Surgery – Radioactive substance applied to body for therapy
Reexamination Certificate
2001-05-09
2004-05-18
Gilbert, Samuel G. (Department: 3736)
Surgery
Radioactive substance applied to body for therapy
Reexamination Certificate
active
06736769
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to local delivery of radioactivity. The present invention also relates to localized inhibition of cell proliferation using radioactivity.
2. Brief Description of the Prior Art
The therapeutic use of radiation therapy to reduce the proliferation of rapidly dividing cells has evolved from the Bergonié and Tribondeau Law of radiobiology which states that proliferative cells are more radiosensitive than normal cells (Bergonié and Tribondeau, 1959, Radiat. Res. 11:587). Hence, radiation therapy can be used to reduce proliferation cells in a tumor. The Bergonié and Tribondeau principle needs not be limited to the treatment of malignant tumors, however. A number of clinical situations require the reduction of cell proliferation: treatment of heterotopic bone formation, prevention of cheloids and more recently the inhibition of intimal hyperplasia. Having discovered that smooth muscle cell proliferation is inhibited after irradiation, radiation therapy has thus been applied to reduce the restenosis process following coronary angioplasty.
Coronary angioplasty is actually a well-established technique for the treatment of obstructive coronary disease. More than 500,000 angioplasties are performed every year worldwide. However, two major problems remain unsolved.
The first problem is acute closure, reported to occur in up to 11% of the cases after balloon angioplasty (Dorros et al., 1983, Circulation 67:723-730). In that context, intracoronary stenting appears as an invaluable procedure for the treatment of extensive dissections occurring after angioplasty. As a scaffolding vessel wall support, it preserves adequate coronary opening and perfusion.
The second problem is restenosis which has been shown to occur in 30 to 50% of the cases. So far, drug therapy has shown limited results in reducing the extent of the phenomenon (Popma J J et al., 1991, Circulation 84:1426-1436). Intracoronary stents have been shown in randomized trials, to reduce restenosis from 42% to 32% in the Stress trial while from 32% to 22% in the Benestent trial (Fischman D L. et al., 1994, N. Engl. J. Med. 331:496-501; Serryus P W. et al., 1994, N. Engl. J. Med. 331:489-495). The beneficial effect of stenting is presumably due to a better vessel geometry after dilation, although stenting has been proved to induce more neo-intima formation than other devices in swine (Karas S P. et al., 1992, J. Am. Coll. Cardiol. 20:467-474). Indeed, swine has been recognized as a relevant animal model for restenosis although the rat and rabbit animal models are also widely used. Morphologically and hemodynamically the porcine coronary vascular system is very similar to the human coronary system. Reproducible intimal proliferation is obtained after balloon injury in the pig coronary arteries. Histologically, the proliferative response to balloon injury in the pig coronary is very similar to the response seen in pathological studies of humans (Schwartz et al., 1990, Circulation 82:2190-2200).
Balloon dilation leads to global vascular lesions which include mechanical deformation of the vessel, extensive destruction of the endothelium and immediate formation of thrombus. All of these act through vasoactive hormones, growth factors, circulating cells and presumably lipids on the media muscle cells. It is observed that smooth muscle cells are activated and migrate to the intima where after proliferation and matrix secretion, a “neo-intima” is generated [Hamon et al., 1995, Eur Heart J 16(
Suppl
1):33-48]. This observation led to the proposal of a cellular mechanism for restenosis (FIG.
1
). The role of elastic recoil and vessel remodeling has also been recognized following angioplasty (Kakuta T. et al., 1994, Circulation 89:2809-2815). Finally, thrombus adhesion through growth factors liberation, also plays a major role in the activation cascade (Fager G. et al., 1995, Circ. Res. 77:645-650).
Until now, drug therapy has consistently been focused on proliferation and thrombus inhibitions (Popma J J et al., 1991, Ibid.). Unfortunately, no significant effects were observed in human coronary restenosis when the drugs were administered systemically (Popma J J et al., 1991, Ibid.). The lack of a sufficient local drug concentration is the most common advocated reason to explain the inability to reduce neointima formation in humans. The research has thus targeted the local delivery of different drugs to prevent restenosis (Lincoff A M et al., 1994, Circulation 90(4):2070-2084). New catheters are already available to deliver drugs locally after angioplasty and feasibility trials are being conducted (Fram D B et al., 1994, J. AM. Coll. Cardiol. 23:186A).
Although the genetic and molecular understanding of the different mechanisms involved in restenosis have also been greatly improved, due to its complexity, the clinical genetic treatment of restenosis is expected to be very expensive and not readily available for still some time (Bennet M R. et al., 1995, Circulation 92:1981-1993).
The use of radiotherapy to reduce neointima formation was thus identified as a possible solution to the restenosis problem. Three basic approaches utilizing radiotherapy have thus been proposed:
1) External Irradiation:
External delivery using Gamma or Beta irradiation, showed that, at the single high dose used, a decrease in hyperplasia is observed. However, some groups detected fibrosis or necrosis in the irradiated region (Schwartz R S. et al., 1992, J. Am. Coll. Cardiol. 19:1106-1113). Moreover, this type of approach encompasses the irradiation of a large field.
2) Radioactive Catheter:
Experiments carried out with endovascular irradiation at the high dose/rate of Beta or Gamma rays produced a significant reduction in neointimal formation. However, this positive effect seems to be accompanied by fibrosis of the vessel resulting in a loss of vascular function thereof, suggesting that in the long term such a type of treatment might be detrimental. Furthermore, the irradiation treatment at the time when peak proliferation potential of the smooth muscle cells occurs (i.e. 24-48 hours) would be at best impractical in a clinical situation. Moreover, arteries receiving higher doses showed an increase diameter suggesting that irradiation would affect vessel remodeling [Waksman R. et al., 1995, J. A. Coll. Cardiol. (Special Issue (February 95)]. Of note, Brenner et al., 1996 (Radiation Oncology Biol. Phys. 36: 805-809) showed that a single high dose does not inhibit restenosis. Also, it has been reported that a 18 Gy single irradiation, failed to show a significant reduction in restenosis.
2) Radioactive Stents:
The group of Fischell studied the effects of P
32
stent wire on smooth muscle cells and endothelial cells proliferation in tissue culture (Fischell T A. et al., 1994, Circulation 90: 2956-2963; and U.S. Pat. No. 5,059,166 and 5,176,617). Titanium wire which was first impregnated with P
31
and then activated in a fission reactor was used. The resulting radioactive stent is thought to be emitting Beta radiation, although contaminating a and y emissions are likely because of the impregnation method. The use of such a stent on muscle cells demonstrated a dose response curve of inhibition at linear activities. However, at the highest wire activity level, there was inhibition observed as far as 10.6 mm from the wire.
This degree of penetration suggests that the stent emitted Gamma rays and that the use thereof in vivo would not deliver the radiation specifically to the targeted site, since a significant amount of normal surrounding tissue would be irradiated. This issue, amongst others, was indeed raised by Crocker et al., 1995 (Circulation 92:1353). The ion implantation technique creates lattice defects in the metallic crystal structure resulting in stoichiometric modification. These defects can contribute to diffusion of ions (leeching) modification of surface potential and alterations in clinical properties. Consequently, this method of radioactivation can alter the
Bertrand Olivier
Mongrain Rosaire
Gilbert Samuel G.
Merchant & Gould P.C.
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