Vasallaje

organs taking advantage of both their anticoagulating and anti-inflammatory properties, but later reports of acute and chronic side effects including chills, fever, muscle pain, abdominal cramps, hemoglobinemia and hemoglobinuria indicated their undesirability (Evans, 1990). Despite great efforts which finally lead to the development of less toxic derivatives, rare earths were excluded from the market as safer, more effective and cheaper drugs, such as heparin, became available.

10.2

Present Use of Rare Earth Elements

10.2.1

Lanthanum Carbonate Used as Phosphate Binder

Though in the past, rare earths failed to be introduced in medicine mostly due to the develop- ment of more effective and less toxic drugs, the inverse has been shown recently. As it is known that patients suffering from chronic renal insufficiency develop hyperphosphatemia, drugs are re- quired to lower phosphate levels. However, the use of former phosphate-binding agents based on aluminium or calcium has been overshadowed by severe side-effects including aluminium-related bone and central nervous system toxicity as well as increased risks of hypercalcaemia and car- diovascular calcification. Although the more recently introduced drug, sevelamer hydrochloride (RenagelR), presented less coronary and aortic calcification and lower cholesterol levels than calcium-based phosphate binders, its application has been limited due to gastrointestinal adverse effects, large pill burdens and high costs.

In search of alternatives, scientists came across lanthanum carbonate, a rare earth salt that pro- vides highly effective phosphate binding properties that make it beneficial for the treatment of hyperphosphatemia. Hyperphosphatemia results from renal failure as the kidney becomes unable to excrete phosphate properly. Left untreated, it will lead to the stimulation of parathyroid hor- mone and the suppression of vitamin D3 production. This further causes renal osteodystrophy,

metastatic calcification and increased morbidity probably due to increased myocardial, vascular calcification and cardiac microcirculatory abnormalities. In the process of vascular calcification, phosphate seems to play a major role. Additionally, it has been stated that hyperphosphatemia is directly associated with reduced life expectancy. Hence, safe and effective phosphate binders were urgently needed to control phosphate serum levels (Harrison and Scott,2004), (Behets et al.,

2004b), (Hutchison and Albaaj, 2005). Preclinical and clinical studies reported lanthanum car- bonate to be an effective phosphate binder with very low toxicity and minimum gastrointestinal absorption thus offering a good safety profile. Oral administration of 1 g of lanthanum carbonate three times daily was proved to be efficient, while additionally showing good tolerability, whether taken during or shortly after eating.

Its efficiency is based upon the formation of a water-insoluble compound after binding to phos- phate which enables lanthanum carbonate to decrease serum phosphorus levels, calcium x phos- phorus product and serum parathyroid hormone (PTH) levels in patients with end-stage renal disease (ESRD) significantly, while the phosphorus balance is maintained (Fiddler et al.,2003b), (Fiddler et al., 2003a), (Sack et al., 2002), (Hutchison and Webster, 2003), (Hutchison et al.,

1998), (Finn et al.,2003), (Finn,2003), (Stewart et al.,2003), (Hutchison and Albaaj,2005). Less than 0,001 % of the lanthanum dose was absorbed into the systemic circulation when given with food and even oral administration of a cumulative 15 g dose only resulted in very low lanthanum plasma levels<1 ng/ml (Stewart et al.,2003), (Fiddler et al.,2003a), (Steward and Frazer,2002). In addition, it is reported to be well tolerated, whereas most adverse events were mild to moderate in severity with gastrointestinal events, such as vomiting, nausea and diarrhoea, being the most

10 THEAPPLICATION OFRARE EARTH ELEMENTS TOMEDICINE

common. Long-term studies have been consistent with previous findings in efficacy and safety. Furthermore, the lack of any acute or long-term central nervous system toxicity confirms the low potential of lanthanum carbonate to enter brain tissue (Harrison and Scott,2004), (Hutchison et al.,

1998), (Pennick et al., 2004), (Jones et al., 2004). Even though it is known that lanthanides are able to bind to DNA, RNA and nucleotides in vitro, lanthanum carbonate has neither in vitro nor in vivo demonstrated genotoxicity, which might be ascribed to the fact that this chemical class is unable to penetrate the cell membrane of healthy, intact cells (Evans, 1990), (Damment et al.,

2004). However,Lacour et al.(2005) hypothesized that the accumulation of lanthanum after oral administration in chronic renal failure might be far above the lanthanum concentration observed under normal conditions. They demonstrated that feeding a lanthanum carbonate containing diet to healthy rats led to a tenfold increase of tissue lanthanum contents in some organs including liver, lung and kidney. However, a close focus on the experimental design and the calculation of tissue contents showed that these results have to be considered as artifacts. High contents found in lung tissue turned out to be the result of inhalation of particles from the diet rather than from oral intake since lanthanum carbonate was applied in terms of powder instead of pellets. Lung deposition of rare earth elements following inhalation has been reported before, while, at present, there is no study describing this after oral application. In accordance with this case, Rambeck

(2005) has pointed out that caution must be paid when interpreting animal data.

Previous experiences with aluminium-based phosphate binders, which revealed bone toxicity, aroused suspicion towards the use of lanthanum carbonate after effects on bone were observed. Further studies, however, proved that high-dose induced effects of lanthanum carbonate on bone mineralization in chronic renal failure rats are attributable to phosphate depletion and not to direct bone toxicity (Damment and Shen, 2005), (Damment et al., 2003), (D’Haese et al., 2003). On the contrary, lanthanum has even been shown to improve bone-cell activity, it thus demonstrated positive effects on bone metabolism. After one year of treatment, the mean lanthanum content was low and the development of renal osteodystrophy was reduced (D’Haese et al.,2003), (Freemont and Denton, 2004). Based on this information, it can be concluded that patients receiving lan- thanum carbonate may be less likely to develop osteopenia. Additional information concerning the possible use of rare earths in the treatment of osteoporosis will be provided in Section10.3.4.

As to their use in the treatment of hyperphosphatemia, lanthanum carbonate has been granted first global approval as a new effective non-calcium, non-aluminium phosphate binder in Swe- den in 2004 (Hutchison et al., 2004). Further marketing approvals were granted in the European Union and the United States in 2005. Presently, lanthanum carbonate is commercially available as FosrenolR, while it will soon be marketed throughout Europe as well (Newswire Europe Ltd,

2005).

Based on these encouraging results, applications might also capitalize on phosphate binding properties of lanthanum carbonate in veterinary medicine. However, first studies designed to investigate phosphate lowering effects of lanthanum carbonate in cats failed to reproduce pre- viously described results. As to phosphate levels in urine no significant differences were observed between animals receiving a lanthanum carbonate containing diet and control animals (Brugge,

2006). Nevertheless, it was reported earlier that phosphate lowering agents successfully used in cats did not affect phosphate levels in humans (Rambeck, 2006b). This indicates that there must be some differences between humans and animals with respect to phosphate metabolism.

10.2 Present Use of Rare Earth Elements

10.2.2

Treatment of Burns

So far rare earth applications have not been able to profit from the specific antimicrobial prop- erties of rare earths which are thought to be useful in combatting bacterial diseases, however, these properties are potentially valuable in new areas. In 1976, an ointment containing cerium nitrate- silver sulphadiazine for the topical treatment of burn wounds was introduced publicly (Monafo et al.,1976). Among its several advantages are easy and painless application and removal as well as the production of a yellow and leathery crust with good resistance to infection.

Burn injuries are still of great importance because they produce significant morbidity and mor- tality in developed countries. In Catalonia, 31 per 100 000 persons each year need special treat- ment, while the incidence and mortality due to burns is similar to other developed countries (Barret et al.,1999). The so-called burn disease, which causes infection with severe complications after a shock phase, constitutes a major problem in burn patients. High susceptibility to infection is based upon an acute and severe systemic and local inflammatory reaction which results from thermal in- jury that can be lethal. It has been proven that prompt excision of burn eschar and wound coverage improve chances for survival and prevent postburn immunosuppression (Deveci et al.,2000). Sim- ilarly, cerium silver sulphadiazine has also been shown to be safe and effective in the treatment of deep and extensive burns. By improving survival rates comparable to prompt excision, it seems to be a good alternative in patients not undergoing early wound excision and closure because of co-morbidity (Kistler et al., 1990), (Luo, 1990), (Boeckx et al., 1992), (Koller and Orsag,1998), (Deveci et al.,2000), (de Gracia, 2001), (Lorenz et al.,1988). Scheidegger et al.(1992) reported that one single bathing with 0.04 mol/l cerium nitrate of not less than 30 min, on the first day of burn, neutralizes eschar toxic material and improves the chances for survival enormously.

Cerium nitrate has a potent antiseptic effect in human burn wounds, especially against gram negative bacteria and fungi (Monafo et al., 1976), (Fox et al., 1977), (Wassermann et al., 1989). Thus, it significantly reduces the degree of Pseudomonas aeruginosa contamination and improves cell-mediated immunity (Zapata Sirvent et al., 1986), (Boeckx et al., 1985). The characteristic yellow-green color of cerium nitrate treated eschars may result from oxidation of trivalent cerium to yellow ceric ions thus providing a continuous source of ionic cerium for microbial inhibition (Fox et al., 1977). Suppression of cell-mediated immunity is associated with the absorption of burn toxin known as lipid protein complex (LPC), which stimulates phagocytic cells and thereby causes the release of a variety of inflammatory mediators (Fang et al., 1996), (Eski et al., 2001), (Boeckx et al., 1992), (Monafo et al., 1976), (Sparkes et al.,1990), (Jakupec et al., 2005). It has been observed that cerium nitrate trivalently binds the lipid protein complexes and thus prevents its entry into the circulation (Sparkes,1993), (Deveci et al.,2000). As an alternative to direct inter- action of cerium nitrate with the burn toxin or immunosuppressive factors, Ce3+ ions might exert direct impact on the cells producing those molecules (Evans,1990). IL-6 and TNF-α are impor- tant mediators of the acute and severe inflammatory reaction in thermal injury. It was reported that cerium nitrate is capable of suppressing the elevation of TNF-α levels by increasing IL-6 levels (Sparkes, 1997), (Deveci et al., 2000). Both its antiseptic and immunomodulatory properties as well as the formation of a physical barrier made of yellow-green eschar contribute to the effects of cerium nitrate. While Hirakawa (1983) stated that prolonged topical treatment of cerium ni- trate/silver sulfadiazine cream or cerium nitrate solution for burn injuries results in considerable absorption of silver and cerium into the liver and the kidney, no increasing toxicity was reported byBoeckx et al.(1992),Fox et al.(1977) andEvans(1990). Nowadays, cerium nitrate-silver sul- phadiazine is marketed throughout Europe, but is only available as FlammaceriumR in the UK (Garner and Heppell,2005).

10 THEAPPLICATION OFRARE EARTH ELEMENTS TOMEDICINE

10.2.3

Diagnosis and Treatment of Cancer

Cancer research in the early twentieth century aroused interest in rare earth treatments as po- tential anticancer drugs. In a first instance, a solution of cerium III iodide was applied to patients suffering from lymphogranulomatosis (M. Hodgkin) or inoperable tumors. The results obtained had been highly promising, reducing tumor sice and improving life quality (Lewin,1924), (Cohn,

1925). It was suggested that cerium might act either on its own or as an activator of iodine. Better effects of cerium iodide, compared to other iodide compounds, had been reinforced in an rabbit sarcoma study (Ito,1937). In contrast to those findings, Maxwell and Bischoff(1931) could not note any effects of cerium chlorides on tumor tissue using an experimental tumor model in rats.

The development of cancer is thought to be associated with iron overload resulting in acti- vation of the ROS which, along with other factors, leads to intranuclear changes and finally to alterations in cell proliferation and differentiation processes. Within this action, the signal trans- duction system, cell cycle and immunological functions are also out of order. Comprising iron uptake blocking, ROS inhibiting, signal transduction influencing as well as cell proliferation mod- ulating properties, which were described in Chapter 5, lanthanides provide several abilities that might interfere with the development of cancer. However, the duality of their actions definitely evokes certain problems and studies on anticancer properties of rare earths are therefore still con- troversial.

Several Chinese studies reported inhibitory effects on growth of sarcoma cells and Lewis lung cancer cells in mice as well as on leukemic cells (Yang et al., 1992b), stomach and lung cancer cells in humans (Wang et al., 2003b). Additionally, Jiang et al.(2004) stated that low dose of lanthanum nitrate could inhibit the progression of preneoplastic lesions in rat hepatocellular car- cinoma studies. Antineoplastic action of rare earth elements were also reported in further studies (Liu et al., 1999a), (Yang et al., 1997). It was assumed that anticancer effects are based upon inhibition of tumor cell proliferation, increase in macrophages and polymorphonuclear leukocytes activity as well as T-cell proliferation or selective cytotoxicity (Wang et al.,2003b).

Yet, antineoplastic effects were not only reported in China. Hence, suppression of tumor ac- tivity in lymphatic leukemia and lymphosarcoma bearing mice was shown byAnghileri (1975), who related the mechanisms involved to effects on tumor metabolism of calcium and magnesium.

Sato et al. (1998) described reduced growth of melanoma cells after lanthanide administration which they attributed to morphological changes and cell cycle arrest in the G0/G1phase. Strong

cytotoxic effects of cerium compounds on cancer cells were also shown byJakupec et al.(2002). They suspected interactions with calcium behind the effect since calcium plays an important role in controlling cell cycle and proliferation processes. Accordingly,Weiss et al.(2001) proved anti- proliferative actions of lanthanides on human colon cancer cells to be caused by an interruption of required calcium supply. Further speculations on the mechanism of anticancer action include enhanced expression of tumor suppressor gene, decreased calmodulin levels (Ji et al., 2000) or apoptosis, as is already seen in leukemic cells (Dai et al.,2002). Furthermore, it has been shown that lanthanides may facilitate the cellular uptake of certain drugs, e.g. cisplatin, by increasing cell permeability (Canada et al., 1995) as suspected earlier by Lewin (1924) and Cohn (1925). Although rare earths seem to provide a certain potential for the use in cancer chemotherapy, more detailed research is necessary before rare earths can be applied clinically.

However, as various radioisotopes exist among lanthanides, their ability to emit α, β or γ - radiation may enable them to approach tumor therapy from another direction. Thus, in nuclear medicine and isotopic diagnostics, radionuclides of heavy rare earths (177Lu,153Sm,171Eu,157Dy)

10.2 Present Use of Rare Earth Elements

have been investigated for their use in bone imaging and internal radiotherapy of bone neoplastic metastases from breast or prostate (Marciniak et al., 1996). In addition, 90Y was shown to be a suitable radionuclide for therapeutic purposes. 90Y is a pureβ - emitter with a penetration depth of 1 cm and a half-life time of 60 hours.

Nevertheless, despite their high metabolic affinity for malign tissue which is useful in tumor scanning, lanthanide radionuclides are rather directly placed at the site of the tumor. This can be done by either intra- or peri-tumor injections or by surgical implantation, thereby minimizing any toxic effect on healthy neighboring tissue. Using colloidal lanthanides, one can take advantage of the fact that insoluble complexes are well retained at the injection site (Evans, 1990). But, intraperitoneal administration of lanthanides may be applied in case of ascites tumor. In the past, lanthanum was shown to be a potent inhibitor of Ehrlich ascites tumors in mice, which could successfully reduce the number of tumor cells and prolong the survival (Lewin et al.,1953). Yet, in human tumors, mainly surgical implantation was used, thereby allowing the successful treatment of Nelson’s syndrom, Cushing syndrom as well as treatment of mammary and prostatic carcinoma (Haley,1979). Treatment of cancers may also take advantage of the fact that tissue concentrations of lanthanides alter during cancer (Evans,1990). Thus, measuring lanthanide concentrations may provide valuable diagnostic and prognostic information. As to bone seeking radionuclides, such as153Sm, it has been reported that they may also be used efficiently to relieve the pain originating from bone metastases (Bayouth et al.,1994), (Serafini,2000).

At present, lanthanide-loaded micro-particulate systems are under investigation for cancer imaging or as radionuclides for therapy. Advanced biodegradable drug delivery systems based on liposomes and polymeric nanoparticle have already significantly improved anticancer thera- pies. They are effective tools that carry anticancer drugs to their site of action. Co-loading with non-radioactive or radioactive lanthanides may further expand their use (Zielhuis et al., 2005). Additionally, based on their inhibitory action on the reticuloendothelial system (RES), lanthanides might also be able to enhance the effectiveness of monoclonal antibodies and liposome-encoated drugs, thereby preventing their sequestration by the RES.

10.2.4

Contrast Agents

Lanthanides have not only become a useful tool in scintigraphic imaging as described above in tumor diagnostic and therapy, but also as contrast agents in several other imaging techniques. Based upon their paramagnetic properties (Chapter4), lanthanides have been introduced as con- trast agents in magnetic resonance imaging, which is one of the most powerful techniques in medical diagnosis and biomedical research. Administration of contrast media is designed to en- hance the contrast between normal and diseased tissue or to indicate organ function or blood flow. Gadolinium was found to be superior to other lanthanides in terms of proton spin-lattice relax- ation times (Evans, 1990). Possessing seven unpaired electrons, each gadolinium particle itself is a micro-magnet, thus capable of accelerating the relaxation of water protons in surrounding tissues. In 1988, [Gd(DTPA)(H2O)]2− was approved as first commercial contrast material (Helm

et al.,2003). Presently, gadolinium(III)chelates are widely used as intravenous contrast agents in clinical practice including mammography, diagnosis of liver metastasis or malign liver tumors, or verification of postoperative results, e.g. after liver transplantation or heart surgery by visualizing the blood flow (Bilow,2002), (Reimer and Vosshenrich,2004). Furthermore, improved diagnostic illustrations of brain tumors have been reported after using gadobenate dimeglumine, a gadolin- ium containing contrast agent (Knopp,2004). In addition, lanthanide containing contrast agents

10 THEAPPLICATION OFRARE EARTH ELEMENTS TOMEDICINE

are also applied in computer tomography to sharply brighten the image. Even small tumors of less than 5 mm, which stand out clearly as they do not take up injected lanthanide particles, have thereby been identified in liver tissue (Evans,1990). Using gadolinium as computer-tomographic contrast agents, good vascular, sufficient renal and suboptimal hepatic enhancements were re- ported (Gierada and Bae,1999).

In addition, lanthanides have also been used in cisternography to delineate cavities of extra- cellular compartments and provide information about fluid flows. Andrews and David (1974) were first to investigate the use of lanthanide DTPA complexes (169Y-DTPA), that are known to be highly stable, for the measurement of spinal fluid kinetics. Thus, images of excellent quality were obtained. Furthermore, intra-articular injections permitted scintographic detection of syn- ovial cysts. As Ln-DTPA complexes are rapidly excreted by the kidneys, they have also become useful markers to monitor glomerular filtration rates (Evans, 1990). Moreover, due to low gas- trointestinal absorption, lanthanides are efficient digesta markers in nutritional studies on both experimental animals and humans (Krysl et al., 1985), (Schuette et al., 1993), (FairweatherTait et al.,1997), (Bernard and Doreau,2000), (Xue and Cui,2001).

10.3

Potential Future Uses of Rare Earth Elements in Hu-