Single photon emission computed tomography/positron emission tomography imaging and targeted radionuclide therapy of melanoma: New multimodal fluorinated and iodinated radiotracers

Journal of Medicinal Chemistry

Volumn 54, Issue 8, 2011, Pages 2745-2766

  Maisonial, Aurélie ^a,e,f   Kuhnast, Bertrand ^b   Papon, Janine ^a,e,f   Boisgard, Raphaël ^b,c   Bayle, Martine ^a,e,f   Vidal, Aurélien ^a,e,f   Auzeloux, Philippe ^a,e,f   Rbah, Latifa ^a,e,f   Bonnet Duquennoy, Mathilde ^a,e,f   Miot Noirault, Elisabeth ^a,e,f   Galmier, Marie Josèphe ^a,e,f   Borel, Michèle ^a,e,f   Askienazy, Serge ^d   Dollé, Frédéric ^b   Tavitian, Bertrand ^b,c   Madelmont, Jean Claude ^a,e,f   Moins, Nicole ^a,e,f   Chezal, Jean Michel ^a,e,f  

^a UNIVERSITÉ CLERMONT AUVERGNE   (France)

^b SERVICE HOSPITALIER FRÉDÉRIC JOLIOT   (France)

^c UNIVERSITÉ PARIS SACLAY   (France)

^d Academisch Centrum Kinder en Jeugdpsychiatrie Curium   (France)

^e INSERM   (France)

^f CENTRE JEAN PERRIN   (France)

Author keywords

[No Author keywords available]

Indexed keywords

FLUORINE 18; IODINE 123; IODINE 124; IODINE 125; IODINE 131; N [2 [N ETHYL N [2 (2 FLUOROPYRIDIN 3 YLOXY)ETHYL]AMINO]ETHYL] 6 IODOQUINOXALINE 2 CARBOXAMIDE F 18; N [2 [N ETHYL N [2 (2 FLUOROPYRIDIN 3 YLOXY)ETHYL]AMINO]ETHYL] 6 IODOQUINOXALINE 2 CARBOXAMIDE I 131; QUINOXALINE DERIVATIVE; TRACER; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CHEMICAL STRUCTURE; CONTROLLED STUDY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG FORMULATION; DRUG SCREENING; DRUG SYNTHESIS; DRUG UPTAKE; FLUORINATION; GAMMA SCINTIGRAPHY; ISOTOPE LABELING; MALE; MELANOMA B16; MOUSE; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; RADIOIODINATION; RADIOISOTOPE THERAPY; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY;

ANIMALS; FLUORINE RADIOISOTOPES; IODINE RADIOISOTOPES; MELANOMA, EXPERIMENTAL; MICE; POSITRON-EMISSION TOMOGRAPHY; TISSUE DISTRIBUTION; TOMOGRAPHY, EMISSION-COMPUTED, SINGLE-PHOTON;

EID: 79955391535     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101574q     Document Type: Article

References (70)

1. Gray-Schopfer, V.; Wellbrock, C.; Marais, R. Melanoma biology and new targeted therapy Nature 2007, 445, 851-857
2. Belhocine, T. Z.; Scott, A. M.; Even-Sapir, E.; Urbain, J. L.; Essner, R. Role of nuclear medecine in the management of cutaneous melanoma J. Nucl. Med. 2006, 47, 957-967 (Pubitemid 46939948)
3. Thompson, J. F.; Scolyer, R. A.; Kefford, R. F. Cutaneous melanoma in the era of molecular profiling Lancet 2009, 374, 362-365
4. MacKie, R. M.; Hauschild, A.; Eggermont, A. M. M. Epidemiology of invasive cutaneous melanoma Ann. Oncol. 2009, 20, vi1-vi7
5. Markovic, S. N.; Erickson, L. A.; Rao, R. D.; Weenig, R. H.; Pockaj, B. A.; Bardia, A.; Vachon, C. M.; Schild, S. E.; McWilliams, R. R.; Hand, J. L.; Laman, S. D.; Kottschade, L. A.; Maples, W. J.; Pittelkow, M. R.; Pulido, J. S.; Cameron, J. D.; Creagan, E. T. Malignant melanoma in the 21st century, part 2: staging, prognosis, and treatment Mayo Clin. Proc. 2007, 82, 490-513 (Pubitemid 46543475)
6. Rass, K.; Hassel, J. C. Chemotherapeutics, chemoresistance and the management of melanoma G. Ital. Dermatol. Venereol. 2009, 144, 61-78
7. Chen, K. G.; Valencia, J. C.; Lai, B.; Zhang, G.; Paterson, J. K.; Rouzaud, F.; Berens, W.; Wincovitch, S. M.; Garfield, S. H.; Leapman, R. D.; Hearing, V. J.; Gottesman, M. M. Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 9903-9907 (Pubitemid 43993595)
8. Xie, T.; Nguyen, T.; Hupe, M.; Wei, M. L. Multidrug resistance decreases with mutations of melanosomal regulatory genes Cancer Res. 2009, 69, 992-999
9. Argenziano, G.; Soyer, H. P.; Chimenti, S.; Talamini, R.; Corona, R.; Sera, F.; Binder, M.; Cerroni, L.; De Rosa, G.; Ferrara, G.; Hofmann-Wellenhof, R.; Landthaler, M.; Menzies, S. W.; Pehamberger, H.; Piccolo, D.; Rabinovitz, H. S.; Schiffner, R.; Staibano, S.; Stolz, W.; Bartenjev, I.; Blum, A.; Braun, R.; Cabo, H.; Carli, P.; De Giorgi, V.; Fleming, M. G.; Grichnik, J. M.; Grin, C. M.; Halpern, A. C.; Johr, R.; Katz, B.; Kenet, R. O.; Kittler, H.; Kreusch, J.; Malvehy, J.; Mazzocchetti, G.; Oliviero, M.; Ozdemir, F.; Peris, K.; Perotti, R.; Perusquia, A.; Pizzichetta, M. A.; Puig, S.; Rao, B.; Rubegni, P.; Saida, T.; Scalvenzi, M.; Seidenari, S.; Stanganelli, I.; Tanaka, M.; Westerhoff, K.; Wolf, I. H.; Braun-Falco, O.; Kerl, H.; Nishikawa, T.; Wolff, K.; Kopf, A. W. Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet J. Am. Acad. Dermatol. 2003, 48, 679-693 (Pubitemid 36583277)
10. Fletcher, J. W.; Djulbegovic, B.; Soares, H. P.; Siegel, B. A.; Lowe, V. J.; Lyman, G. H.; Coleman, R. E.; Wahl, R.; Paschold, J. C.; Avril, N.; Einhorn, L. H.; Suh, W. W.; Samson, D.; Delbeke, D.; Gorman, M.; Shields, A. F. Recommendations on the use of 18F-FDG PET in oncology J. Nucl. Med. 2008, 49, 480-508 (Pubitemid 351355215)
11. Ametamey, S. M.; Honer, M.; Schubiger, P. A. Molecular imaging with PET Chem. Rev. 2008, 108, 1501-1516 (Pubitemid 351796395)
12. Clark, P. B.; Soo, V.; Kraas, J.; Shen, P.; Levine, E. A. Futility of fluorodeoxyglucose F 18 positron emission tomography in initial evaluation of patients with T2 to T4 melanoma Arch. Surg. 2006, 141, 284-288
13. Veit-Haibach, P.; Vogt, F. M.; Jablonka, R.; Kuehl, H.; Bockisch, A.; Beyer, T.; Dahmen, G.; Rosenbaum, S.; Antoch, G. Diagnostic accuracy of contrast-enhanced FDG-PET/CT in primary staging of cutaneous malignant melanoma Eur. J. Nucl. Med. Mol. Imaging 2009, 36, 910-918
14. Jiménez-Requena, F.; Delgado-Bolton, R. C.; Fernandez- Pérez, C.; Gambhir, S. S.; Schwimmer, J.; Pérez-Vasquez, J. M.; Carreras-Delgado, J. L. meta-analysis of the performance of 18F-FDG PET in cutaneous melanoma Eur. J. Med. Mol. Imaging 2010, 37, 284-300
15. 18F- fluorodeoxyglucose positron emission tomography/computed tomography and whole-body magnetic resonance imaging in staging of advanced malignant melanoma Eur. J. Cancer 2007, 43, 557-564 (Pubitemid 46177588)
16. 15O-water using compartment and noncompartment analysis J. Nucl. Med. 2001, 42, 248-256 (Pubitemid 32150515)
17. Jennings, L.; Murphy, G. M. Predicting outcome in melanoma: where are we now? Br. J. Dermatol. 2009, 161, 496-503
18. 111In labeled alpha-melanocyte stimulating hormone peptides as imaging probes for primary and pulmonary metastatic melanoma detection J. Nucl. Med. 2007, 48, 73-80 (Pubitemid 47555378)
19. 188Re labeled α-melanocyte stimulating hormone peptide analogs for melanoma therapy Int. J. Cancer 2002, 101, 480-487
20. 188Re labeled α-melanocyte stimulating hormone peptide analog in murine and human melanoma-bearing mouse models J. Nucl. Med. 2005, 46, 121-129 (Pubitemid 43086006)
21. 111In-DOTA-rhenium cyclised α-MSH analog: a novel cyclic-peptide analog with improved tumor-targeting properties J. Nucl. Med. 2001, 42, 1847-1855 (Pubitemid 34016356)
22. 177Lu labeled alpha-melanocyte stimulating hormone peptide analogues in a murine melanoma model Nucl. Med. Biol. 2005, 32, 485-493 (Pubitemid 40854099)
23. 68Ga-labeled DOTA-rhenium-cyclized α-MSH peptide analog to target MC1 receptors overexpressed by melanoma tumors Nucl. Med. Biol. 2009, 36, 505-513
24. 64Cu-labeled rhenium-cyclized α-MSH peptide analog using a cross-bridged cyclam chelator J. Nucl. Med. 2007, 48, 64-72 (Pubitemid 47555377)
25. 11), a cyclized peptide analogue of α-MSH J. Med. Chem. 2005, 48, 2985-2992 (Pubitemid 40548110)
26. 111In labeled DOTA conjugated rhenium cyclised α-MSH analogs J. Med. Chem. 2002, 45, 3048-3056
27. Miao, Y.; Hylarides, M.; Fisher, D. R.; Shelton, T.; Moore, H. A.; Wester, D. W.; Fritzberg, A. R.; Winkelmann, C. T.; Hoffman, T.; Quinn, T. P. Melanoma therapy via peptide-targeted α-radiation Clin. Cancer Res. 2005, 11, 5616-5621 (Pubitemid 41060840)
28. 203Pb-labeled α-melanocyte- stimulating hormone peptide as an imaging probe for melanoma detection J. Nucl. Med. 2008, 49, 823-829 (Pubitemid 351717549)
29. Miao, Y.; Quinn, T. P. Peptide-targeted radionuclide therapy for melanoma Crit. Rev. Oncol. Hematol. 2008, 67, 213-228
30. 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma Cancer. Res. 2010, 70, 4025-4053
31. Michelot, J. M.; Moreau, M. F. C.; Veyre, A. J.; Bonafous, J. F.; Bacin, F. J.; Madelmont, J. C.; Bussiere, F.; Souteyrand, P. A.; Mauclaire, L. P.; Chossat, F. M.; Papon, J. M.; Labarre, P. G.; Kauffmann, Ph.; Plagne, R. J. Phase II scintigraphic clinical trial of malignant melanoma and metastases with iodine-123- N -(2-diethylaminoethyl 4-iodobenzamide) J. Nucl. Med. 1993, 34, 1260-1266 (Pubitemid 23230353)
32. 123I- N -(2-Diethylaminoethyl)-2-iodobenzamide: a potential imaging agent for cutaneous melanoma staging Eur. J. Nucl. Med. 2002, 29, 1478-1484 (Pubitemid 35232050)
33. Eisenhut, M.; Hull, W. E.; Mohammed, A.; Mier, W.; Lay, D.; Just, W.; Gorgas, K.; Lehmann, W. D.; Haberkorn, U. Radioiodinated N -(2- diethylaminoethyl)benzamide derivatives with high melanoma uptake: structure-affinity relationships, metabolic fate, and intracellular localization J. Med. Chem. 2000, 43, 3913-3922
34. Pham, T. Q.; Greguric, I.; Liu, X.; Berghofer, P.; Ballantyne, P.; Chapman, J.; Mattner, F.; Dikic, B.; Jackson, T.; Loc'h, C.; Katsifis, A. Synthesis and evaluation of novel radioiodinated benzamides for malignant melanoma J. Med. Chem. 2007, 50, 3561-3572 (Pubitemid 47195463)
35. Liu, X.; Pham, T. Q.; Berghofer, P.; Chapman, J.; Greguric, I.; Mitchell, P.; Mattner, F.; Loc'h, C.; Katsifis, A. Synthesis and evaluation of novel radioiodinated nicotinamides for malignant melanoma Nucl. Med. Biol. 2008, 35, 769-781
36. 18F]DAFBA) : a novel potential PET probe to image melanoma tumors Bioconjugate Chem. 2009, 20, 583-590
37. Ren, G.; Miao, Z.; Liu, H.; Jiang, L.; Limpa-Amara, N.; Mahmood, A.; Gambhir, S. S.; Cheng, Z. Melanin-targeted preclinical PET imaging of melanoma metastasis J. Nucl. Med. 2009, 50, 1692-1699
38. 18F] N -(2-(diethylamino)ethyl)-6-fluoronicotinamide: a melanoma positron emission tomography imaging radiotracer with high tumor to body contrast ratio and rapid renal clearance J. Med. Chem. 2009, 52, 5299-5302
39. Denoyer, D.; Greguric, I.; Roselt, P.; Neels, O. C.; Aide, N.; Taylor, S. R.; Katsifis, A.; Dorow, D. S.; Hicks, R. J. High-contrast PET of melanoma using (18)F-MEL050, a selective probe for melanin with predominantly renal clearance J. Nucl. Med. 2010, 51, 441-447
40. Chezal, J. M.; Papon, J.; Labarre, P.; Lartigue, C.; Galmier, M. J.; Decombat, C.; Chavignon, O.; Maublant, J.; Teulade, J. C.; Madelmont, J. C.; Moins, N. Evaluation of radiolabelled (hetero)aromatic analogues of N -(2-diethylaminoethyl)-4-iodobenzamide for imaging and targeted radionuclide therapy of melanoma J. Med. Chem. 2008, 51, 3133-3144 (Pubitemid 351821874)
41. Madelmont, J. C.; Chezal, J. M.; Chavignon, O.; Teulade, J. C.; Moins, N. Labelled analogues of halobenzamides as radiopharmaceuticals. World Patent WO2008012782, 2008.
42. Bonnet-Duquennoy, M.; Papon, J.; Mishellany, F.; Labarre, P.; Guerquin-Kern, J. L.; Wu, T. D.; Gardette, M.; Maublant, J.; Penault-Llorca, F.; Miot-Noirault, E.; Cayre, A.; Madelmont, J. C.; Chezal, J. M.; Moins, N. Targeted radionuclide therapy of melanoma: anti-tumoural efficacy studies of a new (131)I labelled potential agent Int. J. Cancer 2009, 125, 708-716
43. Bonnet, M.; Mishellany, F.; Papon, J.; Cayre, A.; Penault-Llorca, F.; Madelmont, J. C.; Miot-Noirault, E.; Chezal, J. M.; Moins, N. Anti-melanoma efficacy of internal radionuclide therapy in relation with melanin target distribution. Pigm. Cell Melanoma Res. 2010, 23, e1 - e11, doi: 10.1111/j.1755-148X.2010.00716.x.
44. Smart, B. E. Fluorine substituent effects (on bioactivity) J. Fluorine Chem. 2001, 109, 3-11 (Pubitemid 33618184)
45. Chezal, J. M.; Maisonial, A.; Madelmont, J. C.; Miot-Noirault, E.; Moins, N.; Papon, J.; Dollé, F.; Kuhnast, B.; Tavitian, B.; Boisgard, R. Labelled analogues of halobenzamides as multimodal radiopharmaceuticals and their precursors. World Patent WO2009095872, 2009.
46. Dollé, F. Fluorine-18-labelled fluoropyridines: advances in radiopharmaceutical design Curr. Pharm. Des. 2005, 11, 3221-3235 (Pubitemid 41300773)
47. Dolci, L.; Dollé, F.; Jubeau, S.; Vaufrey, F.; Crouzel, C. 2-[F-18]fluoropyridines by no-carrier-added nucleophilic aromatic substitution with [F-18]FK-K-222-A comparative study J. Labelled Compd. Radiopharm. 1999, 42, 975-985 (Pubitemid 29460376)
48. Dollé, F.; Dolci, L.; Valette, H.; Hinnen, F.; Vaufrey, F.; Guenther, I.; Fuseau, C.; Coulon, C.; Bottlaender, M.; Crouzel, C. Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine: a new positron emission tomography ligand for nicotinic receptors J. Med. Chem. 1999, 42, 2251-2259 (Pubitemid 29284245)
49. Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.; Watanabe, M.; Yokoyama, K. Novel 1,4-dihydropyridine calcium antagonists. I. Synthesis and hypotensive activity of 4-(substituted pyridyl)-1,4-dihydropyridine derivatives Chem. Pharm. Bull. 1990, 38, 2446-2458 (Pubitemid 20357296)
50. Pesti, J. A.; Huhn, G. F.; Yin, J.; Xing, Y.; Fortunak, J. M. Efficient pyridinylmethyl functionalization: synthesis of 10,10-bis[(2-fluoro-4-pyridinyl) methyl]-9(10 H)-anthracenone (DMP 543), an acetylcholine release enhancing agent J. Org. Chem. 2000, 65, 7718-7722
51. Jones, J. H.; Holtz, W. J.; Cragoe, E. J. 6-Substituted 5-chloro-1,3-dihydro-2 H -imidazo[4,5- b ]pyrazin-2-ones with hypotensive activity J. Med. Chem. 1973, 16, 537-542
52. Dollé, F.; Valette, H.; Bottlaender, M.; Hinnen, F.; Vaufrey, F.; Guenther, I.; Crouzel, C. J. Labelled Compd. Radiopharm. 1998, 41, 451-463
53. 18F]fluoro-3-[2(S)-2- azetidinylmethoxy]pyridine, a highly potent radioligand for in vivo imaging central nicotinic acetylcholine receptors J. Labelled Compd. Radiopharm. 1998, 41, 451-463 (Pubitemid 28216245)
54. Adcock, W.; Wells, P. R. Substituent effects in naphthalene. I. The syntheses of 4-, 5-, 6-, 7-, and 8-substituted 2-naphthoic acids Aust. J. Chem. 1965, 18, 1351-1364
55. Sunberg, R. J.; Biswas, S.; Murthi, K. K.; Rowe, D.; McCall, J. W.; Dzimianski, M. T. Bis-cationic heteroaromatics as macrofilaricides: synthesis of bis-amidine and bis-guanylhydrazone derivatives of substituted imidazo[1,2- a ]pyridines J. Med. Chem. 1998, 41, 4317-4328 (Pubitemid 28498755)
56. Desbois, N.; Gardette, M.; Papon, J.; Labarre, P.; Maisonial, A.; Auzeloux, P.; Lartigue, C.; Bouchon, B.; Debiton, E.; Blache, Y.; Chavignon, O.; Teulade, J. C.; Maublant, J.; Madelmont, J. C.; Moins, N.; Chezal, J. M. Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma Bioorg. Med. Chem. 2008, 16, 7671-7690
57. Coulson, D. R.; Satek, L. C.; Grim, S. O. Tetrakis(Triphenylphosphine) Palladium (0) Inorg. Synth. 1971, 13, 121-124
58. Guerquin-Kern, J. L.; Hillion, F.; Madelmont, J. C.; Labarre, P.; Papon, J.; Croisy, A. Ultrastructural cell distribution of the melanoma marker iodobenzamide: improved potentiality of SIMS imaging in life sciences BioMed. Eng. OnLine 2004, 3, 10
59. Labarre, P.; Papon, J.; Moreau, M. F.; Moins, N.; Bayle, M.; Veyre, A.; Madelmont, J. C. Melanin affinity of N -(2-diethylaminoethyl)-4-iodobenzamide, an effective melanoma imaging agent Melanoma Res. 2002, 12, 115-121 (Pubitemid 34478451)
60. Berk, L. B. Radiation therapy as primary and adjuvant treatment for local and regional melanoma Cancer Control 2008, 15, 233-238
61. Denoyer, D.; Labarre, P.; Papon, J.; Miot-Noirault, E.; Galmier, M. J.; Madelmont, J. C.; Chezal, J. M.; Moins, N. Development of high-performance liquid chromatographic method for the determination of a new potent radioiodinated melanoma imaging and therapeutic agent J. Chromatogr., B: Anal. Technol. Biomed. Life Sci. 2008, 875, 411-418
62. Armarego, W. L. F.; Perrin, D. D. Purification of laboratory chemicals. 4th ed.; Butterworth-Heinemann: Oxford, 1996.
63. Roe, A.; Cheek, P. H.; Hawkins, G. F. The synthesis of 2-fluoro-4- and 2-fluoro-6-pyridinecarboxylic acid and derivatives J. Am. Chem. Soc. 1949, 71, 4152-4153
64. Konno, A.; Shimojo, M.; Fuchigami, T. Electrolytic partial fluorination of organic compounds. Part 26. Anodic monofluorination of ethyl isonicotinate J. Fluorine Chem. 1998, 87, 137-140 (Pubitemid 128178054)
65. Zhang, Y.; Pavlova, O. A.; Chefer, S. I.; Hall, A. W.; Kurian, V.; Brown, L. V.; Kimes, A. S.; Mukhin, A. G.; Horti, A. G. 5-Substituted derivatives of 6-halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-halogeno-3-((2-(S)- pyrrolidinyl)methoxy)pyridine with low picomolar affinity for α4β2 nicotinic acetylcholine receptor and wide range of lipophilicity: potential probes for imaging with positron emission tomography J. Med. Chem. 2004, 47, 2453-2465 (Pubitemid 38580084)
66. Miot-Noirault, E.; Papon, J.; Gardette, M.; Bonnet-Duquennoy, M.; Labarre, P.; Maisonial, A.; Madelmont, J. C.; Maublant, J.; Chezal, J. M.; Moins, N. The use of [(125)I] scintigraphic in vivo imaging in melanoma-bearing mice for a rapid prescreening of vectors to melanoma tissue Cancer Biother. Radiopharm. 2009, 24, 629-36
67. Labarre, P.; Papon, J.; Moreau, M. F.; Madelmont, J. C.; Veyre, A. A new quantitative method to evaluate the biodistribution of a radiolabeled tracer for melanoma using whole-body cryosectioning and a gaseous detector. Comparison with conventional tissue combustion technology Eur. J. Nucl. Med. 1998, 25, 109-114 (Pubitemid 28130032)
68. 18F]DPA-714, a selective radioligand for imaging the translocator protein (18 kDa) with PET J. Labelled Compd. Radiopharm. 2008, 51, 286-292
69. Lemaire, C.; Plenevaux, A.; Aerts, J.; Del Fiore, G.; Brihaye, C.; Le Bars, D.; Comar, D.; Luxen, A. Solid phase extraction-an alternative to the use of rotary evaporators for solvent removal in the rapid formulation of PET radiopharmaceuticals J. Labelled Compd. Radiopharm. 1999, 42, 63-75 (Pubitemid 29026806)
70. Bissery, M. C.; Guenard, D.; Gueritte-Voegelin, F.; Lavelle, F. Experimental antitumor activity of taxotere (RP 56976, NSC 628503) a taxol analogue Cancer Res. 1991, 51, 4845-4852