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PubMed1986

Animal studies of life shortening and cancer risk from space radiation.

The U.S. Air Force study of the delayed effects of single, total body exposures to simulated space radiation in rhesus monkeys is now in its 21st year. Observations on 301 irradiated and 57 age-matched control animals indicate that life expectancy loss from exposure to protons in the energy range encountered in the Van Allen belts and solar proton events can be expressed as a logarithmic function of the dose. The primary causes of life shortening are cancer and endometriosis (an abnormal proliferation of the lining of the uterus in females). Life shortening estimates permit comparison of the risk associated with space radiation exposures to be compared with that of other occupational and environmental hazards, thereby facilitating risk/benefit decisions in the planning and operational phases of manned space missions. Calculations of the relative risk of fatal cancers in the irradiated subjects reveal that the total body surface dose required to double the risk of death from cancer over a 20-year post exposure period varies with the linear energy transfer (LET) of the radiation. The ability to determine the integrated dose and LET spectrum in space radiation exposures of humans is, therefore, critical to the assessment of lifetime cancer risk.

Animals↗

PubMed1996

Damage to the photoreceptor cells of the rabbit retina from 56Fe ions: effect of age at exposure, 1.

Optic and proximate tissues of New Zealand white (NZW) rabbits at ages (approximately 3.5 years) near the middle of their median lifespan (5-7 years) were given 0.5-3.5 Gy of 465 MeV u-1 56Fe ions in the Bragg plateau region of energy deposition at a linear energy transfer (LET infinity) of 220 +/- 31 keV micrometer-1. Dose-dependent losses of retinal photoreceptor cells (rods) occurred until 1-2 years after irradiation, the period of this interim report. Similar cumulative losses of photoreceptor cells were seen during the period 1-2 years post-irradiation for rabbits given comparable exposures when young (6-9 weeks old). Since losses of photoreceptor cells at early times had not been determined previously, the current experiment, which was designed to simulate the responses of mature astronauts, redressed that deficiency.

Age Factors↗

PubMed1979

Potential for therapeutic gain similar to pions by daily combinations of neutrons and low-LET radiations.

Biological studies with negative pi mesons (pions) at the Los Alamos Meson Physics Facility (LAMPF) have shown a relatively constant reduction of shoulder of the survival curve for single cell cultures and relatively constant reduction in the no response region for multicellular tumor spheroids (MTS) with little change in sensitivity (or slope), in both single dose and fractionated experiments. In clinical studies, a trend toward therapeutic gain for pions has been demonstrated in patients treated at LAMPF, with marked, rapid turmor regression for relatively mild acute normal tissue injury and no untoward effects observed over 7 to 24 months. Since the pion beams used therapeutically at LAMPF are characterized by a small amount of high-linear-energy-transfer (LET) radiation (in the range 10 to 20%), it is hypothesized that pion radiation as compared to x-rays increased the differential tolerance to sublethal injury in favor of normal tissues, resulting in therapeutic gain. It is further proposed that the near simultaneous application of high-LET radiation (such as neutrons) and low-LET radiation (such as x-rays) might create a bilogical situation similar to that of pion treatment, potentially resulting in therapeutic gain, although without the added benefit of dose localization obtainable with pions.

Animals↗

PubMed1982

An interpretation of some biological results obtained in range-modulated negative pion beams.

Recent biological date show little change in relative biological effectiveness (RBE) across the peak region of range-modulated pion beams in contrast to previous works which showed increasing RBE with depth. These biological results are shown to be consistent with each other and with previously measured microdosimetric data. The differences are attributed to differences in the lateral spread of the beams. Large lateral distributions result in an increased dose as a result of neutrons emitted in pion "stars" an effect that is quantified using a high-energy neutron transport code. For a large beam which is of the type used in therapy, the neutron dose is as much as 50% of the total "star" dose and of the high linear energy transfer (LET) dose, this percentage increasing peak volume. Preliminary measurements are in agreement with the calculated results. The rapid increase in neutron dose with field size should be an important factor in pion treatment planning.

Animals↗

PubMed1984

211At radiocolloid therapy: further observations and comparison with radiocolloids of 32P, 165Dy, and 90Y.

We compared the therapeutic efficacy of alpha and beta emitting radiocolloids for the treatment of experimental malignant ascites. 211At is an almost pure alpha-emitter. As 211At-tellurium colloid, the dose survival curve is linear and extrapolates through the origin in a manner similar to other high linear energy transfer radiations. Doses of 25 microCi were curative. Less than curative doses showed a graded prolongation of median survival. In cured mice, long term histological changes were seen in thyroid tissue. Acute changes were seen in the gastrointestinal tract as early as 2 hr after radiocolloid administration; these changes reached a plateau at 6 hr and were essentially gone 36 hr later. By comparison, radiocolloids of the beta emitters 32P, 165Dy and 90Y were not curative, but relatively large doses did substantially prolong median survival. The doses for maximal effect were 150 microCi 32P-chromic phosphate, 8000 microCi ++165Dy-ferric hydroxide macroaggregates and 200 microCi 90Y-citrate. The most compelling reason for the increased therapeutic efficacy of 211At-tellurium colloid is the direct and densely ionizing character of the emitted alpha radiations.

Alpha Particles↗

PubMed1985

Therapeutic dosimetry for Cf-252 neutron brachytherapy of pelvic cancer.

252Cf (Cf) was used to treat tumors of the cervix and uterus with neutron brachytherapy (NT) in an ongoing clinical trial. Tandem and ovoids insertions were used and combinations of single and multiple applications along with high dose whole pelvic irradiation. Dosimetric analysis of treated cases for patterns of tissue dose were carried out. Tissue dose for Cf-NT was, in general, high for neutron components in the central pelvis only, and fell off rapidly with distance from the applicators. The majority and balance of therapeutic dose was contributed by low linear energy transfer (LET) high energy photon beam radiation to the whole pelvis. Comparison with fast neutron beam therapy (NBT) isodose curves showed that much more homogeneous neutron dose was delivered to the pelvic tumor and organs by NBT. Complication frequency has been reported to be higher for neutron beam therapy than for Cf-NT. It appears that the higher integral neutron biological dose to normal tissues for NBT compared to intracavitary Cf-NT probably contributed to the frequency of side effects.

Brachytherapy↗

PubMed1987

Enhancement of IUdR radiosensitization by low energy photons.

The effect of the photon energy on the radiosensitization produced by iododeoxyuridine (IUdR) was examined using Chinese hamster cells in vitro. Radiosensitization by IUdR was considerably higher for 60 keV photons from 241Am sources than for the 860 keV photons (average energy) from 226Ra sources, under continuous low dose rate conditions applicable to intracavitary brachytherapy (a dose rate of 0.57 Gy/hr). Also, IUdR radiosensitization was higher for 250 kV X rays than for 4 MV X rays under the acute exposure conditions used in external beam radiation therapy (dose rates of 1 to 2 Gy/min). These data support the hypothesis that photons with energies just greater than 32.2 keV, the K-absorption edge of iodine, are more effective in causing cell damage than are photons of other energies, because their absorption results in the production of Auger electron cascades and therefore in the production of high linear energy transfer (LET) radiations.

Americium↗

PubMed1987

A microdosimetric model of astatine-211 labeled antibodies for radioimmunotherapy.

Astatine-211 is an alpha-emitter with a short half-life (7.2 hr). This paper discusses the potential of 211At targeted by antibodies for tumor therapy and the possible advantage of 211At over beta- and gamma-emitting radionuclides such as 131I currently employed in the field of radioimmunotherapy. Since the longest range alpha-particle from 211At is only 67 microns and the rate of energy loss is high (track averaged linear energy transfer LT approximately 120 keV/micron), a disintegration of 211At produces a large and extremely localized deposition of energy. A Monte-Carlo model has been developed for studying the stochastic fluctuation of alpha-particle hits and energy deposition in cell nuclei in an attempt to determine the efficacy of 211At-labeled antibodies for tumor cell inactivation. Calculations have been performed for 2 extreme conditions: (a) the case of 211At retained in the capillary, and (b) for a homogeneous distribution of 211At-labeled antibody in the tumor. The results of these two calculations represent the boundary conditions between which any real solution must lie. Finally, developments to the model to include antibody transport across the capillary membrane and through the tumor tissue are discussed.

Antibodies, Neoplasm↗

PubMed1987

Evaluation of incorporated iododeoxyuridine cellular radiosensitization by photon activation therapy.

Halogenated pyrimidines such as iododeoxyuridine (IdUrd), when incorporated into cellular DNA, sensitize cells to radiation. A technique known as photon activation therapy (PAT) has recently been proposed to further enhance IdUrd radiosensitization. This approach relies on the emission of high linear energy transfer Auger electrons as a result of photoelectric absorption of photons with energies slightly above the K shell binding energy for iodine. Thus, additional IdUrd radiosensitization has been predicted for this technique using photons either generated externally from orthovoltage units or with implants of radioisotopes with emissions of the appropriate energy range. We have tested this prediction by comparing the radiosensitization of Chinese V79 cells, which have incorporated IdUrd (16% replacement of thymidine with IdUrd), to megavoltage (15 MV) versus orthovoltage (100 KVp) radiation. Enhancement ratios at 1% survival levels for 15 MV vs. 100 KVp radiation were 1.8 and 1.95, respectively. This modest 10-15% additional enhancement was much less than that predicted by PAT. The discrepancy between experimental data and the theoretical predictions of PAT are discussed.

Animals↗

PubMed1989

Alpha particle radio-immunotherapy: animal models and clinical prospects.

Short-lived isotopes that emit alpha particles have a number of physical characteristics which make them attractive candidates for radioimmunotherapy. Among these characteristics are high linear energy transfer and correspondingly high cytotoxicity; particle range limited to several cell diameters from the parent atom; low potential for repair of alpha-induced DNA damage; and low dependence on dose rate and oxygen enhancement effects. This report reviews the synthesis, testing and use in animal models of an alpha particle emitting radioimmunoconjugate constructed via the noncovalent chelation of Bismuth-212 to a monoclonal IgM antibody specific for the murine T cells/neuroectodermal surface antigen, Thy 1.2. These 212Bi-anti-Thy 1.2 immunoconjugates are capable of extraordinary cytotoxicity in vitro, requiring approximately three 212Bi-labeled conjugates per target cell to suppress 3H-thymidine incorporation to background levels. The antigen specificity afforded by the monoclonal antibody contributes a factor of approximately 40 to the radiotoxicity of the immunoconjugate. Animals inoculated with a Thy 1.2+ malignant ascites were cured of their tumor in an antigen-specific fashion by intraperitoneal doses of approximately 200 microCi per mouse. Alpha particle emitting radioimmunoconjugates show great potential for regional and intracavitary molecular radiotherapy.

Alpha Particles↗

PubMed1989

Response of rat rhabdomyosarcoma tumors to split doses of mixed high- and low-let radiation.

Radiation-induced growth delay was measured in rat rhabdomyosarcoma tumors exposed to split doses of high-LET (linear energy transfer) neon ions in the extended-peak ionization region and low-LET X rays. Top-off doses of 7.5, 15, and 25 Gy of 225-kVp X rays were administered to the tumors at 0.5, 4.0, and 24.0 hr following priming doses of either peak neon ions or X rays. The priming doses used were 7 Gy of peak neon ions and 20 Gy of X rays, both of which produced a 10 day delay in tumor regrowth to a volume twice that measured on the day of irradiation. The tumor response to split doses of X rays indicated rapid repair of sublethal damage, with significant recovery occurring at 0.5 hr and complete recovery by 4 hr after the initial 20-Gy X ray dose. The top-off doses of X rays required to produce an additional 10 or 20 days of tumor growth delay were 18 and 7% larger, respectively, when the priming dose was 20 Gy of X rays as compared to 7 Gy of peak neon ions. This result indicates that relatively little interaction of the neon-ion and X ray radiations occurred, even when the time interval between split-dose irradiations was as short as 0.5 hr. Our data indicate that the interaction of high- and low-LET radiation modalities is small, and approaches a simple additivity of effects when the tumors repair a major portion of the sublethal radiation injury imparted by a priming dose before the second dose is administered.

Animals↗

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

Microdosimetric single event spectra of Ytterbium-169 compared with commonly used brachytherapy sources and teletherapy beams.

Ytterbium-169 has been developed as a possible replacement for Iridium-192 and Iodine-125. The Theory of Dual Radiation Action predicts that the initial slope of the cell survival curve and therefore the relative biological effect at low dose rate is proportional to dose average lineal energy, yd, which is the microscopic analog of the dose average linear energy transferred. The quality factor used in radiation protection has been shown to be a function of the frequency average lineal energy, yf. Single event microdosimetric spectra for 60Co, 137Cs, 192Ir, 125I and 169Yb were measured in air and at several depths in phantom with a Rossi proportional counter. These spectra show marked differences between sources. The microscopic analogs of the track average and dose average LET, (yd and yf, respectively) differ between isotopes by factors of two or even higher in comparison to megavoltage electron beams. These yd's and yf's for 169Yb are consistently higher when compared to 60Co or 137Cs but are approximately equal to those for 125I. Values of yf and yd for 192Ir are intermediate between 60Co and 169Yb. The Theory of Dual Radiation Action predicts a low dose rate RBE (assuming a 1 micron effective site diameter) compared to 60Co (in air) of: 1.00 for 137Cs, 1.29 for 192Ir, 1.60 for 169Yb and 1.77 for 125I.

Brachytherapy↗

PubMed1994

The development of a [211At]-astatinated endoradiotherapeutic drug: Part II. Therapeutic results for transplanted adenocarcinoma of the rectum in mice and associated studies.

PURPOSE: 6-[211At]-astato-MNDP is of a class of a high linear energy transfer endoradiotherapeutic drug, which selectively targets to an onco-APase isoenzyme expressed by certain epithelial and germ cell tumors. The therapeutic efficacy and acute toxicity of its endogenous alpha-particle emissions have been studied in a murine tumor model. METHODS AND MATERIALS: 211At was produced by the 207Bi(alpha,2n)211 At cyclotron-based nuclear reaction. High specific activity 6-[211At]-astato-MNDP was rapidly synthesized by in vacuo thermal heterogeneous isotopic exchange. The therapeutic potential of 6-[211At]-astato-MNDP and 211At- was determined in mice bearing a transplanted CMT-93 rectal carcinoma which exhibited onco-APase activity. RESULTS: Significant therapeutic effects due to targeted alpha-particle emissions have been confirmed for the activity dose range, 10-750 kBq 6-[211At]-astato-MNDP. A therapeutic window has been identified, whereby cure rates of approximately 45-65% were achieved following administration of 55-300 kBq 6-[211At]-astato-MNDP. Estimated tumor absorbed radiation doses were not inconsistent with clinical response. Irreversible hematoxicity or stigmata of acute radiation damage in other critical normal tissues were not encountered. Nonspecifically internalized 211At- exerted no therapeutic effect. CONCLUSION: Therapeutic results for 6-[211At]-astato-MNDP have confirmed the profound in vivo cytotoxicity of its targeted alpha-radiations in the CMT-93 tumor. Acute normal tissue toxicity was acceptable. A rationale for optimal fractionation of targeted 6-[211At]-astato-MNDP endoradiotherapy is discussed, and its putative role in the possible individualized management of certain human tumors has been proposed.

Adenocarcinoma↗

PubMed1994

Methods for radiation dose distribution analysis and treatment planning in boron neutron capture therapy.

This article presents a survey of recent progress in the development and application of analytical methods for calculating macroscopic and microscopic radiation dose distributions for Boron Neutron Capture Therapy (BNCT). Such calculations are an essential component of in vivo BNCT research and will ultimately also be required for human BNCT treatment planning. Calculations of macroscopic absorbed dose distributions for BNCT are more complex than for photon therapy. There are several different dose components, each of which has its own characteristic spatial distribution, linear energy transfer, and relative biological effectiveness (RBE). Three-dimensional (3-D) energy-dependent radiation transport models with a detailed treatment of particle scattering are required. Geometric descriptions for such models are typically constructed directly from medical image data and both the Monte Carlo stochastic simulation method and the discrete-ordinates deterministic approach have been successfully used to perform the necessary radiation transport calculations. Microdosimetric effects can profoundly influence the therapeutic benefit that may be attainable in BNCT. These effects must be carefully taken into account in the interpretation of experimental data, especially when correlating observed in vivo radiobiological response with absorbed radiation dose. Calculations of microdosimetric parameters for BNCT are typically performed using the Monte Carlo method to generate single-event energy deposition frequency distributions for critical targets in various cell types of interest. This information is useful in the development of apparent RBE factors, or "compound factors" for the various dose components in BNCT.

Boron Neutron Capture Therapy↗

PubMed1994

Dose prescription in boron neutron capture therapy.

PURPOSE: The purpose of this paper is to address some aspects of the many considerations that need to go into a dose prescription in boron neutron capture therapy (BNCT) for brain tumors; and to describe some methods to incorporate knowledge from animal studies and other experiments into the process of dose prescription. MATERIALS AND METHODS: Previously, an algorithm to estimate the normal tissue tolerance to mixed high and low linear energy transfer (LET) radiations in BNCT was proposed. We have developed mathematical formulations and computational methods to represent this algorithm. Generalized models to fit the central axis dose rate components for an epithermal neutron field were also developed. These formulations and beam fitting models were programmed into spreadsheets to simulate two treatment techniques which are expected to be used in BCNT: a two-field bilateral scheme and a single-field treatment scheme. Parameters in these spreadsheets can be varied to represent the fractionation scheme used, the 10B microdistribution in normal tissue, and the ratio of 10B in tumor to normal tissue. Most of these factors have to be determined for a given neutron field and 10B compound combination from large animal studies. The spreadsheets have been programmed to integrate all of the treatment-related information and calculate the location along the central axis where the normal tissue tolerance is exceeded first. This information is then used to compute the maximum treatment time allowable and the maximum tumor dose that may be delivered for a given BNCT treatment. RESULTS AND CONCLUSION: The effect of different treatment variables on the treatment time and tumor dose has been shown to be very significant. It has also been shown that the location of Dmax shifts significantly, depending on some of the treatment variables--mainly the fractionation scheme used. These results further emphasize the fact that dose prescription in BNCT is very complicated and nonintuitive. The physician prescribing the dose would need to rely on some method, like the one developed here, to come up with an appropriate dose prescription.

Boron Neutron Capture Therapy↗

PubMed1996

European results in neutron therapy of malignant salivary gland tumors.

In Europe to date, 501 patients with salivary gland tumors have been treated with neutrons alone or with combined modalities. The most common histological types are adenoid cystic carcinomas, mucoepidermoid carcinomas and malignant mixed tumors. The results of conventional radiotherapy are suboptimal in inoperable or incompletely resected salivary gland tumors and in recurrent disease. The pooled data of some international series for low linear energy transfer radiation show a local control of 28%. Especially in advanced tumors neutron therapy can improve local control and should be the treatment of choice. The clinical data from different therapy centers in Europe show local control of 67% in gross disease.

Carcinoma, Adenoid Cystic↗

PubMed2004

Calculations of cellular microdosimetry parameters for alpha particles and electrons.

The cellular microdosimetry parameters including the cellular S-value and the single-event specific energy distribution for alpha particles and electrons are important in radiation dosimetry and biology. These parameters may be used to determine the relative biological effectiveness of radiations in the boron neutron capture therapy. In the present work, such parameters were calculated for different source to target region combinations, i.e. cell surface, cytoplasm, nucleus and cell. Calculations were made using a semi-analytical model that simulated the emission of alpha particles or electrons by the Monte Carlo method and calculated the energy imparted to the target volume by the analytical method. Delta particle equilibrium and partial delta particle equilibrium were applied to alpha particles and electrons, respectively. Range-energy relations were employed to determine the incident and emerging energies of the primary particles. For electrons, the fraction in the energy loss resulting from the generation of bremsstrahlung and high-energy secondary electrons was estimated. The energy loss straggling of electrons entering and leaving a target volume was also estimated. Calculated cellular S-values were compared to corresponding data of the MIRD Committee. Calculated single-event specific energy distributions were also compared to results calculated using the Penelope code.

Alpha Particles↗