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Radionuclide Therapy for the Treatment of Microscopic Ovarian Carcinoma: An Overview Jenny L. Whitlock,*,† John C. Roeske,‡ Mark L. Dietz,§ Chris M. Straus,| John J. Hines,| E. Philip Horwitz,| Richard C. Reba,| and Jacob Rotmensch† Departments of Obstetrics and Gynecology, Section of Oncology, of Radiation and Cellular Oncology, and Department of Radiology, The University of Chicago, Chicago, Illinois 60637, and Chemistry Division, Argonne National Laboratory, Argonne, Illinois 60439
Cancer comprises a group of diseases characterized by the uncontrolled growth of abnormal cells that spread from the anatomical site of origin. For many types of cancer, surgery alone has proven inadequate, necessitating a broader approach to treatment incorporating chemotherapy and radiotherapy. Of particular recent interest has been the use of R-emitters in the treatment of microscopic carcinoma. The effective application of these materials requires an understanding of the physical and biological bases of radiation therapy. In addition, both radiochemical and radionuclidic purity are essential in all clinical applications. Recent work with the R-emitting radionuclide bismuth-212 offers considerable promise in the treatment of microscopic ovarian carcinoma resistant to conventional treatment modalities. Ongoing improvements in methods for its preparation are expected to further improve its therapeutic utility. Introduction This year, it is estimated that 1.3 million new cancer cases will be diagnosed in the United States and nearly 600 000 deaths will occur from the diseasesmore than 1500 Americans/day. This population is in addition to the approximately 12 million Americans with cancer diagnosed since 1990 currently under medical care and does not include some 1 million cases of skin and in situ cancer that eventually will be diagnosed.1 Cancer encompasses a large group of diseases, all originating from a single cell that has lost control of the mechanisms that regulate reproduction. These mutations represent genetic alterations that arise either spontaneously or as a result of outside influences (e.g., carcinogens). These cause cancerous cells (unlike normal cells) to proliferate without regulation, often resulting in the eventual death of the host.2 The growth of cancerous tumors occurs by infiltration and destruction of neighboring cells. This may occur locally followed by metastatic spread to organ surfaces or by transport of cancer cells through the blood and lymph system to form distant metastases. The majority of tumors become clinically recognizable only after the cell mass has completed the bulk of its growth (or metastatic spread) and has begun to have detrimental effects on normal tissues.3 In the example of ovarian carcinoma, peritoneal spread is a key feature in the natural progression of the disease and the major cause of treatment failure. For this and many other types of cancer, surgery as a single modality for treatment is inadequate, and a broader approach including chemotherapy and radiotherapy is often necessary. Although this approach has improved the overall survival of many patients, new therapies are * To whom correspondence should be addressed. † Department of Obstetrics and Gynecology, Section of Oncology, The University of Chicago. ‡ Department of Radiation and Cellular Oncology, The University of Chicago. | Department of Radiology, The University of Chicago. § Argonne National Laboratory.
required for patients for whom conventional therapies fail.4 The development of new treatment modalities requires multidisciplinary expertise involving physicians, biologists, physicists, and chemists. In this paper, we describe a multidisciplinary approach to the development of Bi-212, an R-particle-emitting radionuclide, for the treatment of ovarian cancer. To provide the reader with an understanding of the factors underlying the current interest in the use of R-emitters in cancer therapy, we describe aspects of cellular biology, radiobiology, radiation oncology, and radiochemistry relevant to this new modality. Discussion Cell. The functional and structural unit of all living organisms is the cell, the two major components of which are the cytoplasm and the nucleus. The nucleus is the control center of the cell and contains genetic material called deoxyribonucleic acid (DNA). Suspended in the nucleus are a fixed number (characteristic of a given organism) of linear bodies called chromosomes, which are composed of DNA and determine the cell’s characteristics.5,6 The DNA core is composed of precisely ordered nucleotides in the form of a long double strand, surrounded by a protein matrix. The nucleotides are composed of three components linked together: a phosphate group, a five-carbon sugar, and any of four nitrogenous (pyrimidine or purine) bases including thymine (T), cytosine (C) (the pyrimidines), guanine (G), and adenine (A) (the purines).6 The sugar and phosphate groups alternate to form the outside spiral staircase, while the nitrogenous bases link the two strands together like treads on a stairway. The base pairs are not random, because adenine can bind only to thymine and cytosine only to guanine. The pairing of bases is a major factor in holding the strands together, providing both stability and reproducibility.5,6 Cell Cycle. The cell cycle is defined as the phases between each cell division, which includes the replication of the chromosomes and of the genes they contain.
10.1021/ie000425u CCC: $19.00 © 2000 American Chemical Society Published on Web 09/05/2000
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Figure 1. Schematic representation of the cell cycle: G1 (gap 1), the primary phase of growth regulation; S (synthesis of DNA), replication occurs; G2 (gap 2), growth phase to organize the nucleus for mitosis; M (mitosis), chromosomal condensation and cell division occur; G0 (resting state), connecting one mitosis with the next.
Each cell cycle can be divided into five distinct phases. These include mitosis (M), the pre-DNA synthetic phase (G1), the DNA synthetic phase (S), and the post-DNA synthetic phase (G2); see Figure 1. Recently, another phase (denoted G0) has been identified as a period of suspended growth that occurs after mitosis and before G1.6,7 During replication, each helical chromosome untwists and each existing strand becomes a template for the new strand of DNA.5,8 Each pair of chromosomes, one old and one new, becomes one of the two identical daughter cells. The replication process thus maintains the genetic code through successive generations of cells, as well as continuity from cell to cell within the generation. A disruption of these processes of cell division and regulation is not only the basis for the development of cancers but also the basis for treating malignant cells.2,6,9 Physical Basis of Radiation Therapy. It has been known since the early 1900s that ionizing radiation can interact with biological systems to produce changes in normal and malignant tissues. Ionizing radiation can be classified as either electromagnetic (e.g., X-rays and γ radiation) or particulate (e.g., electrons, R particles, and β particles). Both electromagnetic and particulate radiation deposit energy along their paths as they travel through tissue. X-rays and γ radiation deposit energy through three primary interactions: the photoelectric effect, the Compton effect, and pair production. In the photoelectric effect, an incident photon is completely absorbed by an inner shell electron with the subsequent emission of an electron. In the Compton effect, the photon behaves like a particle as it collides with a loosely bound outer shell electron. Pair production occurs at photon energies greater than 1.02 MeV and results in the creation of an electron-positron pair due to the interaction of the incident photon with an atomic nucleus. After losing its energy, the positron is annihilated, producing two photons traveling in opposite directions.10,11 For photon beams commonly used in external beam radiotherapy (50 kVp to 25 MV), the Compton effect is the most dominant in tissue. The photoelectric effect is the most dominant process for energies below 50 keV, while pair production is the primary interaction at energies above 25 MeV. Charged particles interact with matter through three primary processes: soft collisions, hard “knock-on” collisions, and nuclear field interactions.11 Soft collisions refer to the interaction between the Coulomb forces of the incident particle and outer shell electrons. These
interactions result in excitation and, in some cases, ionization. Hard collisions are those involving the direct interaction between incident photons and orbital electrons, which results in the ejection of an orbital electron from the atom. Nuclear interactions occur between the incident particles and the nucleus. In cases in which the incident particle is an electron, it is usually elastically scattered and does not lose energy; however, in a small fraction of events, the electron is inelastically scattered and produces bremsstrahlung radiation. Typically, a 1 MeV electron will undergo ∼105 interactions before losing its energy.9 Soft collisions account for approximately half of the energy transferred to matter. The remaining energy is transferred primarily by the relatively fewer, but more energetic, hard collisions. Radiation therapy is often delivered externally in the form of X-ray or electron beams produced by linear accelerators. An alternative mode of radiation delivery is known as brachytherapy in which a radioactive source is placed in direct contact with the tumor. These sources may be sealed (e.g., Cs-137 and I-125) or unsealed (e.g., I-131 and Y-90). Sealed sources are typically γ-emitting radionuclides with energies ranging from 30 to 600 keV, while unsealed sources are primarily β/γ emitters. Recently, there has been growing interest in the use of R-particle emitters (e.g., Bi-212, Bi-213, and At-211).12,13 R particles are advantageous because of their short range (40-80 µm), high linear energy transfer (LET), and other radiobiological advantages (to be discussed in the following sections). The short range of R particles ensures minimal irradiation of surrounding normal tissues. LET (typically expressed in units of keV/µm) refers to the amount of energy deposited per unit path length. Photon and electron beams commonly used in radiotherapy have an LET of 0.25 keV/µm and are considered low-LET radiation. Protons, neutrons, and R particles have LET that vary with particle type and energy, ranging from 4 to 200 keV/µm, and are thus referred to as high-LET radiation. Electromagnetic and other types of low-LET radiation are indirectly ionizing via short-lived, free hydroxyl radicals produced primarily by the ionization of cellular H2O. Protons, R particles, and other high-LET radiation are directly ionizing and damage DNA directly. Consequently, different types of radiation have varying degrees of relative biological effectiveness (RBE). Directly ionizing radiation (e.g. neutrons and R particles) has a greater RBE than indirectly ionizing radiation.14 Biological Basis of Radiation Therapy. Along with understanding the physical properties of radiation, it is important to understand the effects of radiation of various types on biological systems. A number of biological factors are relevant to determining the influence of radiation on a biological system. Four factors are particularly important for R-particle emitters: cellular effects, the degree of tissue oxygenation, the cell cycle, and fractionation. Radiation can induce a variety of cellular effects, including damage to DNA and to the nuclear membrane.7,8 The critical target for cell killing, however, is the DNA. Radiation deposition can result in several different types of DNA damage (Figure 2), depending on the intensity and duration of the radiation.7 Lethal damage occurs when a cell loses its capacity to proliferate or repair itself. Although some cells die quickly after a radiation dose, a portion of the population will appear normal after treatment yet will die in
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Figure 2. Types of radiation damage in DNA.
subsequent generations, a result of repeated cellular divisions with damaged and unrepaired DNA. Therefore, the ability of a cell to repair its DNA must be considered.7,15 Sublethal damage refers to radiation damage that is repaired before the abnormal DNA affects cell function. Such damage obviously has a smaller biological effect than major or double-strand breaks in DNA, which are not readily recoverable.16 Thus, the most effective radiation treatments are those that not only hit the intended target but also cause the greatest amount of lethal or nonrepairable damage to DNA. High-LET radiation (such as R particles) is most effective in this respect.6,7 Although the effectiveness of radiation can be enhanced by factors such as chemical and chemotherapeutic agents, the most important modifier of radiation effects is the presence of molecular oxygen within the nucleus of the target cells, with oxygen increasing the susceptibility of the cell to damage by radiation.17 The origin of this “oxygen effect” is not entirely clear, but it has been attributed to the interaction of oxygen with free radicals. A commonly used measure of the effect of cellular oxygen is the oxygen enhancement ratio (OER), defined as the dose required to produce a given effect with no oxygen present divided by the dose required to produce the same effect in a well-oxygenated cell.6,17 The OER for low-LET radiation is typically 2.5-3.0. This translates into a relative resistance by hypoxic cells (i.e., those low in oxygen content), a state common to approximately 10-20% of cells within tumor masses. Consequently, cell survival of the tumor will mimic the relatively radiation-resistant hypoxic cells. High LET damages DNA directly and thus does not rely on cellular oxygen (OER ∼ 1).6,7,17 One important benefit then of using R-particle emitters is that the oxygen effect is negligible. The phase of the cell cycle is an important factor in determining the effects of ionizing radiation on a biological system. The various phases in the cycle follow the same sequence for both cancerous and normal cells. Cells are more susceptible to damage when the DNA is replicating. During this phase of the cell cycle, the DNA is not tightly wound up but unfurled as the strands separate, allowing new strands to form.18,19 Unfurled DNA provides a much larger and more sensitive target for radiation of any type. In general, the most sensitive phases are G2 and M; the least sensitive are G1 and S. Thus, the effectiveness of radiation is increased when doses are distributed over a single cell cycle, because this increases the likelihood of irradiating a cell in the
replication phase and decreases the chance of the cell repairing itself before it replicates.6,7,18 In conventional radiotherapy, the rate at which the dose is given has a significant effect on the biological response of both the tumor and the surrounding normal tissue. Radiation may be delivered with a single large dose or divided into fractions over a period of time, lasting days, weeks, or months.20 Fractionation spares normal tissues and allows for the repopulation of normal cells. Additionally, fractionation increases tumor cell kill by allowing for reoxygenation of hypoxic cells and redistribution of tumor cells into the more sensitive phases of the cell cycle.6,7,17 r-Particle Emitters for Ovarian Carcinoma. Ovarian carcinoma has the highest mortality rate of any gynecological cancer. This is predominantly due to late detection, in particular, the spread of the disease beyond the pelvis by the time of diagnosis. Cytoreductive surgery and systemic therapy have improved the overall survival of these patients; however, even after apparent complete remission, relapses occur secondary to undetected peritoneal spread.4,21 Although the initial treatment of late-stage ovarian carcinoma with multiple chemotherapy agents yields response rates of 90%, after 5 years only approximately 20% of patients are reported to be alive. Current salvage strategies include intraperitoneal chemotherapy or abdominopelvic external beam radiotherapy; however, neither of these is of proven value.4,22 Intraperitoneal administration of radiocolloids (P-32) has been explored as an alternative means of delivering higher radiation doses to the peritoneal cavity. Its effectiveness is limited in the treatment of later stage ovarian carcinoma, however, a likely result of its nonuniform distribution within the peritoneum. Moreover, the use of P-32 is associated with various undesirable side effects, most notably small bowel obstruction.4,21,22 We have therefore turned our attention to R-emitting radionuclides, which have physical properties that make them attractive for therapy. As already noted, unlike X-rays and γ-rays, R emitters have a very high LET. In human tissue, all of their energy is typically deposited in the first few microns of travel, resulting in a very high local radiation dose.7 However, one of the requirements for successful therapy with R emitters is that the distribution of the radionuclide in the target tissue must be uniform, because the range in matter is so short. β emitters are more forgiving because the β particles travel 5-10 mm through tissue and, therefore, typically deliver a dose to the entire target organ even if their distribution is less than ideal. Because these radionuclides are used to destroy cells, one must be very sure that localization of these nuclides in target tissue is optimal. This means that the target-to-nontarget ratio of activity should be very high (>25:1). In addition, it is essential to ascertain both the radionuclide purity and the radiochemical purity. If the radionuclide purity is not very high (>95%), then contaminating radionuclides can significantly increase the radiation dose to the target and surrounding tissues and, possibly, to areas of the body remote from the site of interest. If the radiochemical purity is not high, then the radioisotope is in the wrong radiochemical form. In this case, it might localize in an undesirable place (e.g., bone marrow) instead of in the desired target organ. The potential for a resulting catastrophic illness (leukemia and aplastic anemia) resulting from this poor biological distribution
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is quite significant. Thus, one must perform the appropriate quality control procedures to ensure suitability of drug administration to humans. This will minimize the risk of undesirable effects on the patient.23 Radiochemistry. The importance of effective methods for ensuring radionuclidic purity becomes especially apparent in the case of Bi-212, an R-emitter whose therapeutic potential in the treatment of ovarian carcinoma is of considerable current interest in our laboratory.4,21,22 Bi-212 is produced according to the following decay scheme:
Clinical application of Bi-212, therefore, requires that it be completely separated from its parent, Pb-212, and from traces of several other R-emitting radionuclides: Ra-224, Th-228, and U-232. Given the relatively short half-life of Bi-212 and the need to minimize the radiation exposure of hospital personnel, it is important that the separation process employed be both simple and rapid. Ion exchange involving sequential application of cation- and anion-exchange resins has been shown to provide separation of Th-228, Ra-224, Pb-212, and Bi212. A generator system based on sorbed Ra-224 capable of providing clinically useful quantities of Bi-212 has been described.24,25 The reliance of this approach on a single cation-exchange step to ensure the radionuclidic purity of Bi-212 makes alternative approaches desirable, however. Moreover, Bi-212 eluted from the Ra-224 generator has sometimes been found to contain unacceptable levels of Pb-212 or Ra-224, necessitating the use of additional ion-exchange treatments to obtain Bi212 of adequate purity. An alternative approach to obtaining high-purity Bi-212, one which we have recently been examining, is to employ the Ra-224 generator as a source of Pb-212, which is then purified by sorption on a lead-selective chromatographic medium.26 If this medium exhibits little or no retention of bismuth under conditions where lead is strongly retained, the sorbed Pb-212 can serve as a convenient source of highpurity Bi-212. Measurements of the nitric acid dependency of the sorption of the members of the decay series shown above on a lead-selective extraction chromatographic material (Sr‚Resin, EiChroM Industries, Darien, IL) have shown that, while bismuth is not measurably retained (i.e., the capacity factor, k′, defined as a number of free column volumes required to reach the peak maximum in the elution band, is less than 0.1) on the resin, lead is strongly sorbed (k′ > 100) over the entire range of acidities. Similar measurements for the other members of the decay series indicate that none of them exhibits significant sorption. Such selectivity for lead is not entirely unexpected, given the known binding properties of crown ethers of the type on which this chromatographic material is based.27 These results indicate that if the effluent from an Ra-224 generator (consisting of Bi-212, Pb-212, and, perhaps, traces of Ra224, Th-228, and other adventitious impurities) is passed through Sr‚Resin, only Pb-212 (and stable Pb208) will be appreciably retained. Therefore, after appropriate column rinsing and a suitable period (2-4
h) of Bi-212 ingrowth, substantially impurity-free Bi212 can be eluted from the column. In actual practice, Pb-212 produced by decay of Ra224 sorbed on a cation-exchange column is eluted with 2 N HCl, and the eluent is then passed through the Sr‚ Resin column, where the lead is retained. The column is rinsed with a small volume of 2 N HCl to remove impurities, and after 2 h of Bi-212 ingrowth, Bi-212 is eluted with a 1 N HCl solution (these conditions were chosen on the basis of initial studies indicating that Bi212 recovery can be maximized by elution at 2-h intervals). Before use, the acidic bismuth solution is typically neutralized with NaOH (or another acceptable base) and diluted to produce an isotonic (i.e., 0.85% saline) solution. The solution is also assayed prior to use. (Note that Bi-212 is held for 15 min before the assay to permit equilibrium to be established with Tl-208, its high-energy β/γ-emitting daughter.) In vitro evaluation of the effect of Bi-212 on cancer cells (cell lines EhrlichLettre Ascites [ATCC] and NIH-OVCAR-3) grown as monolayers or multicellular spheroids indicates that its relative biological effectiveness is 3 times greater than that of P-32 β particles or 250 kVp X-rays. In vivo studies involving intraperitoneal administration of a Bi212 (as the oxychloride) solution into rabbits indicate that, unlike P-32, Bi-212 is uniformly distributed within the peritoneal cavity. In addition, the majority of the activity introduced remains in the peritoneal cavity. (A total of 3 h after its administration, 85% of the Bi-212 activity can be recovered in the peritoneal fluid; minimal residual activity is found in the blood, gastrointestinal tract, and carcass.26) Taken together, these results indicate that Bi-212 offers considerable promise in the treatment of microscopic ovarian carcinomas resistant to conventional treatment modalities. Ongoing improvements in the speed and efficiency of methods for its separation and purification are certain to improve its utility as a therapeutic agent.28 Conclusion The inadequacy of single-modality approaches to the treatment of many forms of cancer has made the development of broader methodologies incorporating surgery, chemotherapy, and radiotherapy necessary. Continued advances in this multidisciplinary approach to cancer treatment are dependent on progress in several fields, among them the development of separation techniques with which clinically useful quantities of promising radionuclides can be quickly and easily prepared. Acknowledgment The work at The University of Chicago was supported by the PG Research Foundation, Inc. and the Comer Science and Education Foundation. The work at Argonne National Laboratory was performed under the auspices of the Office of Basic Energy Sciences, Division of Chemical Sciences, U.S. Department of Energy, under Contract W-31-109-ENG-38. Literature Cited (1) McDonald, C. J. Cancer Statistics 1999: Challenges in Minority Populations. Cancer J. Clin. 1999, 49, 6. (2) Braun, A. C. The Biology of Cancer; Addison-Wesley: Reading, MA, 1974.
Ind. Eng. Chem. Res., Vol. 39, No. 9, 2000 3139 (3) Holland, J. F.; Frei, E.; Bast, R. C.; Kufe, D. W.; Morton, D. L.; Weichselbaum, R. R. Cancer Medicine, 3rd ed.; Lea-Febiger: Philadelphia, PA, 1993. (4) Rotmensch, J.; Whitlock, J.; Schwartz, J.; Hines, J.; Reba, R.; Harper, P. In-Vitro and In-Vivo Studies on the Development of the R-Emitting Radionuclide Bismuth 212 for Intraperitoneal use Against Microscopic Ovarian Carcinoma. Am. J. Obstet. Gynecol. 1997, 176, 833. (5) Alberts, B.; Bray, D.; Lewis, J.; Raff, M.; Roberts, K.; Watson, J. D. Molecular Biology of the Cell; Garland, Inc.: New York, 1989. (6) Casarett, A. P. Radiation Biology; Prentice-Hall: Englewood Cliffs, NJ, 1968. (7) Hall, E. J. Radiobiology for the Radiologist, 4th ed.; J. B. Lippincott: Philadelphia, PA, 1994. (8) Prescott, D. M.; Flexer, A. S. Cancer: the Misguided Cell; Scribner: New York, 1982. (9) Farmett, P. B.; Walker, J. M. The Molecular Basis of Cancer; Wiley-Interscience: New York, 1985. (10) Attix, F. H. Introduction to Radiological Physics and Radiation Dosimetry; John Wiley: New York, 1986. (11) Khan, F. The Physics of Radiation Therapy; WilliamsWilkins: Baltimore, MD, 1994. (12) Vaidyanathan, G.; Zalutsky, M. R. Targeted Therapy using Alpha Emitters. Phys. Med. Biol. 1996, 10, 1915. (13) Kennel, S. J.; Stabin, M.; Roeske, J. C.; Foote, L. J.; Lankford, P. K.; Terzaghi-Howe, M.; Patterson, H.; Barkenbus, J.; Popp, D. M.; Bioo, R.; Mirzadeh, S. Radiotoxicity of Bismuth213 Bound to Membranes of Monolayer and Spheroids Cultures of Tumor Cells. Radiat. Res. 1999, 3, 244. (14) Hall, E. J. Radiobiology for the Radiologist, 2nd ed.; Harper & Row: New York, 1978. (15) Dizdaroglu, M. Measurement of Radiation-Induced damage in DNA at the Molecular Level. Int. J. Radiat. Biol. 1992, 61, 175. (16) Kanar, R.; Hoeijmakers, J. H.; van Gent, D. C. Molecular Mechanisms of DNA Double Strand Break Repair. Cell Biol. 1998, 8, 483. (17) Raju, M. R.; Amols, H. I.; Bain, E. A Heavy Particle Comparative Study. III. OER and RBE. Br. J. Radiol. 1978, 51, 712.
(18) DeVita, V. T.; Hellman, S.; Rosenberg, S. A. Cancer Principles and Practice of Oncology, 4th ed.; J. B. Lippincott: Philadelphia, PA, 1993. (19) MacDonald, F.; Ford, C. H. Molecular Biology of Cancer; Bios Scientific: Herndon, VA, 1997. (20) Withers, H. R. Principles and Practice of Radiation Oncology; J. B. Lippincott: Philadelphia, PA, 1987. (21) Rotmensch, J.; Atcher, R.; Hines, J.; Toohill, M.; Herbst, A. Comparison of Short-Lived High-LET R-Emitting Radionuclides Lead-212 and Bismuth-212 to Low-LET X-rays on Ovarian Carcinoma. Gynecol. Oncol. 1987, 35, 297. (22) Rotmensch, J.; Whitlock, J.; Schwartz, J.; Hines, J. In-Vitro Studies using the Alpha-Emitter Bi-212: Development of Therapy for Microscopic Carcinoma. Radiochim. Acta 1997, 79, 127. (23) Wagner, R. H.; Karesh, S. M.; Halama, J. R. Questions and Answers in Nuclear Medicine; Mosby: St. Louis, MO, 1999. (24) Atcher, R.; Hines, J.; Friedman, A. A. Remote System for the Separation of Thorium-228 and Radium-224. J. Radioanal. Nucl. Chem. 1987, 117, 155. (25) Atcher, R.; Friedman, A.; Hines, J. An Improved Generator for the Production of 212-Pb and 212-Bi from 224-Ra. Int. J. Appl. Radiat. Isot. 1988, 39, 283. (26) Whitlock, J. L.; Reba, R. C.; Dietz, M. L.; Horwitz, E. P.; Hines, J. J.; Harper, P. V.; Rotmensch, J. Therapeutic Potential of Alpha-Emitters: Chemistry to Biology to Clinical Applications. In Technetium, Rhenium, and Other Metals in Chemistry and Nuclear Medicine; Nicolini, M., Mazzi, U., Eds.; SGE Editorali: Padova, Italy, 1999; p 805. (27) Izatt, R.; Pawlak, K.; Bradshaw, J. Thermodynamic and Kinetic Data for Macrocycle Interaction with Cations and Anions. Chem. Rev. 1991, 91, 1721. (28) Dietz, M. L.; Horwitz, E. P. An Improved Extraction Chromatographic Material for the Separation and Preconcentration of Strontium from Acidic Media; Invention Report; Argonne National Laboratory: Argonne, IL, 1999.
Received for review April 28, 2000 Accepted May 5, 2000 IE000425U
