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PubMed1979

Transformation of mammalian cells by alpha particles.

Mammalian cells in culture have been shown here for the first time to be transformed by alpha irradiation. Mouse embryo (C3H 10T1/2) cells were transformed with 5.6 MeV alpha particles from a Tandem Van de Graaff machine. Malignant tumours were induced following inoculation of the transformed cells into syngeneic hosts. Unirradiated control cells failed to produce tumours. The morphology of the transformed foci was similar to that obtained by X-rays and chemicals but different from virally transformed cells. The transformation frequency increased approximately as the cube of the dose to a maximum of about 4 per cent ofthe surviving cells which occurred between 1.5 and 2.5 x 10(7) alpha particles per cm2 (205-342 rad). It appears that alpha particle irradiation may exert a direct effect on the genome of the cell to produce malignancy without any external immunological or hormonal influences.

Alpha Particles↗
PubMed1990

Alpha-particles induce preneoplastic transformation of rat tracheal epithelial cells in culture.

To characterize the potential role of high-l.e.t. radiation in respiratory carcinogenesis, the cytotoxic and transforming potency of 5.5 Me V alpha-particles from electroplated sources of 238Pu were determined using primary cultures of rat tracheal epithelial cells. The alpha-particle response was compared to the effects of 280 kVp X-rays and of the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine. Increasing the alpha-particle dose caused an exponential decrease in survival with a D37 of 1.6 Gy. X-rays also caused a dose-dependent decrease in survival (D37 = 3.6 Gy) but the survival curve had a significant shoulder. The RBE for cell killing by alpha-particles versus X-rays varied with dose, and ranged between 4 and 1.5 for alpha doses in the range 0.2-4 Gy. At equally toxic doses (relative survival 0.18-0.2), all three agents induced similar frequencies of preneoplastic transformation. For preneoplastic transformation induced by doses of alpha- and X-radiations giving 80 per cent toxicity, an alpha RBE of 2.4 was derived. The similar RBEs for cell killing and for preneoplastic transformation suggest an association between the type or degree of radiation-induced damage responsible for both cell killing and cell transformation.

Alpha Particles↗
PubMed1992

Direct comparison between protons and alpha-particles of the same LET: I. Irradiation methods and inactivation of asynchronous V79, HeLa and C3H 10T1/2 cells.

A direct comparison was carried out of the biological effectiveness of protons and alpha-particles of the same linear energy transfer (LET) under identical conditions with a variety of in vitro biological systems. Monolayers of mammalian cells were irradiated with accelerated beams of protons (1.2 and 1.4 MeV) and alpha-particles (30 and 35 MeV) corresponding to LETs of 23 and 20 keV microns-1 for each particle type. For V79-4 cells it was observed that the linear term of the dose-response for cell inactivation by protons was significantly greater than that for alpha-particles of the same LET. For HeLa and HeLa S3 cells, also, the linear term appeared to be greater for protons, but this was not observed with more limited data for C3H 10T1/2 cells. The result for V79 cells is in agreement with the report of Belli et al. (1989) who observed that the biological effectiveness of protons rose sharply between 17 and 30 keV microns-1 in strong contrast to alpha-particles which reached a peak effectiveness at greater than 100 keV microns-1. These results place new constraints on the biologically relevant features of the microscopic structure of radiation tracks, and have implications for the mechanistic and practical comparison between radiations.

Alpha Particles↗
PubMed1988

Alpha-particle-induced cancer in humans.

Updated information is given on alpha-particle-induced cancer in persons internally exposed to 222Rn progeny, Thorotrast, long-lived 226Ra and 228Ra, and short-lived 224Ra. The lung cancer risk to persons breathing 222Rn progeny in the indoor air of offices, schools, and homes is of increasing concern. About half of the recent deaths among the German Thorotrast patients have been from liver cancer. Animal studies indicate that the liver cancer risk from Thorotrast is mainly from its radioactivity and that the risk coefficient for the Thorotrast patients can be used provisionally for other alpha emitters in the human liver. Six skeletal cancers have occurred in persons with average skeletal doses between 0.85 and 11.8 Gy from 226Ra and 228Ra. In the low-dose German 224Ra patients, two skeletal sarcomas have occurred at about 0.7 Gy compared to about six cases predicted by results from 224Ra patients at higher doses. The minimal appearance time for radiation-induced bone sarcomas in humans is about 4 y. Following brief irradiation, the vast majority of induced bone sarcomas are expressed by about 30 y. Recent evidence against the "practical threshold" hypothesis is given. With the downward revision of neutron doses to the atomic-bomb survivors, the follow-up of persons exposed to alpha particles may be the best opportunity to evaluate directly the effects of high LET radiation on humans.

Alpha Particles↗
PubMed1989

[Estimation of the energy fraction emitted by alpha particles in the mineralized part of trabecular bone which is absorbed in the bone marrow].

The cells at particular carcinogenic risk in the skeleton are haematopoietic stem cells of the marrow, which are predominantly distributed throughout the haematopoietic marrow within the trabecular bone. The Monte Carlo method for estimating the fraction of the energy of alpha particles emitted in a volume of the mineral part of the bone which is deposited in the marrow is described. The relationship between the absorbed fraction (AF) of the alpha particles and their energy was found to be linear. AF (Red Marrow----Trabecular Bone) is calculated to be 0.016 for the radionuclides emitting 3 MeV alpha particles and 0.080 for those emitting 8 MeV alpha particles. As radionuclides are for purposes of bone dosimetry dichotomously classified as surface and volume seekers, the estimation of energy deposition in the skeletal target organs can be highly dependent on this classification because of complicated geometric relationships between the source and target regions.

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↗
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↗
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↗
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↗
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↗
PubMed1992

Transmission of chromosomal instability after plutonium alpha-particle irradiation.

When investigating the biological effects of ionizing radiation on the haemopoietic system, a confounding problem lies in possible differences between the biological effects of sparsely ionizing, low linear energy transfer radiation such as X-, beta- or gamma-rays, and densely ionizing, high linear energy transfer radiation such as alpha-particles. To address this problem we have developed novel techniques for studying haemopoietic cells irradiated with environmentally relevant doses of alpha-particles from a plutonium-238 source. Using a clonogenic culture system, cytogenetic aberrations in individual colonies of haemopoietic cells derived from irradiated stem cells have been studied. Exposure to alpha-particles (but not X-rays) produced a high frequency of non-clonal aberrations in the clonal descendants, compatible with alpha-emitters inducing lesions in stem cells that result in the transmission of chromosomal instability to their progeny. Such unexpected instability may have important implications for radiation leukaemogenesis.

Alpha Particles↗
PubMed1991

The dose-dependent fragmentation of chromatin in human fibroblasts by 3.5-MeV alpha particles from 238Pu: experimental and theoretical considerations pertaining to single-track effects.

The technique of premature chromosome condensation (PCC) was used to examine the dose-response relationship for the production of interphase (G0) chromosome fragments in noncycling normal human fibroblasts following exposure to 238Pu alpha particles, with special emphasis on the low-dose region. The dose response was convincingly linear from 0.2 to 3.0 Gy. Analysis of further data collected over a dose range of 1.1 to 22.4 cGy provided no evidence of deviation from linearity in this low-dose region. The fact that this lower dose range extends into the region where single-particle effects are dominant suggests that a linear extrapolation of this response from higher to lower doses is valid. Ratios of coefficients for the induction of fragments produced by 238Pu alpha particles versus 60Co gamma rays gave an RBE of 2.34 +/- 0.09. Distributions of fragments among 60Co gamma-irradiated cells were consistent with a Poisson expectation of random damage. In contrast, overdispersion appeared to be a general feature of 238Pu alpha-particle-induced fragmentation, a phenomenon explainable under the assumption that single-particle traversals are capable of producing multiple PCC fragments. Data obtained were used to estimate practical and theoretical lower-dose limits of detection of initial chromatin breaks provided by current PCC methodology.

Alpha Particles↗
PubMed1992

The development of A [211At]-astatinated endoradiotherapeutic drug: Part I. Localization by alpha-particle autoradiography in a murine tumor model.

Alpha-particle track autoradiography has been used to define the in vivo cellular and intracellular distribution of radioactivity from the potential high linear energy transfer endoradiotherapeutic drug, 6-[211At]-astato-2-methyl-1,4-naphthoquinol bis(diphosphate) in tumor and relevant critical normal tissues of mice bearing a transplanted murine rectal carcinoma. A strikingly selective uptake of this compound into tumor cells, particularly into specific tumor cell nuclei, has been demonstrated. Its localization in certain tumor cells appears to depend on the presence of an onco-product, in this case an alkaline phosphatase isoenzyme, which is synthesized in some tumor cells and to which the compound targets. In curable tumors, it selectively concentrates in cells which may be regarded as tumor stem cells. There is low uptake into normal cells, particularly those in bone marrow, colon, and lung, where its sequestration is mainly extranuclear.

Alkaline Phosphatase↗
PubMed1992

Transformation of C3H 10T1/2 cells with 4.3 MeV alpha particles at low doses: effects of single and fractionated doses.

Oncogenic transformation of C3H 10T1/2 cells was determined after exposure to graded doses of 4.3-MeV alpha particles LET = 101 keV/microns. The source of alpha particles was 244Cm and the irradiation was done in an irradiation chamber built for the purpose. Graded doses in the range of 0.2 to 300 cGy were studied with special emphasis on the low-dose region, with as many as seven points in the interval up to 10 cGy. The dose-effect relationship was a complex function. Transformation frequency increased with dose up to 2 cGy; it seemed to flatten at doses between 2 and 20 cGy but increased again at higher doses. A total of 21 cGy was delivered in a single dose or in 3 or 10 equal fractions at an interval of 1.5 h. An inverse dose-protraction effect of 1.4 was found with both fractionation schemes. Measurements of the mitotic index of the population immediately before the various fractions revealed a strong effect on the rate of cell division even after very low doses of radiation. Mitotic yield decreased markedly with the total dose delivered, and it was as low as 50% of the control value after 4.2 cGy and 20% after 14 cGy with both fractionation schemes.

Alpha Particles↗
PubMed1992

Direct comparison of biological effectiveness of protons and alpha-particles of the same LET. III. Initial yield of DNA double-strand breaks in V79 cells.

The results reported form part of a series of experiments to substantiate and extend the findings by Belli et al. (1989) that protons are more biologically effective at cell killing than alpha-particles of the same LET. The irradiations were carried out using the Variable Energy Cyclotron (VEC) at the Harwell Laboratories. V79-4 Chinese hamster cells were exposed to alpha-particles and protons with LETs of 20 and 23 keV microns-1 in the dose range 40-150 Gy. X-rays were also used for comparison. Two methods were used for measurement of initial DNA double-strand breaks: sedimentation and DNA precipitation assays. The dose-response relationships were found to be well fitted by straight lines in all cases. With the sedimentation assay a slightly lower yield of dsb was found from protons than from alpha-particles of the same LET. The yield from X-rays was not significantly different from either. The precipitation assay showed similar yields of DNA damage from both particle types but significantly higher yields from X-rays. This may reflect a difference in the type of lesions scored by the two methods. Since the initial amount of dsb does not account for the observed differences in cellular response to radiations of different qualities, it is likely that these are related to the nature of the dsb (affecting reparability) or to the occurrence of other types of molecular damage.

Alpha Particles↗
PubMed1992

Chromosome damage induced by high-LET alpha-particles in plateau-phase C3H 10T1/2 cells.

Chromosome aberrations induced by X-rays and alpha-particles (LET = 177 keV/microns) were observed at the first mitosis in C3H 10T1/2 cells released from density-inhibited cultures. X-radiation induced more chromosome exchanges than breaks (71% vs 27% of total aberrations), while a predominance of breaks (63%) was observed after alpha-irradiation. A linear-quadratic dose-response relationship was obtained for X-rays, while that for alpha-particles was linear. The RBE values for total aberration induction (ranging from 5.1 at low doses to 4.4 at high doses) were very similar to the RBE for cell killing (from 5.2 to 4.3). The RBE for dicentric induction (approximately 2) was much lower than the RBE for the induction of both breaks (from 7 to 6) and interstitial deletions (from 9 to 7). This behaviour supports the hypothesis that chromosome deletions play a major role in the malignant transformation of 10T1/2 cells. A high correlation between cell killing and number of acentric fragments per cell was found. The number of acentrics/cell at the mean lethal dose was about 1.4. This number was reduced to 1.0 when asymmetrical interchanges, which generally result in very small deletions, were subtracted from acentrics. It could be hypothesized that very small deletions could not impair cell survival. However, an alternative hypothesis related to the aneuploid state of C3H 10T1/2 cells can be formulated. Robertsonian translocations were also observed at the first mitosis. The dose-response curve of these translocations appears to be very similar to the dose-response curve for induction of sister chromatid exchanges (observed at the second mitosis) reported by other authors studying the same cell line. This similarity could indicate a general mechanism of action of radiation on the process of recombination of genetic material.

Alpha Particles↗
PubMed1990

The rejoining of DNA double-strand breaks following irradiation with 238Pu alpha-particles: evidence for a fast component of repair as measured by neutral filter elution.

The induction and repair of DNA double-strand breaks (DSB) following exposure to 238Pu alpha-particles was examined in V79-379A cells. The technique of neutral filter elution was used in these investigations at both pH 9.6 and pH 7.2. The initial dsb yield was found to be similar to that seen after 250 kVp X-ray or 2.3 MeV neutron exposure. However, the pattern of dsb rejoining after alpha-particle irradiation did not follow that seen after X-rays or neutrons. A very fast initial component, complete within 2 min of incubation following irradiation, removed 70 per cent of the dsb seen after 40 Gy alpha-particles; very little slow rejoining was seen. This contrasts sharply with the dsb rejoining seen after X-ray or neutron exposure, and presumably reflects the differences in the nature of the dsb induced and the way they are repaired.

Animals↗