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Applied principles of radiopharmaceutical use in therapy
Nucl. Med. Biol. Vol. 13, No. 4, pp. 461463, hr. J. Radio:. Appl. h.wum. Parr B
0883-2897/86
1986
$3.00 + 0.00
Copyright 0 1986Pergamon Journals Ltd
Printed in Great Britain. All rights reserved
Applied Principles of Radiopharmaceutical Use in Therapy* RICHARD
P. SPENCER
Department of Nuclear Medicine, University of Connecticut Health Center, Farmington, CT 06032, U.S.A.
The initial consideration in use of a radiopharmaceutical in therapy is specificity of localization. A variety of biological principles such as active transport and binding to cellular components have been utilized to achieve this localization. The next concern is to maximize radiation to the lesion while minimizing that to the remainder of the body. This means that there is a major role to be played by emissions with a short path length (such as u particles, weak B particles and Auger electrons). To achieve maximal irradiation of the lesion, dissociation of the radiolabel from the tissue should be minimized; potential approaches for acheiving this are reviewed. Finally, “synergistic effects” between radiation and chemical agettts are discussed
Introduction use of internally administered radiopharmaceuticals began with the availability of cyclotron produced ‘*P and reactor generated “‘1. Although historically his dates back about 40 years, it has only been in the last decade that a variety of radiolabels for therapy have become widely used and the principles underlying their application have become somewhat clarified. Rather than dwell on the evolution of the concepts, we will present a brief summary of their use. Therapeutic
Principles (1) Perhaps the most important factor is specificity of localization. That is, the radiopharmaceutical must be delivered to the site of the lesion and binding has to occur. This means there must be an available pathway for flow, diffusion or other arrival at the lesion. In addition, there must be an avidity of the radiolabeled compound for the specific cells or their subcomponents. This has been achieved by several techniques. (A) Active transport. Transport against an electrochemical gradient achieves a high concentration, since the cell is expending energy to move the material. (B) Antibodies to receptors. These are usually directed toward components on the cell wall (truly tumor-specific antibodies have not yet been developed). *Supported by USPHS CA 17802 from the National Cancer Institute.
(C) Binding to intracellular components. A variety of techniques are employed, such as enzyme inhibitors and intercalators of the DNA chain. (2) The second factor of concern is to deliver radiation (as much as possible) to the lesion, while sparing nearby tissues and the body in general. Localization is the first requirement, while the second is to employ radiopharmaceuticals based on nuclides that have limited range emissions (such as a particles, /l particles, or Auger electrons). That is, while y ray emitters can potentially deliver a high radiation dose to a region, the accompanying radiation exposure of normal tissue is of serious concern. “Figures of merit” have been described for /I particles used in therapy, in terms of lesion/surrounding area and lesion/whole body. (I) Still greater specificity may be required, in terms of where the radiolabel localizes in or on a cell. That is, we may be able to select a radionuclide with emissions of sufficient energy to irradiate part of a cell but not surrounding areas. For example, calculations have appeared in the literature as to the distance (volume) within which 90% of the energy of a particular emission will be absorbed.(*) Appropriate choices may be possible, based on knowledge of whether the radiopharmaceutical has bound to the cell membrane, a cytoplasmic component or intranuclear molecule and knowledge of cell binding heterogeneity. (3) The third consideration is to effect greatest use of the radiolabel which has achieved localization. That is, once binding or entry has occurred, efforts have to be made to keep it on (in) the cell. At maximum efficiency, turnover of the radiolabel would be identical to cell turnover. In other words, the effective life within the lesion would approach the life 461
RICHARD P. SPENCER
462
span of the cells, and any shorter biological turnover of the label would be negligible. This might be achievable by avid binding to a cellular component with low turnover, such as nuclear DNA, or by metabolic trapping. In most cases however, it is probable that techniques will have to be employed to retard egress. A well documented example involves inhibition of release of iodinated compounds from the thyroid, by the lithium ion.@) In most biological systems the entry or transport pathways are distinct from the exit mechanisms; hence, as knowledge of the efflux systems increases, it may be possible to achieve their inhibition (and hence most efficient use of therapeutic radionuclides). (4) Finally, we have to consider possible synergistic effects between therapy with radiopharmaceuticals and other agents. That is, can tissues be “sensitized” to therapy by radiopharmaceuticals, or can one or more therapeutic modalities be used at the same time? The relationship between externally and internally delivered radiation exposures has been described in the 1iterature.(4) Can we extrapolate further and build upon the known ability of some compounds to make hypoxic tissue susceptible to externally delivered ionizing radiation? The answer is not presently known. However, any progress in this area might be followed by the ability to treat lesions which are now only marginally treatable, or to reduce the whole body radiation dose during therapy of susceptible areas. Availability of tomographic techniques has permitted more accurate delineation of lesion size and spatial distribution. A corollary is that following this distribution in a time-dependent manner should allow better design of dose delivery. For example, a y ray emitter might be used first to determine distribution and, based on this, an tl, B or Auger electron emitter (preferably of the same element) then used in therapy. It is also conceivable that the residence time of an agent containing therapeutic activity levels might be shorter (due to cell damage) than that of a tracer amount of radiopharmaceutical. If this could be documented by sequential tomographic images, compensation might be possible by means of a larger therapeutic dose. The “classical” formulation for fi ray dosage (homogeneous radionuclide distribution) is: Dose (rad) = Ea.C.t,,,
(73.8)
Here E, is the average /I ray energy in MeV, C is the concentration in the lesion (pa/g), t,,* is the effective half-life in days, and the numerical term is a conversion factor. The formula is linear in concentration (amount in the tumor), but is not truly linear in terms of E,.t1,2. That is, a long-lived (say 20 d physical t,,*) radionuclide of 0.2 MeV B particle energy would not give the same biological effect as a 2d t,,z material with a 2 MeV /? ray. Part of this would be due to the different effective half-lives, part due to the different size of the irradiated zone, and part would result from “escape” of a small amount of the energetic /? energy
in the form of bremsstrahlung. The energy escape results in less radiation of the lesion and more radiation of surrounding tissues. This means that the figure of merit is reduced. The escape of energy also has deleterious effects when two organ systems are intertwined, and irradiation of one leads to irradiation of the other. For example, bone spicules border and project into the bone marrow. Delivery of radiation to the bone matrix, by deposition of radiopharmaceuticals on the surface of the calciumphosphorus substrate, invariably results in some radiation of bone marrow. In this situation, the requirement for a low energy B particle (or a particle, or Auger electron emitter) is particularly apparant.
Binding Considerations Short-lived (short physical t,,,) radionuclides may have two advantages for internal radiation therapy. (1) If physical t,,z is shorter than the rate of biological turnover, and the uptake is rapid, then essentially all of the radiation (total decay) is delivered to the area. (2) The number of atoms in a millicurie of a short-lived material is less than that in a longer-lived radionuclide. The number of atoms in a therapeutic radiopharmaceutical is crucial to the success of therapy; for example, a cubic centimeter of tissue has about IO9 cells. The number of atoms (N) in a radioactive material is given by the expression: 1 dN N=K.dt or: N=5&$ Where K is the decay constant and t,,* is the physical half-life; for 1 mCi of a material (dN/dt = 3.7 x lO’/s), the number of atoms present is directly proportional to the half-life of the radionuclide. That is, there are more atoms in 1 mCi of a long-lived radionuclide than there are in a short-lived one. For example, for “C (t,,2 = 20 min), 1 mCi contains 6.4 x lOi atoms. With “‘In (t,,, = 2.8 d), there are 1.3 x lOI atoms present in the “carrier free” material. (A) This becomes important when there are a limited number of tissue binding sites, since a longlived radionuclide (or a shorter-lived one with nonradioactive “carrier” present) may present too many atoms. That is, a substantial portion may remain unbound increasing whole body radiation (and increasing imaging difficulty if a y emitter is utilized). (B) A short-lived material will dissipate more rapidly; there is thus less likelihood of the radiolabel being “lost” prior to cell turnover.
Principles of radiopharmaceutical
Most desirable are compounds (C) that have a high binding affinity for the cellular receptor (R). C+R+C.R.
A metabol1arn
That is, in addition to the specific activity of the compound, we have to be concerned with the “forward rate constant” (K,) or rate constant for binding. In the most favorable cases, K, is appreciable, while K, and K, are considerably smaller in magnitude. It is apparent that the principles to employ with therapeutic radiopharmaceuticals are evolving. The ultimate test of usefulness, clinical applications, are still before us. The use of these therapeutic agents might eventually be integrated into overall schemes
use in therapy
463
for treating tumors. For example, surgical “dechemotherapy and therapeutic radiobulking”, pharmaceuticals might all have sequential or concurrent use in a treatment scheme.
References Spencer R. P. Inr. J. Nucl. Med. Biol. 6, 212 (1979). Jungerrnan J. A., Yu K. H. P. and Zanelli C. I. Int. J. Appl. Radiat. Isot. 35, 883 (1984).
Burrow G. N. and Spaulding S. W. In Therapy In Medicine. (Ed. Spencer R. P.) pp. 113~119. (Grune & Stratton, New York. 1978). Bigler R. E. In Therapy In Nuclear Medicine. (Ed. Spencer R. P.) pp. 17-31. (Grune & Stratton, New York. 1978). Nuclear
0883-2897/86
1986
$3.00 + 0.00
Copyright 0 1986Pergamon Journals Ltd
Printed in Great Britain. All rights reserved
Applied Principles of Radiopharmaceutical Use in Therapy* RICHARD
P. SPENCER
Department of Nuclear Medicine, University of Connecticut Health Center, Farmington, CT 06032, U.S.A.
The initial consideration in use of a radiopharmaceutical in therapy is specificity of localization. A variety of biological principles such as active transport and binding to cellular components have been utilized to achieve this localization. The next concern is to maximize radiation to the lesion while minimizing that to the remainder of the body. This means that there is a major role to be played by emissions with a short path length (such as u particles, weak B particles and Auger electrons). To achieve maximal irradiation of the lesion, dissociation of the radiolabel from the tissue should be minimized; potential approaches for acheiving this are reviewed. Finally, “synergistic effects” between radiation and chemical agettts are discussed
Introduction use of internally administered radiopharmaceuticals began with the availability of cyclotron produced ‘*P and reactor generated “‘1. Although historically his dates back about 40 years, it has only been in the last decade that a variety of radiolabels for therapy have become widely used and the principles underlying their application have become somewhat clarified. Rather than dwell on the evolution of the concepts, we will present a brief summary of their use. Therapeutic
Principles (1) Perhaps the most important factor is specificity of localization. That is, the radiopharmaceutical must be delivered to the site of the lesion and binding has to occur. This means there must be an available pathway for flow, diffusion or other arrival at the lesion. In addition, there must be an avidity of the radiolabeled compound for the specific cells or their subcomponents. This has been achieved by several techniques. (A) Active transport. Transport against an electrochemical gradient achieves a high concentration, since the cell is expending energy to move the material. (B) Antibodies to receptors. These are usually directed toward components on the cell wall (truly tumor-specific antibodies have not yet been developed). *Supported by USPHS CA 17802 from the National Cancer Institute.
(C) Binding to intracellular components. A variety of techniques are employed, such as enzyme inhibitors and intercalators of the DNA chain. (2) The second factor of concern is to deliver radiation (as much as possible) to the lesion, while sparing nearby tissues and the body in general. Localization is the first requirement, while the second is to employ radiopharmaceuticals based on nuclides that have limited range emissions (such as a particles, /l particles, or Auger electrons). That is, while y ray emitters can potentially deliver a high radiation dose to a region, the accompanying radiation exposure of normal tissue is of serious concern. “Figures of merit” have been described for /I particles used in therapy, in terms of lesion/surrounding area and lesion/whole body. (I) Still greater specificity may be required, in terms of where the radiolabel localizes in or on a cell. That is, we may be able to select a radionuclide with emissions of sufficient energy to irradiate part of a cell but not surrounding areas. For example, calculations have appeared in the literature as to the distance (volume) within which 90% of the energy of a particular emission will be absorbed.(*) Appropriate choices may be possible, based on knowledge of whether the radiopharmaceutical has bound to the cell membrane, a cytoplasmic component or intranuclear molecule and knowledge of cell binding heterogeneity. (3) The third consideration is to effect greatest use of the radiolabel which has achieved localization. That is, once binding or entry has occurred, efforts have to be made to keep it on (in) the cell. At maximum efficiency, turnover of the radiolabel would be identical to cell turnover. In other words, the effective life within the lesion would approach the life 461
RICHARD P. SPENCER
462
span of the cells, and any shorter biological turnover of the label would be negligible. This might be achievable by avid binding to a cellular component with low turnover, such as nuclear DNA, or by metabolic trapping. In most cases however, it is probable that techniques will have to be employed to retard egress. A well documented example involves inhibition of release of iodinated compounds from the thyroid, by the lithium ion.@) In most biological systems the entry or transport pathways are distinct from the exit mechanisms; hence, as knowledge of the efflux systems increases, it may be possible to achieve their inhibition (and hence most efficient use of therapeutic radionuclides). (4) Finally, we have to consider possible synergistic effects between therapy with radiopharmaceuticals and other agents. That is, can tissues be “sensitized” to therapy by radiopharmaceuticals, or can one or more therapeutic modalities be used at the same time? The relationship between externally and internally delivered radiation exposures has been described in the 1iterature.(4) Can we extrapolate further and build upon the known ability of some compounds to make hypoxic tissue susceptible to externally delivered ionizing radiation? The answer is not presently known. However, any progress in this area might be followed by the ability to treat lesions which are now only marginally treatable, or to reduce the whole body radiation dose during therapy of susceptible areas. Availability of tomographic techniques has permitted more accurate delineation of lesion size and spatial distribution. A corollary is that following this distribution in a time-dependent manner should allow better design of dose delivery. For example, a y ray emitter might be used first to determine distribution and, based on this, an tl, B or Auger electron emitter (preferably of the same element) then used in therapy. It is also conceivable that the residence time of an agent containing therapeutic activity levels might be shorter (due to cell damage) than that of a tracer amount of radiopharmaceutical. If this could be documented by sequential tomographic images, compensation might be possible by means of a larger therapeutic dose. The “classical” formulation for fi ray dosage (homogeneous radionuclide distribution) is: Dose (rad) = Ea.C.t,,,
(73.8)
Here E, is the average /I ray energy in MeV, C is the concentration in the lesion (pa/g), t,,* is the effective half-life in days, and the numerical term is a conversion factor. The formula is linear in concentration (amount in the tumor), but is not truly linear in terms of E,.t1,2. That is, a long-lived (say 20 d physical t,,*) radionuclide of 0.2 MeV B particle energy would not give the same biological effect as a 2d t,,z material with a 2 MeV /? ray. Part of this would be due to the different effective half-lives, part due to the different size of the irradiated zone, and part would result from “escape” of a small amount of the energetic /? energy
in the form of bremsstrahlung. The energy escape results in less radiation of the lesion and more radiation of surrounding tissues. This means that the figure of merit is reduced. The escape of energy also has deleterious effects when two organ systems are intertwined, and irradiation of one leads to irradiation of the other. For example, bone spicules border and project into the bone marrow. Delivery of radiation to the bone matrix, by deposition of radiopharmaceuticals on the surface of the calciumphosphorus substrate, invariably results in some radiation of bone marrow. In this situation, the requirement for a low energy B particle (or a particle, or Auger electron emitter) is particularly apparant.
Binding Considerations Short-lived (short physical t,,,) radionuclides may have two advantages for internal radiation therapy. (1) If physical t,,z is shorter than the rate of biological turnover, and the uptake is rapid, then essentially all of the radiation (total decay) is delivered to the area. (2) The number of atoms in a millicurie of a short-lived material is less than that in a longer-lived radionuclide. The number of atoms in a therapeutic radiopharmaceutical is crucial to the success of therapy; for example, a cubic centimeter of tissue has about IO9 cells. The number of atoms (N) in a radioactive material is given by the expression: 1 dN N=K.dt or: N=5&$ Where K is the decay constant and t,,* is the physical half-life; for 1 mCi of a material (dN/dt = 3.7 x lO’/s), the number of atoms present is directly proportional to the half-life of the radionuclide. That is, there are more atoms in 1 mCi of a long-lived radionuclide than there are in a short-lived one. For example, for “C (t,,2 = 20 min), 1 mCi contains 6.4 x lOi atoms. With “‘In (t,,, = 2.8 d), there are 1.3 x lOI atoms present in the “carrier free” material. (A) This becomes important when there are a limited number of tissue binding sites, since a longlived radionuclide (or a shorter-lived one with nonradioactive “carrier” present) may present too many atoms. That is, a substantial portion may remain unbound increasing whole body radiation (and increasing imaging difficulty if a y emitter is utilized). (B) A short-lived material will dissipate more rapidly; there is thus less likelihood of the radiolabel being “lost” prior to cell turnover.
Principles of radiopharmaceutical
Most desirable are compounds (C) that have a high binding affinity for the cellular receptor (R). C+R+C.R.
A metabol1arn
That is, in addition to the specific activity of the compound, we have to be concerned with the “forward rate constant” (K,) or rate constant for binding. In the most favorable cases, K, is appreciable, while K, and K, are considerably smaller in magnitude. It is apparent that the principles to employ with therapeutic radiopharmaceuticals are evolving. The ultimate test of usefulness, clinical applications, are still before us. The use of these therapeutic agents might eventually be integrated into overall schemes
use in therapy
463
for treating tumors. For example, surgical “dechemotherapy and therapeutic radiobulking”, pharmaceuticals might all have sequential or concurrent use in a treatment scheme.
References Spencer R. P. Inr. J. Nucl. Med. Biol. 6, 212 (1979). Jungerrnan J. A., Yu K. H. P. and Zanelli C. I. Int. J. Appl. Radiat. Isot. 35, 883 (1984).
Burrow G. N. and Spaulding S. W. In Therapy In Medicine. (Ed. Spencer R. P.) pp. 113~119. (Grune & Stratton, New York. 1978). Bigler R. E. In Therapy In Nuclear Medicine. (Ed. Spencer R. P.) pp. 17-31. (Grune & Stratton, New York. 1978). Nuclear