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PubMed2005

Melanoma therapy via peptide-targeted {alpha}-radiation.

PURPOSE: The therapeutic efficacy of a unique melanoma-targeting peptide conjugated with an in vivo generated alpha-particle-emitting radionuclide was evaluated in the B16/F1 mouse melanoma animal model. alpha-Radiation is densely ionizing, resulting in high concentrations of destructive radicals and irreparable DNA double-strand breaks. This high linear energy transfer overcomes radiation-resistant tumor cells and oxygen effects resulting in potentially high therapeutic indices in tumors such as melanoma. EXPERIMENTAL DESIGN: The melanoma targeting peptide, 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-Re(Arg(11))CCMSH, was radiolabeled with (212)Pb, the parent of (212)Bi, which decays via alpha and beta decay. Biodistribution and therapy studies were done in the B16/F1 melanoma-bearing C57 mouse flank tumor model. RESULTS: (212)Pb[DOTA]-Re(Arg(11))CCMSH exhibited rapid tumor uptake and extended retention coupled with rapid whole body disappearance. Radiation dose delivered to the tumor was estimated to be 61 cGy/muCi (212)Pb administered. Treatment of melanoma-bearing mice with 50, 100, and 200 muCi of (212)Pb[DOTA]-Re(Arg(11))CCMSH extended their mean survival to 22, 28, and 49.8 days, respectively, compared with the 14.6-day mean survival of the placebo control group. Forty-five percent of the mice receiving 200 muCi doses survived the study disease-free. CONCLUSIONS: Treatment of B16/F1 murine melanoma-bearing mice with (212)Pb[DOTA]-Re(Arg(11))CCMSH significantly decreased tumor growth rates resulting in extended mean survival times, and in many cases, complete remission of disease. (212)Pb-DOTA-Re(Arg(11))CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.

Alpha Particles↗

PubMed1993

Energy deposition clusters in nanometer regions of charged-particle tracks.

Energy deposition clusters in the nanometer scale have been investigated systematically in electron, proton, and alpha-particle tracks. The mean absolute frequency distributions of ionization clusters in nanometer sites have been computed. For locally multiply damaged sites and especially for double-strand breaks, the threshold numbers of ionizations in a site of a given diameter necessary for their induction have been estimated. At least three to six ionizations localized in sites of 1 to 4 nm diameter, respectively, are required to produce the double-strand break.

Alpha Particles↗

PubMed1993

Induction of sister chromatid exchange as a function of charged-particle linear energy transfer.

Frequencies of sister chromatid exchanges (SCEs) were evaluated in chromosome spreads of CHO-AA8 cells at the second mitosis after irradiation with charged particles of 10, 40, 80, and 120 keV/microns. At each LET there was a dose-dependent increase in the frequency of SCEs. In contrast to the majority of end points where relative biological effectiveness increases as LET increases up to an optimum and then declines, it was found that the most biologically effective particles were protons at 10 keV/microns, followed by deuterons at 40 keV/microns, then alpha particles at 80 and 120 keV/microns. Nuclear cross-sectional areas of these cells were log-normally distributed with a mean of 77 microns 2. When induced SCEs per chromosome were related to charged particles per cell nucleus (down to a mean of 0.5 particles per nucleus), results at low fluences favored a linear relationship between SCEs and particles which was relatively independent of LET. These observations are not compatible with the origin of radiation-induced SCEs being DNA double-strand breaks and favor the notion that they may be consistent with DNA single-strand breaks.

Alpha Particles↗

PubMed1997

Molecular alteration of alpha-induced transformed Syrian hamster embryo cells.

Syrian hamster embryo (SHE) cells are irradiated by alpha particles emitted from Plutonium-238 in vitro. Transfection frequencies of donor DNA derived from passaged cells, including monocloned cells from 20th passage cells, after irradiation are parallel with their tumorigenicity of donor cells. After transformation, expressions of H-ras and c-myc genes are in the state of activation, which might be resulted from occurrence of mutation in H-ras gene and hypomethylation of c-myc gene respectively, even though no alteration was observed on their restriction fragment length polymorphisms (RELP) patterns of both genes. On the other hand, expression of p53 gene is also found to be in the state of activation in transformant, but no heavy staining of p53 protein appeared in the transformant-derived tumor with p53 specific McAb HD 200. This might be result from the partial deletion of p53 cDNA in transformant by reverse transcriptional polymerase chain reaction (RT-PCR). These results imply that activation of H-ras and c-myc genes coupled with inactivation of p53 tumor suppressor gene play important role in alpha particle-induced cell transformation.

Alpha Particles↗

PubMed1997

Mutagenic effects at HPRT locus induced in Chinese hamster ovary cells by thermal neutrons with or without boron compound.

CHO cells were exposed to thermal neutrons and their mutation frequency was determined. The Kyoto University Research Reactor (KUR), which has a very low level of contamination by gamma-rays and fast neutrons was used as a thermal neutron source. Cells were irradiated in the presence or absence of boric acid to determine mutation frequency and cell survival. Thermal neutron irradiation was 2.5 times as mutagenic as gamma-irradiation without boron. In the presence of boron, however, thermal neutron irradiation was from 4.2 to 4.5 times as mutagenic as gamma-irradiation. When the mutation frequency was plotted against the survival fraction, a higher degree of mutagenicity was observed in the presence than in the absence of boron. These results suggest that the enhancement of thermal neutron-induced mutation with boron is strongly associated with alpha-particles released by 10B(n, alpha)7 Li reaction.

Animals↗

PubMed2004

Pharmacokinetics, dosimetry, and toxicity of the targetable atomic generator, 225Ac-HuM195, in nonhuman primates.

UNLABELLED: Short-lived alpha-emitting isotopes individually conjugated to monoclonal antibodies have now reached human use, but little is still known about their toxicity. Use of antibody targetable (225)Ac nanogenerators is a new approach in the field of alpha-immunotherapy offering the advantage of a 10-d half-life (t(1/2)) and increased potency due to generation of 3 new atoms, yielding a total of 4 alpha-particles. However, the 3 alpha-emitting daughter elements generated have the potential for significant toxicity as these nuclides are no longer bound to the carrier IgG. METHODS: Cynomolgus monkeys were used to evaluate the toxicity of prototype (225)Ac nanogenerators. Monoclonal antibody HuM195 (anti-CD33) is the carrier for planned human clinical trials of (225)Ac; there are no CD33 sites in cynomolgus monkeys. In one experiment, 2 monkeys received a single intravenous dose of (225)Ac-HuM195 at 28 kBq/kg. This dose level is approximately the planned initial human dose. In another experiment, 2 animals received a dose escalation schedule of 3 increasing (225)Ac-HuM195 doses with a cumulative activity of 377 kBq/kg. The whole-blood t(1/2) of (225)Ac, ratios of (225)Ac to its ultimate alpha-emitting daughter nuclide (213)Bi, generation of monkey anti-HuM195 antibodies (MAHA), hematologic indices, serum biochemistries, and clinical parameters were measured. Monkeys were euthanized and examined histopathologically when the dose escalation reached toxicity. RESULTS: The blood t(1/2) of (225)Ac-HuM195 was 12 d, and 45% of generated (213)Bi daughters were cleared from the blood. MAHA production was not detected. Approximately 28 kBq/kg of (225)Ac caused no toxicity at 6 mo, whereas a cumulative dose of approximately 377 kBq/kg caused severe toxicity. In the cumulative dosing schedule, single doses of approximately 37 kBq/kg resulted in no toxicity at 6 wk. After approximately 130 kBq/kg were administered, no toxicity was observed for 13 wk. However, 28 wk after this second dose administration, mild anemia and increases of blood urea nitrogen and creatinine were detected. After administration of an additional 185 kBq/kg, toxicity became clinically apparent. Monkeys were euthanized 13 and 19 wk after the third dose administration (cumulative dose was 377 kBq/kg). Histopathologic evaluation revealed mainly renal tubular damage associated with interstitial fibrosis. CONCLUSION: (225)Ac nanogenerators may result in renal toxicity and anemia at high doses. The longer blood t(1/2) and the lack of target cell antigens in cynomolgus monkeys may increase toxicity compared with human application. Therefore, a dose level of at least 28 kBq/kg may be a safe starting dose in humans. Hematologic and renal function will require close surveillance during clinical trials.

Actinium↗

PubMed2001

Advancements in cancer therapy with alpha-emitters: a review.

PURPOSE: This synopsis attempts to shed light on the progresses made in the field of cancer therapy using alpha-particles. HURDLES AND PROGRESSES: The rationale of selection of radionuclides focusing on comparison of alpha- and beta-emitters, the hurdles and their solutions, and recent developments are addressed. The efforts made in the field of alpha-radioimmunotherapy of hematologic malignancies are emphasized. A good deal of progress has been achieved in the past decade, and preclinical studies with a variety of radioimmunoconjugates with astatine and bismuth radioisotopes (At-211, Bi-212, and Bi-213) have generated encouraging results, providing an impetus for future clinical trials. CONCLUSION: The onset of early clinical trials with alpha-emitters will hopefully enable the cancer researchers to come up with extremely effective and highly specific "smart bombs" to target cancer cells.

Actinium↗

PubMed2000

Self absorption of alpha and beta particles in a fiberglass filter.

Environmental air sampling uses fiberglass filters to collect particulate matter from the air and then a gas flow detector to measure the alpha and beta activity on the filter. When counted, the filter is located close to the detector so the alpha and beta particles emerging from the filter travel toward the detector at angles ranging from zero to nearly 90 degrees to the normal to the filter surface. The particles at small angles can readily pass through the filter, but particles at large angles pass through a significant amount of filter material and can be totally absorbed. As a result, counting losses can be great. For 4 MeV alpha particles, the filter used in this experiment absorbs 43% of the alpha particles; for 7.5 MeV alphas, the absorption is 13%. The measured beta activities also can have significant counting losses. Beta particles with maximum energies of 0.2 and 2.0 MeV have absorptions of 44 and 2%, respectively.

Absorption↗

PubMedDate not supplied

Radiation, the two-edged sword: cancer risks at high and low doses.

Diagnostic Radiology and Radiation Oncology represent beneficial uses of radiation. The possible price tag is that radiation can cause, as well as diagnose or cure, cancer. Cancer risks at high doses are well known from epidemiologic studies of the Japanese survivors. Risks at low doses must be extrapolated from the high-dose data. The standard-setting bodies recommend a linear no-threshold extrapolation, but this is controversial. A knowledge of mechanisms, while not replacing epidemiology as a source of radiation-induced cancer risks, may provide insights into the shape of the dose-response relationships, and therefore on the validity of the linear extrapolation. The spectrum of second malignancies in radiotherapy patients sheds some light on mechanisms. More useful are new experiments involving the single-particle microbeam; these have demonstrated a bystander effect, that is, biologic effects in cells that are not directly irradiated, as well as mutations in cells where the cytoplasm, but not the nucleus, has been traversed by an alpha-particle.

Alpha Particles↗

PubMed1983

PCC technique reveals severe chromatin lesions and repair in G2-arrested cells after alpha irradiation.

Exponentially growing Chinese hamster V79 cells were exposed to 4 MeV alpha particles emitted by an americium-241 source. The chromatin of cells arrested in G2 by alpha irradiation is severely damaged, though all cells were still capable to condensate their chromatin after fusion with mitotic cells. In addition to the common types of aberrations (breaks, gaps, dicentrics and exchanges) cells were found possessing one or more chromosomes with long stretches of undercondensed chromatin. Repair of these lesions was indicated by site-specific unscheduled DNA synthesis and by the observation that condensation of these regions improved during G2 arrest.

Alpha Particles↗

PubMed1988

Continuous monitoring for airborne alpha emitters in a dusty environment.

Disposal of radioactive wastes in underground facilities requires continuous monitoring for airborne radioactive materials, both on the surface and underground. In addition to a natural background of nonradioactive and radioactive aerosols, there may be a sizeable dust contribution from ongoing work such as mining and vehicular traffic. In the monitoring of alpha-emitting radionuclides, these aerosols may lead to self-absorption in the source and a deterioration of the energy spectrum of the detected alpha particles. In this paper, the influence of a realistic background aerosol on the performance of an alpha monitoring system is evaluated theoretically. It is shown that depositing alpha emitters and background aerosol on a surface for counting leads rapidly to a considerable loss of counts, a deterioration of the alpha spectra, an eventual saturation of the count rates, and interference from the natural background of Rn daughters.

Air Pollution, Radioactive↗

PubMed2001

Risks of fatal cancer from inhalation of 239,240plutonium by humans: a combined four-method approach with uncertainty evaluation.

The risk per unit dose to the four primary cancer sites for plutonium inhalation exposure (lung, liver, bone, bone marrow) is estimated by combining the risk estimates that are derived from four independent approaches. Each approach represents a fundamentally different source of data from which plutonium risk estimates can be derived. These are: (1) epidemiologic studies of workers exposed to plutonium; (2) epidemiologic studies of persons exposed to low-LET radiation combined with a factor for the relative biological effectiveness (RBE) of plutonium alpha particles appropriate for each cancer site of concern; (3) epidemiologic studies of persons exposed to alpha-emitting radionuclides other than plutonium; and (4) controlled studies of animals exposed to plutonium and other alpha-emitting radionuclides extrapolated to humans. This procedure yielded the following organ-specific estimates of the distribution of mortality risk per unit dose from exposure to plutonium expressed as the median estimate with the 5th to 95th percentiles of the distribution in parentheses: lung 0.13 Gy(-1) (0.022-0.53 Gy(-1)); liver 0.057 Gy(-1) (0.011-0.47 Gy(-1)); bone 0.0013 Gy(-1) (0.000060-0.025 Gy(-1)); bone marrow (leukemia), 0.013 Gy(-1) (0.00061-0.05 Gy(-1)). Because the different tissues do not receive the same dose following an inhalation exposure, the mortality risk per unit intake of activity via inhalation of a 1-microm AMAD plutonium aerosol also was determined. To do this, inhalation dose coefficients based on the most recent ICRP models and accounting for input parameter uncertainties were combined with the risk coefficients described above. The following estimates of the distribution of mortality risk per unit intake were determined for a 1-microm AMAD plutonium aerosol with a geometric standard deviation of 2.5: lung 5.3 x 10(-7) Bq(-1) (0.65-35 x 10(-7) Bq(-1)), liver 1.2 x 10(-7) Bq(-1) (0.091-20 x 10(-7) Bq(-1)), bone 0.11 x 10(-7) Bq(-1) (0.0030-4.3 x 10(-7) Bq(-1)), bone marrow (leukemia) 0.049 x 10(-7) Bq(-1) (0.0017-0.59 x 10(-7) Bq(-1)). The cancer mortality risk for all sites was estimated to be 10 x 10(-7) Bq(-1) (2.1-55 x 10(-7) Bq(-1))--a result that agrees very well with other recent estimates. The large uncertainties in the risks per unit intake of activity reflect the combined uncertainty in the dose and risk coefficients.

Administration, Inhalation↗

PubMed2005

Cancer radioimmunotherapy with alpha-emitting nuclides.

In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with beta-emitters for the treatment of refractory cases. The development of novel RIT with alpha-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with alpha-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of alpha-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an alpha-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with alpha-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of alpha-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies.

Alpha Particles↗

PubMed2005

Choosing an alpha radiation weighting factor for doses to non-human biota.

The risk to non-human biota from exposure to ionizing radiation is of current international interest. In calculating radiation doses to humans, it is common to multiply the absorbed dose by a factor to account for the relative biological effectiveness (RBE) of the radiation type. However, there is no international consensus on the appropriate value of such a factor for weighting doses to non-human biota. This paper summarizes our review of the literature on experimentally determined RBEs for internally deposited alpha-emitting radionuclides. The relevancy of each experimental result in selecting a radiation weighting factor for doses from alpha particles in biota was judged on the basis of criteria established a priori. We recommend a nominal alpha radiation weighting factor of 5 for population-relevant deterministic and stochastic endpoints, but to reflect the limitations in the experimental data, uncertainty ranges of 1-10 and 1-20 were selected for population-relevant deterministic and stochastic endpoints, respectively.

Alpha Particles↗

PubMed2002

Direct effect in DNA radiolysis. Boron neutron capture enhancement of radiolysis in a medical fast-neutron beam.

SècheThis paper is devoted to the study of the molecular basis of the boron neutron capture enhancement of fast-neutron radiotherapy. Plasmid DNA was irradiated with a medical fast-neutron beam in the presence of either (10)B or (11)B. The number of induced SSBs and DSBs was much higher in samples containing (10)B compared to (11)B. The additional breaks are attributed to the nuclear reaction (10)B(n, alpha)(7)Li induced by the capture by (10)B of thermal neutrons produced in the medium by scattering and slowing down of neutrons. Irradiation in the presence of DMSO (OH radical scavenger) allows the number of nonscavengeable breaks to be determined. The ratio DSB/SSB is within the range of those observed with heavy ions, in good agreement with the hypothesis that the additional breaks are due to alpha particles and recoil lithium nuclei. The simulation of the energy deposition along the paths of the alpha and (7)Li particles allows the calculation of core and penumbra track volumes. Further, the number of plasmids encountered by the core and the penumbra was evaluated. Their number was compared to the nonscavengeable additional breaks. Since the two sets of values are of the same order of magnitude, we conclude that the nonscavengeable additional SSBs and DSBs could be due to direct effects.

Alpha Particles↗

PubMed1999

Comment on the use of GOES solar proton data and spectra in solar proton dose calculations.

There is a need to understand the calibration and response of the GOES solar particle detectors since the GOES data are being used to evaluate high energy solar particle events. We share some of our experience in utilizing these data in the analysis of solar particle ground-level events (GLEs). For the 29 September 1989 event, we have evaluated the solar proton and alpha particle spectral characteristics throughout the event. The results show that the solar cosmic ray spectrum is extremely hard at low energies with the magnitude of the slope increasing with increasing energy and with time.

Alpha Particles↗

PubMed1993

Determining the specific alpha activity of thick sources using a large-area zinc sulfide detector.

A simple method using a large-area zinc sulfide detector to determine the total specific alpha activity of thick sources is presented. A previous paper shows how the linear absorption properties of weightless alpha sources can be applied to thick sources placed in direct contact with a varying thickness of window material. A quadratic relationship between the detector response and absorber thickness was derived for sources whose thickness exceeds the range of the alpha particle. The coefficient of the linear term in the quadratic expression is used to calculate the total specific alpha activity of a source in contact with the window of the detector. This relationship is tested by obtaining alpha absorption data from solid sources of known specific alpha activity, fitting the data to the theoretical relationship and comparing the results to the known activities.

Alpha Particles↗

PubMed1996

Alpha- and beta-emitting radiolanthanides in targeted cancer therapy: the potential role of terbium-149.

The efficacy of systemic cancer therapy rests on the ability of a toxin to be preferentially located in cancer cells, so that cancer cell kill is maximized and normal tissue spared. This requires that the lifetime of the toxin be less than the lifetime of the carrier in the body, effectively ruling out chemical toxins, as they remain effective until excreted from the body. The requirement of localization of dose to the cancer cell makes radioactive beta-emitting radionuclides unattractive. Alpha-emitting radionuclides are much more appropriate toxins, as their efficacy depends on the high energy and short range of the alpha particles, and terbium-149 is shown to be the most efficacious of these. However, the merit of various alpha- and beta-emitting radionuclides depends on the stage and type of cancer. Recommendations are made with respect to the matching of the target cancer with required properties of the radiolabel and carrier.

Alpha Particles↗