Chapter Introduction

Transcription

1 Chapter 1 Introduction Malignancy is a life-threatening condition in which tumor cells are of a highly invasive character and penetrate normal organs and exhibit an obstinate resistance against cancer therapy. Glioblastoma multiforme (GBM) in the brain, undifferentiated carcinoma of the thyroid gland, small cell lung cancer, and malignant melanoma are typically malignant and their five-year survival rates are very low, 5 10%. It is an earnest wish to control them in human being. However, malignant tumors are highly invasive, they easily metastasize to the lymph nodes and other organs at a very early stage. As a rule, a malignant brain tumor (e.g. GBM) does not invade extracranially, but it invades throughout the brain at an early stage. Generally, malignancies are treated by multidisciplinary modalities, such as extirpation + radiation + chemotherapy as shown in Fig As for radiation therapy, malignant tumors are resistant to photon therapies, such as X-ray and γ-ray, thus high linear energy transfer (LET) radiation such as heavy ionizing particles and neutron capture therapy must be employed. Neutron capture therapy (NCT) is a binary cancer treatment in which a cytotoxic event is triggered when an atom, placed in a cancer cell, absorbs a low energy, thermal, neutron. It is a seemingly ideal form of therapy, in that it kills cancer cells while sparing healthy cells. Although many of the references cited in this book are quite recent, the basic concept of neutron capture therapy was first proposed in 1936 by Gordon L. Locher 1 when he formulated his binary concept of treating 1

2 2 Boron and Gadolinium Neutron Capture Therapy for Cancer Treatment Figure 1.1 The treatment strategy for malignancies. cancer: enough knowledge of the remarkable behavior of neutrons has been accumulated through physical research to enable the prediction of certain biological effects, and to see, in a general way at least, certain therapeutic potentialities of this new kind of corpuscular radiation. In particular, there exist the possibilities of introducing small quantities of strong neutron absorbers into the regions where it is desired to liberate ionization energy (a simple illustration would be the injection of a soluble, nontoxic compound of boron, lithium, gadolinium, or gold into a superficial cancer, followed by bombardment with slow neutrons. This remarkable approach to cancer treatment was proposed shortly after the discovery of the neutron. It not only outlines the general approach but also gives the two elements, boron and gadolinium, which are currently studied as NCT agents. These two elements are unusual in that several of their isotopes have very high abilities to absorb thermal neutrons. The probability that a particular isotope will absorb a thermal neutron is given by its nuclear capture cross section, σ th, measured in barns (b = cm 2 ). This should not be taken as a measure of physical size, but rather as a measure of the probability of a nucleus absorbing a neutron. In general the capture cross section of a nucleus increases as the velocity of the bombarding neutron decreases; slow neutrons spend

3 Introduction 3 Figure 1.2 the neutrons. Change in the neutron capture cross section with the energy of more time around a nucleus and hence are more likely to be captured. Figure 1.2 shows the change in cross section as a function of neutron speed. In the low-energy region (thermal neutrons) the cross section varies as 1/v (v = speed of the neutron), this is the 1/v region and the cross section is large. This is followed by a region of resonance peaks where the cross sections rise and fall sharply, depending on whether the energy of the neutron closely matches the discrete quantum levels of the nucleus. The fast neutron region, where the cross sections are very small, follows this. In NCT, one is interested in the region of thermal neutrons. Boron-10, has an unusually high capture cross section of 3838 b, while the isotopes 155 Gd and 157 Gd have even larger ones of 60,900 b and 255,000 b, respectively, for thermal neutrons. These cross sections are orders of magnitude higher than those of the elements that constitute the

4 4 Boron and Gadolinium Neutron Capture Therapy for Cancer Treatment Table 1.1 Thermal neutron capture cross sections of common biological tissue. Thermal Thermal Neutron Capture Neutron Capture Cross Section Cross Section sth[b] Weight % in sth[b] Weight % in 1 barn = Mammalian 1 barn = Mammalian Nuclide cm 2 Tissue Nuclide cm 2 Tissue 1 H P C S N Cl K Na Ca Mg Fe He 2+ (1.47 MeV) + 7 Li 3+ (0.84 MeV) + γ (0.48ΜeV) 94% 10 B+n th [ 11 B] 6% 4 He Li MeV Scheme 1.1 Boron neutron capture reaction. bulk of biological tissue (see Table 1.1.) The magnitude of these cross sections depends on nuclear structure, for example, σ th for 11 B is only b. This is significant in that natural abundant boron is only about 20% 10 B. n absorption of a thermal neutron (E < 0.4 ev) by 10 B, an excited 11 B is formed that almost immediately ( s) undergoes a fission reaction producing two high-energy heavy ions, 4 He 2+ (α-particle) and 7 Li 3+, and a low energy γ-ray (see Scheme 1.1). The high kinetic energy 4 He 2+ and the 7 Li 3+ transfer their energies over a very short distance, ~ 4 9 µm in biological tissue, this LET is of the order of a cell diameter. Therefore, if sufficient compounds containing

5 Introduction Gd+n th 158 *Gd 158 Gd + γ +7.9MeV internal conversion (IC) electrons Auger Coster Kronig (ACK) electrons Scheme 1.2 Gadolinium neutron capture reaction. 10 B can be preferentially absorbed in a cancer cell, and bombarded with thermal neutrons, cell damage would be confined to that particular cell, sparing neighboring healthy cells. This is the basis of all BNCT treatments. The gadolinium neutron capture (GdNC) reaction, 157 Gd(n,γ) 158 Gd, is more complex than that of boron, and it is not a fission reaction. f its seven stable isotopes, gadolinium has two isotopes that are of interest to NCT, 155 Gd (σ th = 55,000 b) and 157 Gd (σ th = 255,000 b). The 157 Gd has the highest thermal neutron capture cross section of all the stable isotopes in the periodic table. The GdNC reaction initiates complex inner-shell transitions, as shown in Scheme 1.2, that generate prompt γ emission displacing an inner core electron which, in turn, induces internal-conversion (IC) electron emission and finally Auger Coster Kronig (ACK) electron emission along with soft X-ray and photon emissions. 3 8 The low-let γ-rays have an average energy of 2.2 MeV with a range of several centimeters. The IC electrons possess average energies of around 45 ev, paired with a range of several millimeters in physiological tissue. Finally, the range of the very low energy ACK electrons is only several nanometers in aqueous solutions. Although low in absolute energy, the ultra-short range of the ACK electron energy deposition effectively makes the ACK radiation component of the GdNC reaction a high-let-type and is radiologically the most relevant component of the GdNC. 9. The ACK electrons provoke high LET-type damage with a mean free path of 12.5 nm. Since this ionizing radiation is limited to molecular dimensions, it is essential to place the gadolinium atoms within the DNA helix to induce significant DNA damage in cancer cells. Both clinical and chemical studies related to BNCT have progressed since the early 1950s. Boron compounds are easily incorporated in organic

6 6 Boron and Gadolinium Neutron Capture Therapy for Cancer Treatment N N N Gd H H Figure 1.3 MRI contrast agent [Gd(DTPA)(H 2 )] 2 magnevist. structures and their chemistry has been extensively investigated. 10 n the other hand, the toxicity of Gd 3+ had prevented its use until the development of suitable complexes of Gd 3+, such as gadopentetate dimeglumine, [Gd(DTPA)(H 2 )] 2 (see Fig. 1.3), and their use as magnetic resonance imaging (MRI) contrast agents in As a consequence, there is much more literature available on BNCT than there is on GdNCT. 11