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PubMed1995

The quality of DNA double-strand breaks: a Monte Carlo simulation of the end-structure of strand breaks produced by protons and alpha particles.

The quality of DNA damage induced by protons and alpha-particles of various linear energy transfer (LET) was studied. The aim was to single out specific lesions in the DNA molecule that might lead to biological endpoints such as inactivation. A DNA model coupled with a track structure code (MOCA-15) were used to simulate the lesions induced on the two helixes. Four categories of DNA breaks were considered: single-strand breaks (ssb), blunt-ended double-strand breaks (dsb, with no or few overlapping bases), sticky-ended double-strand breaks (with cohesive free ends of many bases), and deletions (complex lesions which involve at least two dsb within a small number of base pairs). Calculations were carried out assuming various sets of parameters characterizing the production of these different DNA breaks. No large variations in the yields of ssb and blunt- or sticky-ended dsb were found in the LET range between 10 and 200 keV/mu m. On the other hand, the yield of deletions increases up to about 100 keV/mu m and seems to reach a plateau at higher LET values. In the LET interval from 30 to 60 keV/mu m, protons proved to be more efficient than alpha-particles in inducing deletions. The induction of these complex lesions is thus dependent not simply on LET but also on the characteristics of the track structure. Comparison with RBE values for cell killing shows that this special class of dsb might play an important role in radiation-induced cell inactivation.

Alpha Particles↗
PubMed1976

Rapid appearance of transient secondary adrenocortical insufficiency after alpha-particle radiation therapy for Cushing's disease.

A 17-year-old women received 12,000 rads of alpha-particle radiation for the treatment of Cushing's disease. One day after the completion of therapy, the patient developed nausea, vomiting, headache, and postural hypotension. Laboratory evaluation demonstrated a marked fall of the previously elevated urinary 17-hydroxycorticosteroids (17-OHCS) and undetectable plasma cortisols. The urinary 17-OHCS transiently returned to supranormal levels but over a 2 1/2-week period decreased and then remained low. The patient also demonstrated a subnormal urinary aldosterone excretion in relation to plasma renin activity (PRA) during 10 mEq/24 h sodium restriction. The remainder of the endocrine evaluation was normal, suggesting that pituitary function otherwise remained intact. One and one-half years after alpha-particle therapy, the patients's urinary 17-OHCS were normal and responded normally to metyrapone. The relationship between urinary aldosterone excretion and PRA also was normal. It is postulated that there was an infarction of an ACTH secreting pituitary tumor leaving the remainder of the pituitary intact. Achronically elevated circulating level of ACTH with sudden loss of ACTH secretion appeared to have been responsible for the initial low urinary aldosterone as well as the low urinary 17-OHCS. This is the first reported case of a presumed pituitary tumor infarction in association with alpha-particle pituitary radiation.

17-Hydroxycorticosteroids↗
PubMed1994

Plutonium-catalyzed oxidative DNA damage in the absence of significant alpha-particle decay.

Plutonium is considered to be a carcinogen because it emits alpha particles that may result in the irradiation of stem cell population. In the present study we show that plutonium can also catalyze reactions that induce hydroxyl radicals in the absence of significant alpha-particle irradiation. Using the low specific activity isotope, 242Pu, experiments were performed under conditions in which chemical generation of hydroxyl radicals was expected to exceed the radiolytic generation by one hundred thousand-fold. The results showed that markers of oxidative DNA base damage, thymine glycol and 8-oxoguanine could be induced from plutonium-catalyzed reactions of hydrogen peroxide and ascorbate similarly to those occurring in the presence of iron catalysts. Plutonium-242, as a neutralized nitrate in phosphate buffer, was 4.8-fold more efficient than iron at catalyzing the oxidation of ascorbate at pH 7. The results suggest that plutonium complexes could participate in reactions at pH 7 that induce oxidative stress--a significant tumor-promoting factor in generally accepted models of carcinogenesis.

Alpha Particles↗
PubMed1992

Cellular kinetics, dosimetry, and radiobiology of alpha-particle radioimmunotherapy: induction of apoptosis.

Though clinical results for radioimmunoconjugate therapy of most common epithelial tumors have been disappointing, dramatic responses have been observed repeatedly in the treatment of high- and low-grade malignant lymphomas. This high clinical responsiveness after radioimmunoconjugate therapy sometimes appears to be out of proportion to the calculated radiation dose absorbed by the lymphoma tissue. Here we describe some key aspects of the kinetics, dosimetry, and cellular radiobiology of murine lymphoma cells exposed to 212Bi-radiolabeled alpha-particle-emitting immunoconjugates specific for the differentiation antigen Thy 1.2. Approximately 25 cell-bound alpha-particle-emitting immunoconjugates per target cell were required to reduce clonogenic survival by 90% (the radiobiological D10). Serial kinetic analyses of the antibody and radioisotope components of the immunoconjugates revealed significant levels of dechelation and up to 7.5% cellular internalization of the isotope. Cellular radiation dosimetry performed by Monte Carlo computer simulation of alpha-particle energy deposition patterns based on the observed radiopharmacokinetics showed that the D10 resulted from approximately four alpha-particle traversals through the nucleus, corresponding to an absorbed radiation dose of approximately 0.95 Gy to the cell nucleus. Electron micrographs and DNA gel studies of murine lymphoma cells undergoing radioimmunoconjugate therapy in vivo and in vitro demonstrated bizarre blebbing patterns, condensation of chromosomal material, and internucleosomal DNA fragmentation patterns characteristic of programmed cell death (apoptosis). We conjecture that the efficacy of radioimmunoconjugates against responsive cell types may be the result of passive DNA damage by ionizing radiation and the initiation of apoptosis in response to radioimmunotherapy.

Alpha Particles↗
PubMed1983

Lipid peroxidation by ultraviolet light and high energy alpha particles from a cyclotron.

High energy alpha-particles (approximately 16 MeV) and 254 nm ultraviolet light produced dose dependent linear increase of lipid hydroperoxides in the dried thin film state. For both types of radiation, an inverse dose-rate effect, i.e., a protracted radiation dose was more effective than a shorter, more intense one of larger size, was observed. Ultraviolet light (254 nm) produced higher yields of hydroperoxides in the aqueous liposomal suspension of lipid than in its dried thin film state.

Alpha Particles↗
PubMed1978

Energy dependence of W for alpha particles in N2, CO2, CH4, Ar, H2 and Rossi-type tissue-equivalent gases.

Average energy required to form an ion pair (W) was determined in N2, CO2, CH4, Ar, H2 and Rossi-type tissue-equivalent gas. Alpha particles from a 241Am source were used. W was determined at alpha energies of 5.37, 3.12, 1.08 and 0.46 MeV. The ratio of total ionisation produced (for fixed alpha particle energy) in experimental gas to that produced in argon was measured. This ratio was then multiplied by the previously determined W value for argon gas (26.29 eV per ion pair) to yield W for various experimental gases. Energy of the 241Am alpha particles was degraded by using air as an absorbing material. Empirical relations W = alpha + betaE-1/2 and W = alpha1 + beta1E-1 were fitted to the experimental data. Both functions fit reasonably well in the range 0.4--5.37 MeV. Below about 0.4 MeV the first function provides a better fit to the data of Boring et al. (1965).

Alpha Particles↗
PubMed1992

Induction of sister chromatid exchanges by extremely low doses of alpha-particles.

The induction of sister chromatid exchanges (SCE) was examined in Chinese hamster ovary cells irradiated in the G1 phase of the cell cycle with alpha-particles from a plutonium-238 source. A significant increase in the frequency of SCE occurred with doses as low as 0.31 mGy (31 millirads). Although 30% of the cells showed an increased frequency of SCE at this dose, less than 1% of cell nuclei were actually traversed by an alpha-particle. A dose of approximately 2.0 Gy was necessary to produce a similar increase in SCE by X-rays. These results indicate that genetic damage may be induced by low doses of alpha-radiation in cell nuclei not actually traversed by an alpha-particle. This phenomenon may have important implications in the estimation of risks of such exposures.

Alpha Particles↗
PubMed1994

Radioimmunotherapy of neoplastic meningitis in rats using an alpha-particle-emitting immunoconjugate.

Because of their short range and high linear energy transfer, alpha-particles may be particularly effective in the treatment of neoplastic meningitis. Monoclonal antibody 81C6 was labeled with alpha-particle-emitting 211At using N-succinimidyl3-[211At]astatobenzoate, and the efficacy and toxicity of this immunoconjugate were evaluated in an athymic rat model. Animals were given injections via a chronic indwelling catheter with 5 x 10(5) TE-671 human rhabdomyosarcoma cells and treated 8 days later with single intrathecal doses of either saline or 4-18 microCi of 211At-labeled specific 81C6 antibody or isotype-matched control 211At-labeled 45.6 antibody. In the first experiment, 4, 7, and 13 microCi 211At-labeled 81C6 produced statistically significant (P = 0.004-0.02) increases in median survival of 33, 29, and 51%, respectively, as compared with saline. Two of 10 animals receiving the 13-microCi dose lived for 6 months before being killed for histological analysis. In the second experiment, 12 microCi of 211At-labeled 45.6 did not increase median survival significantly relative to saline control, while 12 microCi of 211At-labeled 81C6 increased median survival by 113% (P < 0.005) and resulted in 33% apparent cures. Five of 10 animals receiving 18 microCi of 211At-labeled 81C6 survived until they were killed at 295 days. An additional study was performed in animals given intrathecal injections of 5 x 10(6) TE-671 cells and given a single dose of 18 microCi of 211At-labeled 81C6 or 211At-labeled 45.6. At this higher cell number, significantly prolonged survival was still seen for specific antibody as compared with saline (P < 0.001) and control antibody (P < 0.05). These results suggest that treatment with 211At-labeled monoclonal antibodies may be a valuable approach for neoplastic meningitis.

Alpha Particles↗
PubMed1990

Energy deposition by protons and alpha particles in spherical sites of nanometer to micrometer diameter.

Monte Carlo stimulated proton- and alpha-particle tracks in water vapor were used to develop an analytical function for calculating number distributions of ionizations induced in spherical sites. For charged particles crossing the site, Fermi-like functions were used to approximate the ionization distributions. Ionization event distributions due to particles passing outside the site were approximated with an exponentially decreasing function. The function parameters were calculated for protons and alpha particles in the energy range 0.3-5.0 MeV/amu and for site diameters of 1 to 1000 nm. The quality of fit obtained is very good for the particles, energy range and site diameters considered.

Alpha Particles↗
PubMed1994

Effects of in vitro alpha-particle irradiation on osteogenic bone marrow cultures.

Murine bone marrow contains osteogenic precursor cells that undergo differentiation during in vitro cultivation. In vitro these cells are potential target cells for alpha-irradiation-induced bone tumour formation. Under defined tissue culture conditions these differentiating cells were directly exposed to alpha-particle irradiation from the radon daughter 210Po. Po deposits in soft tissue and it was shown to be associated with marrow cells and with the extracellular marrow tissue formed in vitro. These differentiating marrow cultures showed high sensitivity to alpha-irradiation. Cell death was observed at 210Po concentrations in tissue culture medium (TCM) > 7 Bq 210Po/ml. At lower concentrations (between 1 and 5 Bq 210Po per ml TCM) proliferation was enhanced as measured by uptake of 3H-thymidine, also differentiation was stimulated as measured by alkaline phosphatase activity and incorporation of 3H-proline in newly synthesized collagen. At several times of culture, the association of 210Po with the extracellular matrix and cells was measured. These retention data enabled us to calculate the daily alpha-particle fluence. At 1 Bq 210Po present per ml tissue culture, a daily alpha-particle fluence as low as 3-6 per 1000 cells seemed very efficient in changing the expression of osteogenic differentiation of marrow cells.

3T3 Cells↗
PubMed1996

No association between p53 status and alpha-particle-induced chromosomal instability in human lymphoblastoid cells.

Previous work has demonstrated that alpha-particle irradiation of primary human bone marrow cells leads to the transmission of chromosomal instability in the descendants of the irradiated cell, although there is some interindividual variation. We have extended these studies to human EBV-transformed lymphoblastoid cell lines in order to establish an in vitro model system. The five cell lines analyzed, including one from a Fanconi anaemia patient, exhibited high levels of persistent chromatid aberrations up to approximately 40 cell generations after alpha-irradiation. The p53 status of the cell lines was defined according to whether cellular p53 levels were induced by irradiation, translocated to the nucleus and were able to bind a p53 DNA consensus recognition sequence in vitro. Together with the primary bone marrow cell studies, we conclude that alpha-particle induced chromosomal instability is independent of the p53 status of the cell as defined in these studies.

Alpha Particles↗
PubMed1996

Long-term in vivo transmission of alpha-particle-induced chromosomal instability in murine haemopoietic cells.

We have previously reported non-clonal cytogenetic aberrations in the clonal descendants of murine haemopoietic stem cells irradiated in vitro with alpha-particles. The data are consistent with a transmissible chromosomal instability induced in a stem cell resulting in a diversity of aberrations in its clonal progeny many cell divisions later. To determine whether this instability is transmissible in vivo, bone marrow cells obtained from the male mouse have been irradiated with alpha-particles in vitro and transplanted into female recipients. In the repopulated haemopoietic system we have observed persisting chromosomal instability up to 1 year post-transplantation. The findings demonstrate a long-lived effect of the alpha-particle-induced lesion in the donor repopulating stem cells.

Alpha Particles↗
PubMed1983

Interpretation of cytogenetic damage induced in the germ line of male mice exposed for over 1 year to 239Pu alpha particles, fission neutrons, or 60Co gamma rays.

The relative biological effectiveness (RBE) of 239Pu alpha particles, fission neutrons (0.85 MeV), and 60Co gamma rays has been evaluated for the induction of reciprocal chromosome translocations in spermatogonia and of chromosome/chromatid fragments and chromatid rearrangements in the primary spermatocyte of adult male B6CF1 mice. Age concurrency was maintained for both internal and external radiations which were delivered at about 1 rad/week for 239Pu (single intravenous dose of 10 microCi/kg), 0.67, 1.67, and 2.67 rad/week for neutrons, and 6.95, 17.4, and 32 rad/week for gamma rays for at least 60 weeks. In terms of frequency of translocations, the response to the alpha emitter was nonlinear (concave downward) with little dose-response predictability; to cumulative neutron exposures the response was linear, without evidence of a dose-rate effect; and to gamma radiation the responses were linear, and a significant dose-rate effect was seen. RBE estimates are variable. For translocations, the n/gamma ratio is between 10 and 24, depending upon weekly dose level, and the ratio is 1 or less for the alpha particle relative to the neutron. For fragments, the n/gamma ratio is 18 to 22, depending upon age factors, and alpha/n is 1.5. For chromatid rearrangements, n/gamma is 7 and alpha/n is essentially indeterminate, but much below one. The overall response to the alpha emitter is interpreted to be a complex function of (a) microdosimetric heterogeneity, (b) a nearly invariant deposition pattern in the gonad, (c) the high sensitivity of differentiating spermatogonia to cell killing, and (d) the capacity of stem cells in relatively radiation-free areas to progressively assume the major spermatogenic role.

Alpha Particles↗
PubMed1990

Induction of chromosomal aberrations and sister chromatid exchanges by alpha particles in density-inhibited cultures of mouse 10T1/2 and 3T3 cells.

We examined the dose-response relationships for the induction of cell killing, chromosomal aberrations and sister chromatid exchanges (SCE) by 220 kV X-rays and 5.3 MeV alpha particles from a 238Pu source. The cells were irradiated in density-inhibited, confluent cultures. The D0 values for the X-ray and alpha particle survival curves were 1.7 Gy and 0.7 Gy, and the extrapolation numbers 2.5 and 1.0, respectively, for mouse 3T3 cells. Chromosomal aberrations increased linearly with dose for alpha-radiation and roughly with the square of dose for X-rays in 3T3 cells. At 37 per cent survival, 1.0 chromosomal aberration per cell was induced by X-rays and 1.7 per cell by alpha-radiation, but the fraction of cells without aberrations was similar. In confluent holding recovery experiments there was a 50 per cent reduction in X-ray-induced aberrations during the first 4 h of confluent holding. No decline in alpha-induced aberrations was observed with holding times up to 24 h. The dose-response relationship for the induction of SCE by X-rays increased linearly with doses up to 100 cGy in both 3T3 and 10T1/2 cells, then declined, reaching nearly background levels after 400 cGy. The induction of SCE increased rapidly in these cell lines with doses of 2.5-5.0 cGy of alpha-radiation, then declined. The relative biological effectiveness (RBE) was 15-25 for the induction of SCE by low doses (2.5-5.0 cGy) of alpha particles.

Alpha Particles↗
PubMed1981

[Combined action of UV light and alpha particles on yeast cells of different genotypes].

Combined action of ultraviolet (UV) light and alpha-particles on yeast cells of different genotypes has been studied. Under combined action, after small doses of UV-light the oscillated changes of cell survival were registered for wild-type cells independent of the ploidy and the sequence of application of radiations. Additive effect of high doses of UV-light and ionizing radiation was expressed for strains incapable of the recovery of damages induced by ionizing radiation. For yeast cells possessing such a capability, the synergistic interaction of damages inflicted by high doses of UV-light and alpha-particles was noted. Possible reasons of the observed cell responses are discussed.

Alpha Particles↗
PubMed1997

Radon and lung carcinogenesis: mutability of p53 codons 249 and 250 to 238Pu alpha-particles in human bronchial epithelial cells.

Radon-222, a decay product of uranium-238 and a source of high linear energy transfer (LET) alpha-particles, has been implicated in the increased risk of lung cancer in uranium miners as well as non-miners. p53 mutation spectrum studies of radon-associated lung cancer have failed to show any specific mutational hot spot with the exception of a single study in which 31% of squamous cell and large cell lung cancers from uranium miners showed a p53 codon 249 AGGarg --> ATGmet mutation. Although the results of laboratory studies indicate that double-strand breaks and deletions are the principal genetic alterations caused by alpha-particles, uncertainty still prevails in the description of DNA damage in radon-associated human lung cancer. In the present study, we have evaluated the mutability of p53 codons 249 and 250 to alpha-particles in normal human bronchial epithelial (NHBE) cells using a highly sensitive genotypic mutation assay. Exposure of NHBE cells to a total dose of 4 Gy (equivalent to approximately 1460 working level months in uranium mining) of high LET alpha-radiation induced codon 249 AGG --> AAG transitions and codon 250 CCC --> ACC transversions with absolute mutation frequencies of 3.6 x 10(-7) and 3.8 x 10(-7) respectively. This mutation spectrum is consistent with our previous report of radon-associated human lung cancer.

Adolescent↗
PubMed1995

Genetic control of RBE of alpha-particles for yeast cells irradiated in stationary and exponential phase of growth.

Survival curves of S. cerevisiae wild type and rad 50, 51, 52 and 54 mutants in haploid and diploid strains were measured after gamma-ray and alpha-particle irradiation in stationary and exponential phase of growth. The values of RBE of high-LET radiation, defined as the ratio of the mean lethal doses after sparsely and densely ionizing radiations, were determined. A correlation between the RBE of alpha-particles and cell repair capacity was supported for stationary phase cultures. For the first time, it was shown for all strains studied that at exponential phase of growth the RBE of alpha-particle-induced survival was decreased in comparison with that for stationary cells. For most mutant cells RBE was close to unity, i.e. cell radiosensitivity was almost identical for both sparsely and densely ionizing radiation. Possible reasons for the observed radiation responses are discussed.

Alpha Particles↗