RESUMO
A new radio-HPLC detection system for measuring radioactivity in plasma samples during Positron Emission Tomography [PET] studies was developed. It is based on detecting both the positron and one of the annihilation photons. The system focused on improving the measurement of radioactivity concentrations on an unmetabolized positron emitting a radiopharmaceutical [PER] in the presence of its radioactive metabolites, all containing the same positron emitter. This paper presents a new detection configuration that improves the minimal detectible activity (MDA), simplify the measuring systems and reduces the error caused by the metabolites. The detector is based on a plastic scintillator and a BGO scintillation crystal, that produces different light output spectra for signal and noise events. By summing the positron and the annihilated photon light outputs, different spectra are obtained for the metabolite and for the parent compound tracer and for tracer marked by different positron emitting isotopes. This new detection system can improve quantitative analysis of plasma samples. The spectrum change provides up to a three-fold improvement in sensitivity compared to the currently used detection systems that measure only the annihilation coincidence events. Results showed that for 11C the MDA was improved by approximately 520%. Furthermore, it provides the additional advantage of reliability by providing a method for separating the signal and noise readings from the gross detector readout. Accurate reconstruction algorithm of the signal was achieved over a wide measuring range even when the signal was only 5% of the gross measurement.
Assuntos
Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/sangue , Algoritmos , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Telomerase activation and an alternative lengthening of telomeres (ALT) mechanism are two telomere-lengthening cancer cell survival mechanisms elicited by both chemo- and/or radiotherapy. Telomere lengthening interferes with cell lethality and results in the immortalization of cancer cells. To counteract these mechanisms, we developed a drug delivery system (DDS) consisting of a polymeric implant that is inserted directly into tumors. The DDS releases, continuously and gradually, a cationic porphyrin (PdTMPyP4) for >30 days after a single application, and inhibits telomerase activation. METHODS: The PdTMPyP4 porphyrin is incorporated into a poly(co-glycolic lactic)acid (PLGA) polymer, solidified and cut into small rods. PdTMPyP4 release from the rods was measured spectrophotometrically over time. Uptake of Pd in the DNA of in L428 Hodgkins lymphoma cells was measured by ICP-MS, and telomerase activation by the TRAP assay. The rods were placed into the growth medium of cells whose growth rate was measured for 11 and 19 days. The cylinders were also inserted directly into KHJJ murine mammary tumors borne on the thighs of BALB/c mice and the tumor growth rate measured. RESULTS: In vitro, >10(9)Pd atoms were measured in the DNA of each L428 cell and telomerase activity was reduced by ~15% within 24 h. A one-time application of the rod in the cell medium induced a factor of >5 greater lethality compared to a blank rod or untreated controls. In vivo, a one-time insertion of the rod into tumors resulted in the retardation of the growth rate by factors of 3-5 compared to untreated controls. Systemic uptake after intratumoral insertion of the rod was negligible. CONCLUSION: The results suggest that the direct intratumoral insertion of a PdTMPyP4-containing polymeric rod would be of benefit as an adjuvant treatment for patients undergoing chemo- or radiotherapy. By preventing the lengthening of telomeres and therefore the unrestricted growth of cancer cells, our DDS will provide a significant therapeutic advantage to these treatments without affecting normal tissues.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Doença de Hodgkin/prevenção & controle , Neoplasias Mamárias Animais/prevenção & controle , Porfirinas/administração & dosagem , Telômero/genética , Inibidores da Angiogênese/farmacologia , Animais , DNA de Neoplasias/genética , Feminino , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Humanos , Ácido Láctico/química , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Paládio/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Porfirinas/farmacologia , Telomerase/metabolismo , Células Tumorais CultivadasRESUMO
Effectiveness of trimming external carcass surfaces from subprimals during fabrication to reduce Escherichia coli O157:H7 surrogates was evaluated. Carcass sides (n = 10 sides) were inoculated along the hide pattern opening before entering the blast chill cooler with a gelatin slurry containing a bacterial cocktail of three rifampicin-resistant, nonpathogenic E. coli biotype I strains. Following a 48 h chill, sides were fabricated to produce eight subprimals. Microbiological samples were taken from the original carcass fat surface area, initial lean surface area, trimmed fat surface area (where applicable), and trimmed lean surface area (where applicable). Newly exposed lean surfaces had lower (P < 0.05) counts of rifampicin-resistant E. coli than did the external fat surfaces. However, fat and lean surfaces that were not inoculated became contaminated during the fabrication process. Trimming external surfaces reduced levels of pathogens, but under normal fabrication processes, pathogens were still spread to newly exposed surfaces.
Assuntos
Escherichia coli O157/isolamento & purificação , Manipulação de Alimentos/métodos , Carne/microbiologia , Animais , Bovinos , Contagem de Colônia Microbiana , Escherichia coli O157/patogenicidade , Contaminação de Alimentos/prevenção & controle , Microbiologia de AlimentosRESUMO
We postulated that nitroimidazoles, previously used for radiosensitizing solid tumors, may be interesting templates as carriers of 10B for boron neutron capture therapy. To test this hypothesis, we synthesized a 10B-enriched nitroimidazole, 1-2[(undecahydro-closo-dodecaborato)thio]ethyl]-2- methyl-5-nitroimidazole (imidocaptate), by coupling the Cs salt of BSH (Cs2-10B12H11SH) with 1-(2-bromoethyl)-2-methyl-5-nitroimidazole followed by purification of the adduct. Imidocaptate was taken up by V-79 cells in culture and showed no inherent toxicity under euoxic conditions up to 1.05 mM (126 micrograms of 10B/mL of culture medium). Imidocaptate showed a dose-dependent decrease in D0 when the treated cells were irradiated with a thermal neutron beam. At the highest dose tested (126 micrograms of 10B/mL of culture medium), the ratio of control to sample D0 values was 2.6 for both linear quadratic and single-hit multitarget models. At 33 micrograms of 10B/mL, imidocaptate showed a control/treated D0 ration (1.5) equal to that observed with the disulfide form of BSH at 28 micrograms of 10B/mL. Compared to BSH and its disulfide, the reduced toxicity and equipotency of imidocaptate suggest that this agent may be useful for boron neutron capture therapy of cancer.
Assuntos
Compostos de Boro/síntese química , Compostos de Boro/farmacologia , Terapia por Captura de Nêutron de Boro , Sobrevivência Celular/efeitos dos fármacos , Nitroimidazóis/síntese química , Nitroimidazóis/farmacologia , Animais , Compostos de Boro/metabolismo , Linhagem Celular , Cricetinae , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Neoplasias/radioterapia , Nitroimidazóis/metabolismoRESUMO
The present study reports the results of V-79 Chinese hamster cell survival studies in which Auger electron emission was stimulated in gadolinium (Gd) after thermal neutron capture. When a porphyrin that had previously been labeled with boron (10BOPP) was also labeled with Gd (Gd-10BOPP), the cells were incubated with Gd-10BOPP to assess the compound's ability to physiologically transport the Gd into the cell, and localize the Gd atoms in or near the cell's critical target, presumably the DNA. It was anticipated that Auger electron emission, stimulated during the 157Gd (n, gamma)158Gd interaction, would impart additional high LET damage to that observed from the alpha-particle and Li ion during the 10B(n, alpha) 7Li reaction. Following irradiation with thermal neutrons from the Brookhaven Medical Research Reactor, the effectiveness of the Auger electrons was determined by comparing the response of cells incubated with 10BOPP, where damage was imparted by the boron neutron capture (BNC) products, to that from Gd-10BOPP, with equal concentration of 10B in both solutions. An Auger effectiveness factor of approximately 2 was found for the Gd-10BOPP cells. The Auger effectiveness observed with Gd strongly suggested that the 10BOPP molecule physiologically transported the Gd3+ ion intracellularly where it probably bound to DNA. Others have reported that Gd3+ does, in fact, complex with DNA. While depositing less energy per interaction than the high LET BNC reaction by-products, Auger electron ionization was more effective.
Assuntos
Boro/farmacocinética , Gadolínio/farmacocinética , Transferência Linear de Energia , Animais , Linhagem Celular/metabolismo , Linhagem Celular/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Cricetinae , Cricetulus , Análise de Ativação de Nêutrons , Porfirinas/metabolismo , Eficiência Biológica RelativaRESUMO
As a follow-on study to the feasibility of neutron capture therapy (NCT) with 235U brachytherapy seeds, physical doses were calculated and measured for the radiation from a 235U foil in a lucite phantom which was irradiated at the epithermal neutron irradiation port of the Brookhaven Medical Research Reactor. In addition, cell survival experiments were performed to obtain the relative biological effectiveness (RBE) for the neutron part of the radiation. The calculated absorbed doses agree with the measured ones. From cell survival experiments, it is deduced that the fission neutrons from the 235U foil have a RBE of 3.0 while the fast neutrons in the beam have a RBE of 3.8. Also observed is that, with the cells 7 mm from the foil, a significant amount of absorbed dose comes from the beta rays of 235U fission events. This absorbed dose from beta rays is a significant addition to the therapeutic dose. Due to the limited ranges of beta rays in tissue, this absorbed dose is restricted to the vicinity of the foil. This is the first demonstration of beta rays as part of NCT.
Assuntos
Braquiterapia/métodos , Modelos Estruturais , Terapia por Captura de Nêutron/métodos , Urânio , Partículas beta , Sobrevivência Celular/efeitos da radiação , Estudos de Viabilidade , Raios gama , Humanos , Método de Monte CarloRESUMO
The resurgence of interest in boron neutron capture therapy (BNCT) as a potential treatment for glioblastomas and melanomas has resulted in a quest to identify and synthesize candidate compounds which can physiologically target the 10B atoms to tumor cells. Numerous boron-carrying compounds are now available and awaiting evaluation. Because the products of the boron neutron capture (BNC) reaction generally contribute greater than 50% of the dose in BNCT, the evaluation of the efficacy of boron compounds would be more precise if it were possible to remove, quantitatively, the dose contributed by the external reactor radiations. The purpose of this study is to report a method which does just that, i.e., leaves for precise evaluation the biological effect that is ascribable to the BNC products only. The evaluation involves a series of separately quantifiable factors, the product of which provides an overall "figure of merit" for the compound.
Assuntos
Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro , Animais , Compostos de Boro/farmacocinética , Células Cultivadas , Cricetinae , Cricetulus , Avaliação Pré-Clínica de Medicamentos/métodos , Transferência Linear de EnergiaRESUMO
Photon activation therapy is a binary system being investigated as a potential therapeutic modality to improve the treatment of malignancies, particularly the highly lethal and malignant brain tumor, glioblastoma multiforme. Its success relies upon the incorporation of a target atom in the immediate vicinity of a tumor cell's critical site, followed by the activation of this atom with photons of energies suitable for the induction of the photoelectric effect and its concomitant Auger cascades. The collective action of the Auger electrons imparts high-LET type damage at the critical site. Photon activation therapy uses iodine from stable iododeoxyuridine (IdUrd) as the target atom, and monochromatic photons above the K absorption edge of iodine (33.2 keV) as the activating agent. Although IdUrd is a cell-sensitizing agent, work described was designed to separate the biological efficacy due to sensitization from that of the Auger effect. Chinese hamster V79 cells with and without IdUrd in cellular DNA were irradiated at the X17B1 beam line in the National Synchroton Light Source of Brookhaven National Laboratory. Monochromatic photons above (33.4 keV) and below (32.9 keV) the K absorption edge were used to determine if any additional biological damage would accrue from the Auger cascades. The 33.4-keV photons were found to be a factor of 1.4 times more effective than 32.9-keV photons in damaging iodinated cells. The sensitizing effect, evaluated separately, was found to be a factor of 2.2 at 10% survival, regardless of photon energy. Thus the total therapeutic gain was 1.4 x 2.2 = 3.1. Irradiations of noniodinated control cells showed no difference in their response to energies above and below the iodine K edge.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Idoxuridina/efeitos da radiação , Animais , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Cricetinae , Cricetulus , Relação Dose-Resposta à Radiação , Elétrons , Idoxuridina/farmacologia , RadiaçãoRESUMO
Low-density lipoproteins (LDLs) are known to be internalized by the cell through receptor-mediated mechanisms. There is evidence that LDLs may be taken up avidly by tumor cells to provide cholesterol for the synthesis of cell membranes. Thus, the possibility exists that LDLs may provide an ideal vehicle for the transport of boron to tumor cells for boron neutron capture therapy. A boronated analogue of LDL has recently been synthesized for possible application in boron neutron capture therapy. The analogue was tested in cell culture for uptake and biological efficacy in the thermal neutron beam at the Brookhaven Medical Research Reactor. It was found that boron concentrations 10 times higher than that required in tumors for boron neutron capture therapy were easily obtained and that the amount of uptake was consistent with a receptor-mediated binding mechanism. The measured intracellular concentration of approximately 240 micrograms 10B/g cells is significantly higher than that obtained with any other boron compound previously evaluated for possible clinical application.
Assuntos
Boro/metabolismo , Lipoproteínas LDL/metabolismo , Nêutrons , Animais , Ácidos Bóricos/metabolismo , Boro/uso terapêutico , Linhagem Celular , Veículos FarmacêuticosRESUMO
Epithermal neutron beams are under development in a number of locations in the U.S. and abroad. The increased penetration in tissue provided by these neurons should circumvent problems associated with the rapid attenuation of thermal neutron beams encountered in previous clinical trials of neutron capture therapy (NCT). Physical and radiobiological experiments with two "intermediate energy" or "epithermal" beams have been reported. A comparison is made here between the 24-keV iron-filtered beam at Harwell, England, and the broad-spectrum Al2 O3 moderated beam at the Brookhaven Medical Research Reactor (BMRR). In addition, parameters which are relevant for NCT, and which are best suited for evaluation and comparison of beams, are discussed. Particular attention is paid to the mean neutron energy which can be tolerated without significant reduction of therapeutic gain (TG), where TG is the ratio of tumor dose to maximum normal tissue dose. It is suggested that the simplest and most meaningful parameters for comparison of beam intensity and purity are the epithermal neutron fluence rate, and the fast neutron dose per epithermal neutron (4.2 X 10(-11) rad/neutron for the broad-spectrum beam and 29 X 10(-11) rad/neutron for the 24-keV beam). While the Al2O3 beam is close to optimal, the 24-keV beam produces a significant fast neutron dose which results in a lower TG.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Nêutrons , Fenômenos Biofísicos , Biofísica , Neoplasias Encefálicas/radioterapia , Estudos de Avaliação como Assunto , Nêutrons Rápidos/uso terapêutico , Humanos , Dosagem Radioterapêutica , Eficiência Biológica RelativaRESUMO
Quantitative evaluation of the dose enhancement obtained with analog nucleoside agents such as iododeoxyuridine (IdUrd) requires knowledge of the degree to which the thymidine (Thd) in DNA is replaced by IdUrd. In the present investigation, mice were infused with IdUrd using an intravenous infusion apparatus capable of delivering continuous multi-day infusions without restraining the mice. The absolute incorporation of IdUrd in DNA was measured by 125IdUrd label, both in whole tissue and extracted DNA, showing a good correlation between levels observed in DNA and whole tissue. Replacement in a Harding-Passey murine melanoma tumor carried in BALB/c mice approached 10%. In addition, a Neutron Activation Analysis (NAA) technique was developed which showed in vitro, a sensitivity sufficient to evaluate the % replacement of Thd by IdUrd in small biological samples with a sensitivity greater than 0.1 ppm, at 1% replacement in mg samples. This method can provide information on iodine substitution in DNA in humans where the use of a radioactive DNA-seeking substance would be undesirable. Analyses of IdUrd incorporation in cultured cells by NAA and 125I counting showed good agreement.
Assuntos
DNA de Neoplasias/metabolismo , Idoxuridina/uso terapêutico , Melanoma Experimental/radioterapia , Radiossensibilizantes , Animais , Idoxuridina/administração & dosagem , Bombas de Infusão , Radioisótopos do Iodo , Camundongos , Camundongos Endogâmicos BALB C , Análise de Ativação de Nêutrons , Timidina/metabolismoRESUMO
A major problem remaining in the evaluation of boronated compounds for neutron capture therapy (NCT) is the need to know the intra- or extracellular microdistribution of boron. This is a consequence of the short range of the 10B(n,alpha)7Li reaction products (approximately 10 microns), such that biological efficacy is dependent upon intracellular distribution. In particular, if boron location is predominantly extracellular, a significant reduction in efficacy would be expected. The in vitro procedure described here was developed mainly to provide information regarding the intra- and extracellular location and concentration of boron. However, use of the technique also allows the measurement of compound uptake and retention (binding) and the determination of biological efficacy by the evaluation of survival curves obtained following irradiation with thermal neutrons. Comparison is made to results obtained with boric acid (H3(10)BO3) and to results calculated for various boron distributions. Concomitantly, an indication of compound toxicity can be obtained from the plating efficiency of unirradiated control cells. Currently, most investigators utilize in vivo systems for testing and evaluating boron uptake from various carrier molecules. Given the large number of boron compounds being synthesized and needing evaluation as to their usefulness for NCT, the in vitro technique described here is simple and advantageous for initial compound screening. In addition to sparing animal lives, it is both time and cost effective and utilizes much smaller quantities of test compound than are required for an in vivo assay. A boronated porphyrin (BOPP) evaluated by the above procedure shows an uptake and retention approximately 20 times that of sulfhydryl boron hydride monomer (BSH); the latter compound is currently being used clinically for NCT in Japan and is anticipated for use in clinical trials in the United States. If the advantages demonstrated by BOPP in these in vitro studies are validated in animal experiments, BOPP should be considered for clinical application.
Assuntos
Boranos/farmacologia , Boroidretos , Boro/uso terapêutico , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Nêutrons , Radioterapia/métodos , Compostos de Sulfidrila/farmacologia , Sulfetos/farmacologia , Animais , Boranos/síntese química , Divisão Celular/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Isótopos , Cinética , Compostos de Sulfidrila/síntese química , Sulfetos/síntese químicaRESUMO
NCT is a binary system, in which 10B is physiologically targeted to tumor and then allowed to interact with thermal neutrons generated in the treatment volume by an externally applied neutron beam. Consequently, an unusually large number of parameters are obtained, which bear on the resultant Therapeutic Gain (TG). However, a perusal of these data, as illustrated in Figure 7, indicates that the TG would increase significantly beyond values projected in this paper if the absolute amount of 10B could be increased above 30 ppm. For example, increasing 10B concentration in tumor to 45 ppm would increase TG by approximately 33% (with a T/N of 5). A similar increase in TG would follow an increase in T/N from 5 to 10. Those associated with the development of boron compounds for NCT feel that such developments are within reach.
Assuntos
Nêutrons/uso terapêutico , Reatores Nucleares/instrumentação , Compostos de Boro/uso terapêutico , Neoplasias Encefálicas/radioterapia , Arquitetura de Instituições de Saúde , Humanos , Modelos Estruturais , Radiossensibilizantes , Dosagem RadioterapêuticaRESUMO
A technique to produce radiation enhancement during interstitial brain tumor irradiation by using a radiation sensitizer (iododeoxyuridine-IdUrd) and by stimulation of Auger electron cascades through absorption of low-energy photons in iodine is described. Clinical studies using iododeoxyuridine, 192Ir as a brachytherapy source, and external radiation have produced promising results. Substituting 145Sm for 192Ir in this protocol is planned to evaluate the enhanced dose resulting from photon activation therapy.
Assuntos
Braquiterapia/métodos , Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Idoxuridina/administração & dosagem , Radiossensibilizantes , Técnicas Estereotáxicas , Humanos , Radioisótopos/uso terapêutico , Dosagem Radioterapêutica , Samário/uso terapêuticoRESUMO
Thiouracil (TU) selectively binds to the pigment melanin during melanogenesis and is rapidly cleared from normal tissues. This compound shows little affinity for pre-formed melanin. BALB/c mice, carrying the subcutaneously transplanted Harding-Passey melanoma, were given i.p. injections of 35S-labeled thiouracil in a range of doses and administration schedules. Injected doses ranged from 1.3 to 10 mCi per mouse with resultant tumor dose rates of 10 to 30 cGy/hr, respectively. At the lower dose rates, growth delay of approximately 1 to 2 weeks was observed in all tumors. At the highest doses used, complete tumor regression (no regrowth) was observed in some cases, with extended growth delays of approximately 6 weeks in the rest. These results illustrate the possible utility of radiolabeled thiouracil as a systemically administered brachytherapy agent for melanoma.
Assuntos
Braquiterapia/métodos , Melanoma Experimental/radioterapia , Radioisótopos de Enxofre/uso terapêutico , Tiouracila/farmacocinética , Animais , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos BALB CRESUMO
A number of groups in the United States have received funding that will permit evaluation of the clinical efficacy of the neutron capture therapy (NCT) procedure. Various reactors are being modified to allow the construction of an epithermal neutron beam. At the Brookhaven Medical Research Reactor (BMRR), the patient irradiation facility is being modified to produce an optimized epithermal neutron beam. An 80-cm-thick A1-D2O mixture (184 g/cm2, 25% D2O by volume) is being installed in the shutter assembly. One-dimensional calculations indicate that this configuration should provide an epithermal neutron flux density of approximately 1 x 10(9) n/cm2/sec at 3 MW and a concomitant fast neutron dose rate of approximately 2 x 10(-11) rad per epithermal neutron (assuming a homogeneous A1-D2O mixture). The actual geometry will be an inhomogeneous array of D2O and A1 layers producing parameters somewhat less favorable than those listed above; experimental verification is in progress. Significant gains have recently been made in selectively targeting B to melanoma with various melanaffinic compounds, including p-boronophenylalanine, and with boronated porphyrins that may be applicable to a variety of tumors. Neutron capture radiographs have been obtained with the above compounds, and efforts have been made to quantitate boron uptake in growing and quiescent or necrotic regions of tumor via double-labeling techniques obtained with tritiated thymidine. A correlation between therapeutic efficacy and the ability to deliver boron to viable areas of tumor has been observed.
Assuntos
Boro/uso terapêutico , Melanoma Experimental/radioterapia , Nêutrons , Animais , Boro/metabolismo , Compostos de Boro/metabolismo , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Reatores NuclearesRESUMO
The conditions for the possible initiation of clinical trials with neutron capture therapy at a number of locations in the U.S. is reviewed. There are several new technical developments or plans at the Brookhaven Medical Research Reactor (BMRR), the Power Burst Facility (PBF) at INEL, the Massachusetts Institute of Technology Reactor (MITR) and the Georgia Institute of Technology Research Reactor (GTRR). Emphasis is on the development of epithermal beams for the treatment of deepseated tumors with neutron fluxes in between 10(9) to 10(10) n/cm2s. Therapeutic dose gains, defined as the ratio of tumour dose to maximum normal tissue dose in the treatment volume are expected to be between 2 and 4, depending on the degree of suppression of fast neutron dose. Boron concentrations considered in this case in the tumour are around 35 micrograms 10B/g and tumour/normal tissue concentrations are around 10. The compound development throughout three generations is discussed. The compound proposed nowadays, Na2B12H11SH (or BSH), employed in the treatments in Japan, will likely be replaced in the future by analogous of biomolecules being enriched in the tumour by physiological pathways. Examples are p-boronophenylalanine or boronated porphyrius. The most promising solution envisaged would be the employment of tumour cell specific brononated monoclonal antibodies. Finally the mode of therapy is discussed which will likely be based on a fractioned scheme, to achieve optimized results.