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.

Pre-existent humoral antibody to adenovirus potentially confounds human clinical trials involving intravascular administration of adenovirus. Using the LNCaP prostate cancer xenograft model in BALB/c nu/nu mice and the prostate-specific attenuated replication-competent adenovirus (ARCATM) CN706, we developed an animal model that systematically controls both the dose of intravascularly administered adenovirus and the titer of the pre-existent anti-Ad5 antibody, and then measures the virus-induced toxicity as well as antitumor activity. We prepared hyperimmune sera to adenovirus in rabbits, passively injected the purified rabbit anti-Ad5 antibody into tumor-bearing mice, and established measurable humoral anti-Ad5 antibody titers. CN706 was intravenously injected into the tail vein of animals 24 hr after passive anti-Ad5 antibody administration. In the absence of pre-existent antibody, the lethal dose (LD100) for BALB/c nu/nu mice was 2.5x10(11) CN706 particles, whereas 1x10(11) CN706 particles was not lethal. However, in the presence of a 1:80 pre-existent titer of Ad5 neutralizing antibody (NAb), intravenous injection of 5x10(11) CN706 particles was no longer lethal. In addition, pre-existent antibody also prevented antitumor activity in a dose-dependent manner: 1x 10(11) CN706 particles prevented LNCaP xenograft tumor progression, but antitumor activity was eliminated by a pre-existent 1:80 NAb titer. These results led us to propose transient removal of pre-existent adenovirus antibody by immunoapheresis. An affinity column of cloned virus capsid proteins was constructed that was able to specifically remove adenovirus antibody from human clinical serum samples. A 5-min disposable immunoassay was also developed to monitor the level of pre-existent antibody in sera before and after immunoapheresis. Clinically, this approach may enable controlled clinical studies of intravenously administered adenovirus in patients with pre-existent anti-adenovirus antibody.

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.

Two sources of individual Auger electron spectra and an electron track code were used with a simple model of the DNA to successfully simulate the single-strand DNA breakage measured by Martin and Haseltine (1981). The conditions of the calculation were then extended to examine patterns of single-strand breaks in both strands of the DNA duplex to score double-strand breaks. The occurrences of five types of break were scored. The total number of double-strand breaks (dsb) per decay at the site of the decay was 0.90 and 0.65 for the different Auger electron spectra. It was shown that for mammalian cells an additional source of double-strand breaks from low LET radiation added approximately 0.17 dsb/decay to each, giving a final total of 1.07 and 0.85 dsb/decay for mammalian cells depending on the electron spectrum. Further is is shown that the energy deposition in the DNA from the iodine decay is very complex, with a broad range of energy depositions and products. Even for a particular energy deposited in the DNA different types of strand break are produced. These are identified and their probabilities calculated.

The energy imparted to biological tissue after the decay of incorporated Auger emitters stems from two sources: (a) energy deposition by the Auger and Coster-Kronig electrons and (b) the charge potential which remains on the multiple ionized atom after the end of the cascade. For the numerical assessment of both the kinetic energy of the released electrons and the charge potential, a new and--for purposes of microdosimetry--precise method is presented. Based on relativistic Dirac-Fock calculations and a rigorous bookkeeping, this method provides a perfect energy balance of the considered atomic system when applied to Monte Carlo simulations of Auger cascades. By comparing the results for charge distribution for krypton and iodine with experimental data and the electron spectrum of 125I with theoretical data, it can be shown that the approach followed in this work is reasonable and appropriate for the determination of the energy deposited by incorporated Auger emitters in small volumes of condensed matter. The total energy deposited by 125I in a volume of 20-nm diameter is 2.03 keV which is made up by multiple ionization (1.07 keV) and energy deposition by the emitted Auger electrons (0.96 keV).

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Track structure techniques are applied to calculate energy depositions in cylindrical targets 20 A in diameter (simulating the DNA duplex) containing, or near, 125I decays. Two problems are examined: (1) The possible effects of incorporated versus nonincorporated 125I are evaluated; (2) the extent of the radiological damage along the DNA is described and discussed for individual decays taking place in the DNA. The results of three different calculations are presented: (1) The distribution of the total energy deposited in the target per decay: Here it is shown that the 125I decays deposit considerably more energy than 5-MeV alpha particles when the decay occurs on the central axis of the cylinder. When the decay occurs at 40 A from the axis, the energy depositions are small and infrequent, showing that the iodine decay must occur within this distance to produce a high LET-like effect. (2) The distribution of average energy depositions around a curved cylinder simulating the DNA duplex encircling the nucleosome: There is a rapid decrease in the energy deposited in elements (of size resembling a base pair) away from the location of the decay. At approximately 17 A (approximately 5 bp) from the decay the mean energy deposited in an element is reduced by a factor of 10. (3) The energy deposited in individual elements of the cylinder is presented for single decays: The smooth decrease in average energy depositions with distance from the decay ((2) above) is not reflected in individual decays.

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.