Franssen, EJF

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Proceedings - University of Groningen

   University of GroningenUnderstanding Intracellular MetabolismFranssen, EJFPublished in:Journal of Nuclear MedicineIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1994Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Franssen, EJF. (1994). Understanding Intracellular Metabolism: A Key to the Rational Design for TargetingDrugs and Radionuclides. Journal of Nuclear Medicine, 35(9), 1559-1560.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 04-06-2022to toxic nodules within the frame of Graves' disease that cannot.Furthermore, hyperthyroid patients with an increased ITI aremore resistant to treatment (3). We also showed that a high IU(>40%) does not exclude iodine excess, nor does a normal urinaryiodide, and the PB*I at 24 hr correlates negatively with ITI so thatthis measurement can be used to predict the iodide stores of thegland (4).Of course, we are aware that the possibilities of measuring ITIare very scarce. Nevertheless, as we estimate that more than 30%of our hyperthyroid population present with iodine excess (especially the elderly as they need more radiodine), it is important torecognize some indicators that can be overlooked. Aside from theclassical features, such as knowledge of iodine intake, a low IUand an increase of urinary iodide, the following factors shouldalert the physician to the possibility of iodine excess (at least inareas with relatively low iodine intake): a nonautoimmune toxicnodular goiter with a low PB* I at 24 hr and a suspiciously highT4H3 ratio. Radioiodine treatment should then be adapted accordingly.REFERENCES1. Shapiro B. Optimization of radioiodine therapy of thyrotoxicosis: what havewe learned after 50 years? (Editorial). J NucÃ-Med 1993;34:1638-1641.2. Bockisch A, Jamitzky T, Derwanz R, Biersack HJ. Optimized dose planning of radioiodine therapy of benign thyroid diseases. J NucÃ-Med 1993;34:1632-1638.3. Jonckheer MH, Velkeniers B, Vanhaelst L, Van Blerk M. Further characterization of iodide-induced hyperthyroidism based on the direct measurement of intrathyroidal stores. NucÃ-Med Comm 1992;13:114-118.4. Jonckheer MH, Flamen P, Velkeniers B, Vanhaelst L, Kaufman L. Radio-iodine turnover studies as a means to predict stable intrathyroidal iodinestores and comments upon its use in the diagnosis and treatment of hyper-thyroidism. Thyroid 1993;3:11-16.M.H. JonckheerVrije Universiteit BrÃ¼sselBrussels, BelgiumREPLY: Your concurrence with the important differences between thyroid disease in Europe and the United States is ofinterest.The points you make about the in intrathyroidal iodine pool arevery well taken. Indeed I meant for this to be included as one ofthe many influences under the specified and unspecified "fudgefactors" in Table 2.X-ray fluorescent thyroid scanning to depict and quantify intrathyroidal iodide stores is an important and unique technique(providing data unavailable by RIU or urinary iodide measurements). My reason for not discussing the problems of variableintrathyroid iodide stores was primarily the space limitation forsuch editorials and the unfortunate fact that the technology offluorescent thyroid scanning has not become widely disseminatedand is not generally available in the U.S. (indeed no commercialdevices are available). The alternative and much more readilyperformed study which is to determine the 131I-PBI, as well as the131I-RIU, at 24 hr after tracer administration is an excellent suggestion and should be more widely practiced since it is within theability of almost any laboratory with a wellcounter.B. ShapiroUniversity of Michigan Medical CenterAnn Arbor, MichiganUnderstandingIntracellularMetabolism:A Key tothe RationalDesignfor TargetingDrugsandRadionuclidesTO THE EDITOR: I read with interest the article by Duncan andWelch on the intracellular metabolism of 1HIn-DTPA-labeled receptor-targeted proteins (7 ). They demonstrate that in vitro theseproteins are degraded in the lysosomes and that low molecularweight catabolites are formed containing the '"In label. In follow-up studies, they have identified the metabolite as ulln-DTPA-lysine. This metabolite remains in the lysosomes and isonly slowly released from the cell. This may be one of the causesof the high renal and hepatic tracer accumulation as observed inscintigraphy of '"In-labeled monoclonal antibodies.This work shows an interesting relation with my studies on thetargeting of drugs to the kidney and the liver using low molecularweight proteins and neoglycoproteins as carriers (2-5). In thisconcept of drug targeting, the lysosomal apparatus regeneratesthe active (parent) drug. In these studies, drugs were conjugatedto proteins using a method similar to that applied by Duncan andWelch for mIn-DTPA conjugation, i.e., an amide bond betweenthe drug and the amino groups of proteins. My co-workers and Ihave demonstrated that lysosomal digestion of these conjugatesresults in drug-lysine compounds rather than the parent drugs (2).For instance, the anti-inflammatory agent naproxen conjugated tothe low molecular weight protein lysozyme or to (neoglyco)albu-mins renders naproxen-lysine in lysosomal lysates. This is similarto the finding by Duncan and Welch that luIn-DTPA-lysine is themajor radioactive metabolite of lysosomal targeted proteins.In contrast, as observed for IUIn-DTPA-lysine in vitro,naproxen-lysine is capable of leaving cells. This has been demonstrated for the lysosomal processing of naproxen-lysozyme andvarious naproxen-(neoglyco)albumin conjugates in vitro as well asin vivo (3,4). This suggests that derivatization of the e-aminogroups of lysines per se does not prevent lysosomal-efflux oflysine-derivatives; rather, other molecular characteristics such assize, charge and lipophilicity of the drug or nuclide-chelator complex may determine lysosomal efflux properties. Therefore, itmight be interesting to learn whether '"In-DTPA-COOH can belysosomally regenerated in its parent form and whether it is capable of leaving lysosomes.In targeting drugs with proteins, a spacer between the drug andthe protein is essential to regenerate the coupled drugs in theirparent form in the lysosomes. In this respect it will be interestingto investigate whether the lysosomal efflux can be modulated byusing different coupling modalities to the protein. In principle, twodifferent approaches may be of interest. One is the use of enzy-matically degradable spacers, like L-lactic acid derivatives andthe other is the use of acid-sensitive linkages. In the former case,DTPA can be indirectly attached to the protein via an ester bond.Ester bonds may be lysosomally cleaved by various carboxyes-terases as demonstrated for naproxen coupled to proteins viaalpha-hydroxy-acid spacers (2,5).Due to the narrow specificity of lysosomal enzymes, the connecting bonds between drugs and amino acids often remain intactin lysosomes (2); therefore, an even more viable approach may beusing acid-sensitive spacers between the chelator and the protein-backbone. One possibility may be the use of a cÂ¿s-aconityl-likeamide bond (2 ). In this concept the amide bond that is stable in thebloodstream is selectively cleaved in lysosomes due to the acidenvironment (pH = 4-5). The advantage of this approach aboveLetters to the Editor 1559the enzymatic approach is that in principle no enzymes are required to cleave these kinds of bonds.I share the authors' view that intracellular metabolism can verywell be studied in in vitro model systems; however, it should benoted that in vitro procedures may suffer from limitations likedecreased enzyme activity of cell-homogenates and lysosomallysates. These can be caused by isolation artefacts, like loss ofco-factors during the work-up of these preparations. Therefore, acombination of in vitro and in vivo studies are needed to obtainoptimal results on the intracellular metabolism of receptor-targeted proteins. Finally, the identification of metabolites like'"In-DTPA-lysine contributes to the understanding why highbackground radioactivity of labeled monoclonal antibodies is observed in the liver and kidneys. Improved knowledge on this pointaids in the rational design of improved drug/nuclide targetingpreparations.REFERENCES1. Duncan JR, Welch MJ. Intracellular metabolism of indium-111-DTPA-labeled receptor targeted proteins. J NucÃ-Med 1993;34:1728-1738.2. Franssen EJF, Koiter J, Kuipers CAM, et al. Low molecular weight proteins for renal drug targeting: preparations of drug-protein conjugates anddrug-spacer derivatives and their catabolism in renal cortex homogenatesand lysosomal lysates. J Med Chem 1992;35:1246-1259.3. Franssen EJF, van Amsterdam R, Visser J, et al. Low molecular weightproteins for renal drug targeting: Naproxen-Lysozyme. Pharm Res 1991;8:1223-1230.4. Franssen EJF, Jansen RW, Vaalburg M, et al. Hepatic and intrahepatictargeting of an anti-inflammatory agent with human serum albumin andneoglycoproteins as carrier molecules. Biochem Pharmacol 1993;45:1215-1226.5. Franssen EJF, Moolenaar F, de Zeeuw D, et al. Low molecular weightproteins for renal drug targeting: naproxen coupled to lysozyme via thespacer L-lactic acid. Phaim Res 1993;10:963-969.K.J.F. FranssenUniversity Hospital GroningenGroningen, the NetherlandsREPLY: We appreciate Dr. Franssen's interest and insightfulcomments. We agree entirely with the central theme of his letter:an understanding of intracellular metabolism will be key in therational design of targeted drugs and diagnostic agents. We alsoagree with his contention that derivatization of the e-amino groupof lysine does not prevent lysosomal efflux of lysine derivativesper se. Rather, we suggested that ulIn-DTPA-amino acids wouldremain within the lysosome since their positive and negativecharges would limit diffusion across the membrane (1). We alsobelieve that size, charge and lipophilicity of the drug or nuclide-chelator will determine lysosomal efflux properties. When identifying in vivo metabolites, we found the predominant metabolitewas ulIn-DTPA-e-lysine and only small amounts of mIn-DTPAwere produced (2). We were pleased to find Dr. Franssen's work,as well as other reports that suggest that lysosomes infrequentlyhydrolyze the amide bonds between lysine and "foreign" substances such as drugs and chelates.We also hope to modulate the rates of lysosomal efflux throughappropriate choices of chelates and their linkages to protein backbones. We plan to test these using reconstituted systems, cellculture models and in vivo experiments.In summary, we hope all our correspondence with this journalwill be in the same tone of complete agreement.REFERENCES1. Duncan JR, Welch MJ. Intracellular metabolism of indium-111-DTPA-labeled receptor targeted proteins. J NucÃ-Med 1993;34:1728-1738.2. Franano FN, Edwards WB, Welch MJ, Duncan JR. Metabolism of receptortargeted ' ' 'In-DTPA-grycoproteins: identification of ' "In-DTPA-e-lysine asthe primary metabolic and excretory product. Nuc! Med Biol 1994:in press.JamesR. DuncanMichaelJ. WelchF. NicholasFrananoMallinckrodt Institute of RadiologyWashington University Medical CenterSt. Louis, MissouriTBI Is Not MIBITO THE EDITOR: I read with great interest the case report byDesai and Yuille describing 99mTc-MIBI uptake in a recurrentcarcinoid tumor (1). Three 99mTc-labeled isonitriles have beenevaluated in detail in humans: TBI (tertiarybutyl isonitrile), CPI(carbomethoxyl isopropyl isonitrile) and MIBI (methoxy isobutylisonitrile) (2-4). High uptake in the lung and liver limited theclinical use of 99mTc-TBI (2,5-7). However, "mTc-MIBI, anether-substituted analog of 99rnTc-TBI, has gained wide clinicalacceptance.Desai and Yuille stated that Ramanathan et al. (8) had used"Tc-MIBI for visualization of suppressed thyroid tissue, confusing TBI with MIBI. In fact, Ramanathan et al. have used"Tc-TBI for this purpose. Although both 99mTc-MIBI and""Tc-TBI are essentially isonitriles, they have different chemicalstructures, biological behavior and in vivo distribution (2,5-11).REFERENCES1. Desai SP, Yuille DL. Visualization of a recurrent carcinoid tumor and anoccult distant metastasis by technetium-99m-sestamibi. J NucÃ-Med 1993;34:1748-1751.2. Holman BL, Jones AG, Lister-James J, et al. A new "Tc-labeled myo-cardial imaging agent, hexakis (t-butylisonitrile) technetium (I) ["Tc-TBI]:initial clinical experience in human. J NucÃ-Med 1984;25:1350-1355.3. Holman BL, Sporn V, Jones AG, et al. Myocardial imaging with techne-tium-99m-CPI: initial clinical experience in human. J NucÃ-Med 1987;28:13-18.4. Wackers FJTh, Berman DS, Maddahi J, et al. Technetium-99m hexakis2-methoxyisobutyl isonitrile: human biodistribution, dosimetry, safety andpreliminary comparison to thallium-201 for myocardial perfusion imaging.J NucÃ-Med 1989;30:301-311.5. Jones AG, Abrams MJ, Davison A, et al. Biological studies of a new classof technetium complexes: the hexakis (alkylisonitrile) technetium (I) cations. Int J NucÃ-Med Biol 1984;ll:225-234.6. McKusick KA, Holman BL, Jones AG, et al. Comparison of three "Tcisonitriles for detection of ischemie heart disease in humans [Abstract]. JNucÃ-Med 1986;27:878.7. Williams SJ, Mousa SA, Morgan RA, et al. Pharmacology of "Te isonitriles: agents with favorable characteristics for heart imaging [Abstract]../NucÃ-Med 1986;27:877.8. Ramanathan P, Patel RB, Subrahmanyam N, et al. Visualization of suppressed thyroid tissue by technetium-99m-tertiarybutyl isonitrile (""Tc-TBI): an alternative to post-TSH stimulation scanning. J NucÃ-Med 1990;31:1163-1165.9. Picard M, Dupras G, Taillefer R, et al. Myocardial perfusion agents: compared biodistribution of 2Â°'TI,"Tc-tertiary butyl isonitrile (TBI), and"Tc-methoxyisobutyl isonitrile (MIBI) [Abstract]. J NucÃ-Med 1987;28:654.10. Gerundini P, Munitili L. Cationic complexes of technetium for myocardialimaging. J NucÃ-Med 1989;30:1415-1419.11. Piwnica-Worms D, Krounage JF, Holman BL, Davison A, Jones AG.1560 The Journal of Nuclear Medicine â€¢Vol. 35 â€¢No. 9 â€¢September 1994

Understanding Intracellular Metabolism:A Key to the Rational Design for Targeting Drugs and Radionuclides

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Understanding Intracellular Metabolism:A Key to the Rational Design for Targeting Drugs and Radionuclides

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