: Telomeres are specialized DNA-protein complexes found at the ends of eukaryotic chromosomes. In normal somatic cells these become shorter with each cell division and appear to control their replicative lifespan. However almost all tumours show activation of the enzyme telomerase, a specialised reverse transcriptase/DNA polymerase, that can add new telomeric repeats to the ends of chromosomes and this appears to be a key factor in the cell immortalization process. Consequently there is much current interest in the potential for inhibitors of telomere extension in the treatment of cancer. Several groups have found that it is possible to produce inhibitory molecules that target the telomeric repeat (substrate) DNA rather than the telomerase enzyme itself. This is thought to work because it has been found that in vitro, these DNA sequences can fold up into a four-stranded (quadruplex) structure that the drugs recognise and stabilize, but which is not recognised by the enzyme. However, while medicinal chemists continue to base rational design programs on this hypothesis, there is currently very little evidence that these structures form in vivo, and that in vivo the drugs work by binding to them. To have incontrovertible evidence of where and how these telomerase inhibitors and DNA interact is therefore a pressing concern for a basic understanding of their mechanism of action and effective drug development. MATERIALS AND METHODS: Radioprobing represents a valuable new approach to the study of DNA structures. Recently we have shown through computer simulations of radioprobing that the technique is a remarkably sensitive probe of quite fine details of DNA conformation. Here we report on our simulations of the binding of a radiolabelled telomerase inhibitor, related to a class of novel inhibitors under development at Nottingham, to a variety of possible structures for telomeric DNA. RESULTS AND CONCLUSIONS: The predicted cleavage patterns prove to be very sensitive to the DNA structure, and the mode of binding of the drug. These results suggest that radioprobing experiments should be able to provide unambiguous evidence as to the 'true' nature of the telomere-drug complexes, and so aid the rational design programme.

Animals↗