Ceramide synthesis and metabolism as a target for cancer therapy

Cancer Letters

Volumn 206, Issue 2, 2004, Pages 169-180

  Reynolds, C Patrick ^a   Maurer, Barry J ^a   Kolesnick, Richard N ^b  

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^b MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

Author keywords

Ceramide; Clinical trials; Fenretinide; Glucosylceramide synthase; Serine palmitoyltransferase; Sphingolipids; Sphingosine kinase; Spingomyelin

Indexed keywords

CERAMIDE; CERAMIDE GLUCOSYLTRANSFERASE; CERAMIDE GLUCOSYLTRANSFERASE INHIBITOR; DAUNORUBICIN; DOXORUBICIN; ETOPOSIDE; FENRETINIDE; FLUDARABINE; IRINOTECAN; PACLITAXEL; RETINOID; SAFINGOL; SPHINGOMYELIN; VALSPODAR; VINCRISTINE;

ACYLATION; ADVANCED CANCER; BIOSYNTHESIS; CANCER CHEMOTHERAPY; CANCER RADIOTHERAPY; CANCER THERAPY; CATABOLISM; CELL DEATH; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL TRIAL; CYTOTOXICITY; GLYCOSYLATION; HUMAN; NONHUMAN; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SIDE EFFECT; VISUAL DISORDER;

EID: 1542358155     PISSN: 03043835     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.canlet.2003.08.034     Document Type: Article

References (94)

1. Kolesnick R.N. Sphingomyelin and derivatives as cellular signals. (Review) (328 refs). Prog. Lipid Res. 30:1991;1-38.
2. Kolesnick R.N. 1,2-Diacylglycerols but not phorbol esters stimulate sphingomyelin hydrolysis in GH3 pituitary cells. J. Biol. Chem. 262:1987;16759-16762.
3. Kolesnick R.N., Clegg S. 1,2-Diacylglycerols, but not phorbol esters, activate a potential inhibitory pathway for protein kinase C in GH3 pituitary cells. Evidence for involvement of a sphingomyelinase. J. Biol. Chem. 263:1988;6534-6537.
4. Kolesnick R.N. Sphingomyelinase action inhibits phorbol ester-induced differentiation of human promyelocytic leukemic (HL-60) cells. J. Biol. Chem. 264:1989;7617-7623.
5. Okazaki T., Bell R.M., Hannun Y.A. Sphingomyelin turnover induced by vitamin D3 in HL-60 cells. Role in cell differentiation. J. Biol. Chem. 264:1989;19076-19080.
6. Okazaki T., Bielawska A., Bell R.M., Hannun Y.A. Role of ceramide as a lipid mediator of 1 alpha, 25-dihydroxyvitamin D3-induced HL-60 cell differentiation. J. Biol. Chem. 265:1990;15823-15831.
7. Hannun Y.A., Luberto C., Argraves K.M. Enzymes of sphingolipid metabolism: from modular to integrative signaling. (Review) (144 refs). Biochemistry. 40:2001;4893-4903.
8. Mathias S., Pena L.A., Kolesnick R.N. Signal transduction of stress via ceramide (Review) (303 refs). Biochem. J. 335:1998;465-480.
9. Grassme H., Schwarz H., Gulbins E. Molecular mechanisms of ceramide-mediated CD95 clustering. Biochem. Biophys. Res. Commun. 284:2001;1016-1030.
10. Schissel S.L., Keesler G.A., Schuchman E.H., Williams K.J., Tabas I. The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene. J. Biol. Chem. 273:1998;18250-18259.
11. Schissel S.L., Jiang S., Tweedie-Hardman J., Jeong T., Camejo E.H., Najib J., et al. Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J. Biol. Chem. 273:1998;2738-2746.
12. Liu P., Anderson R.G. Compartmentalized production of ceramide at the cell surface. J. Biol. Chem. 270:1995;27179-27185.
13. Kirschnek S., Paris F., Weller M., Grassme H., Ferlinz K., Riehle A., et al. CD95-mediated apoptosis in vivo involves acid sphingomyelinase. J. Biol. Chem. 275:2000;27316-27323.
14. Grassme H., Jendrossek V., Bock J., Riehle A., Gulbins E. Ceramide-rich membrane rafts mediate CD40 clustering. J. Immunol. 168:2002;298-307.
15. Segui B., Bezombes C., Uro-Coste E., Medin J.A., Andrieu-Abadie N., Auge N., et al. Stress-induced apoptosis is not mediated by endolysosomal ceramide. Fed. Am. Soc. Exp. Biol. J. 14:2000;36-47.
16. Gulbins E., Grassme H. Ceramide and cell death receptor clustering. Biochim. Biophys. Acta. 1585:2002;139-145.
17. Grassme H., Schwarz H., Gulbins E. Molecular mechanisms of ceramide-mediated CD95 clustering. Biochem. Biophys. Res. Commun. 284:2001;1016-1030.
18. Gulbins E. Regulation of death receptor signaling and apoptosis by ceramide. Pharmacol. Res. 47:2003;393-399.
19. Santana P., Pena L.A., Haimovitz-Friedman A., Martin S., Green D., McLoughlin M., et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell. 86:1996;189-199.
20. Haimovitz-Friedman A., Kan C.C., Ehleiter D., Persaud R.S., McLoughlin M., Fuks Z., Kolesnick R.N. Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J. Exp. Med. 180:1994;525-535.
21. Jaffrezou J.P., Bruno A.P., Moisand A., Levade T., Laurent G. Activation of a nuclear sphingomyelinase in radiation-induced apoptosis. Fed. Am. Soc. Exp. Biol. J. 15:2001;123-133.
22. Horinouchi K., Erlich S., Perl D.P., Ferlinz K., Bisgaier C.L., Sandhoff K. Acid sphingomyelinase deficient mice: a model of types A and B Niemann-Pick disease. Nat. Genet. 10:1995;288-293.
23. Liu B., Andrieu-Abadie N., Levade T., Zhang P., Obeid L.M., Hannun Y.A. Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J. Biol. Chem. 273:1998;11313-11320.
24. Jayadev S., Linardic C.M., Hannun Y.Y. Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to tumor necrosis factor alpha. J. Biol. Chem. 269:1994;5757-5763.
25. Chan T.A., Morin P.J., Vogelstein B., Kinzler K.W. Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc. Natl. Acad. Sci. USA. 95:1998;681-686.
26. O'Brien N.W., Gellings N.M., Guo M., Barlow S.B., Glembotski C.C., Sabbadini R.A. Factor associated with neutral sphingomyelinase activation and its role in cardiac cell death. Circ. Res. 92:2003;589-591.
27. Brann A.B., Tcherpakov M., Williams I.M., Futerman A.H., Fainzilber M. Nerve growth factor-induced p75-mediated death of cultured hippocampal neurons is age-dependent and transduced through ceramide generated by neutral sphingomyelinase. J. Biol. Chem. 277:2002;9812-9818.
28. Takeda Y., Tashima M., Takahashi A., Uchiyama T., Okazaki T. Ceramide generation in nitric oxide-induced apoptosis. Activation of magnesium-dependent neutral sphingomyelinase via caspase-3. J. Biol. Chem. 274:1999;10654-10660.
29. Chatterjee S. Neutral sphingomyelinase: past, present and future. Chem. Phys. Lipids. 102:1999;79-96.
30. Tonnetti L., Veri M.C., Bonvini E., D'Adamio L. A role for neutral sphingomyelinase-mediated ceramide production in T cell receptor-induced apoptosis and mitogen-activated protein kinase-mediated signal transduction. J. Exp. Med. 189:1999;1581-1589.
31. Kilkus J., Goswami R., Testai F.D., Dawson G. Ceramide in rafts detergent-insoluble fraction mediates cell death in neurotumor cell lines. J. Neurosci. Res. 72:2003;65-75.
32. Tomiuk S., Hofmann K., Nix M., Zumbansen M., Stoffel W. Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling? Proc. Natl. Acad. Sci. USA. 95:1998;3638-3643.
33. Sawai H., Domae N., Nagan N., Hannun Y.A. Function of the cloned putative neutral sphingomyelinase as lyso-platelet activating factor-phospholipase C. J. Biol. Chem. 274:1999;38131-38139.
34. Hofmann K., Tomiuk S., Wolff G., Stoffel W. Cloning and characterization of the mammalian brain-specific. Mg2+-dependent neutral sphingomyelinase. Proc. Natl. Acad. Sci. USA. 97:2000;5895-5900.
35. Marchesini N., Luberto C., Hannun Y.A. Biochemical properties of mammalian neutral sphingomyelinase 2 and its role in sphingolipid metabolism. J. Biol. Chem. 278:2003;13775-13783.
36. Liu B., Hassler D.F., Smith G.K., Weaver K., Hannun Y.A. Purification and characterization of a membrane bound neutral pH optimum magnesium-dependent and phosphatidylserine-stimulated sphingomyelinase from rat brain. J. Biol. Chem. 273:1998;34472-34479.
37. Bernardo K., Krut O., Wiegmann K., Kreder D., Micheli M., Schafer R. Purification and characterization of a magnesium-dependent neutral sphingomyelinase from bovine brain. J. Biol. Chem. 275:2000;7641-7647.
38. Ogretmen B., Pettus B.J., Rossi M.J., Wood R., Usta J., Szulc Z., et al. Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide. J. Biol. Chem. 277:2002;12960-12969.
39. Bose R., Verheij M., Haimovitz-Friedman A., Scotto K., Fuks Z., Kolesnick R. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell. 82:1995;405-414.
40. Liao W.C., Haimovitz-Friedman A., Persaud R.S., McLoughlin M., Ehleiter D., et al. Ataxia telangiectasia-mutated gene product inhibits DNA damage-induced apoptosis via ceramide synthase. J. Biol. Chem. 274:1999;17908-17917.
41. Li C.M., Park J.H., Simonaro C.M., He X., Gordon R.E., Friedman A.H., et al. Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes. (erratum appears in Genomics 2002 Jun;79(6):890 Note: Hepbiloikler Stefan corrected to Hepbildikler Stefan). Genomics. 79:2002;218-224.
42. Kohama T., Olivera A., Edsall L., Nagiec M.M., Dickson R., Spiegel S. Molecular cloning and functional characterization of murine sphingosine kinase. J. Biol. Chem. 273:1998;23722-23728.
43. Liu H., Sugiura M., Nava V.E., Edsall L.C., Kono K., Poulton S., et al. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J. Biol. Chem. 275:2000;19513-19520.
44. Abe A., Shayman J.A. Purification and characterization of 1-O-acylceramide synthase, a novel phospholipase A2 with transacylase activity. J. Biol. Chem. 273:1998;8467-8474.
45. Abe A., Shayman J.A., Radin N.S. A novel enzyme that catalyzes the esterification of N-acetylsphingosine. J. Biol. Chem. 271:1996;14383-14389.
46. Okabe H., Kishimoto Y. In vivo metabolism of ceramides in rat brain. Fatty acid replacement and esterification of ceramide. J. Biol. Chem. 252:1977;7068-7073.
47. Taniyama Y., Shibata S., Kita S., Horikoshi K., Fuse H., Shirafuji H., et al. Cloning and expression of a novel lysophospholipase which structurally resembles lecithin cholesterol acyltransferase. Biochem. Biophys. Res. Commun. 257:1999;50-56.
48. Hiraoka M., Abe A., Shayman J.A. Cloning and characterization of a lysosomal phospholipase A2, 1-O-acylceramide synthase. J. Biol. Chem. 277:2002;10090-10099.
49. Tepper A.D., Diks S.H., van Blitterswijk W.J., Borst J. Glucosylceramide synthase does not attenuate the ceramide pool accumulating during apoptosis induced by CD95 or anti-cancer regimens. J. Biol. Chem. 275:2000;34810-34817.
50. Kolesnick R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J. Clin. Invest. 1:2002;3-8.
51. Cuvillier O., Pirianov G., Kleuser B., Vanek P.G., Coso O.A., Gutkind S., Spiegel S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature. 381:1996;800-803.
52. Olivera A., Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature. 365:1993;557-560.
53. Hla T., Lee M.J., Ancellin N., Paik J.H., Kluk M.J. Lysophospholipids- receptor revelations. (Review) (53 refs). Science. 294:2001;1875-1878.
54. Lozano J., Berra E., Muncio M.M., Diaz-Meco M.T., Dominguez I., Sanz L., Moscat J. Protein kinase C zeta isoform is critical for kappa B-dependent promoter activation by sphingomyelinase. J. Biol. Chem. 269:1994;19200-19202.
55. Leitges M., Sanz L., Martin P., Duran A., Braun U., Garcia J.F., et al. Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. Mol. Cell. 8:2001;771-780.
56. Diaz-Meco M.T., Berra E., Muncio M.M., Sanz L., Lozano J., et al. A dominant negative protein kinase C zeta subspecies blocks NF-kappa B activation. Mol. Cell Biol. 13:1993;4770-4775.
57. Senchenkov A., Litvak D.A., Cabot M.C. Targeting ceramide metabolism-a strategy for overcoming drug resistance. (Review) (150 refs). J. Natl Cancer Inst. 93:2001;347-357.
58. el Bawab S., Roddy P., Qian T., Bielawska A., Lemasters J.J., Hannun Y.A. Molecular cloning and characterization of a human mitochondrial ceramidase. J. Biol. Chem. 275:2000;21508-21513.
59. Selzner M., Bielawska A., Morse M.A., Rudiger H.A., Sindram D., Hannun Y.A., Clavien P.A. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res. 61:2001;1233-1240.
60. Liu Y.Y., Han T.Y., Giuliano A.E., Hansen N., Cabot M.C. Uncoupling ceramide glycosylation by transfection of glucosylceramide synthase antisense reverses adriamycin resistance. J. Biol. Chem. 275:2000;7138-7143.
61. Maurer B.J., Melton L., Billups C., Cabot M.C., Reynolds C.P. Synergistic cytotoxicity in solid tumor cell lines between N-(4-hydroxyphenyl) retinamide and modulators of ceramide metabolism. J. Natl Cancer Inst. 92:2000;1897-1909.
62. Banno Y., Kato M., Hara A., Nozawa Y. Evidence for the presence of multiple forms of Sph kinase in human platelets. Biochem. J. 335:1998;301-304.
63. Edsall L.C., Van Brocklyn J.R., Cuvillier O., Kleuser B., Spiegel S. N,N-Dimethylsphingosine is a potent competitive inhibitor of sphingosine kinase but not of protein kinase C: modulation of cellular levels of sphingosine 1-phosphate and ceramide. Biochemistry. 37:1998;12892-12898.
64. Schwartz G.K., Ward D., Saltz L., Casper E.S., Spiess T., Mullen E., et al. A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. Clin. Cancer Res. 3:1997;537-543.
65. Potten C.S. A comprehensive study of the radiobiological response of the murine (BDF1) small intestine(Review) (106 refs). Int. J. Radiat. Biol. 58:1990;925-973.
66. Paris F., Fuks Z., Kang A., Capodieci P., Juan G., Ehleiter D., Haimovitz-Friedman A., Cordon-Cardo C., Kolesnick R. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. (comment). Science. 293:2001;293-297.
67. Ponzoni M., Bocca P., Chiesa V., Decensi A., Pistoia V., Raffaghello L., Rozzo C., Montaldo P.G. Differential effects of N-(4-hydroxyphenyl)retinamide and retinoic acid on neuroblastoma cells: apoptosis versus differentiation. Cancer Res. 55:1995;853-861.
68. Maurer B.J., Metelitsa L.S., Seeger R.C., Cabot M.C., Reynolds C.P. N-(4-hydroxyphenyl)retinamide increases ceramide and reactive oxygen species and induces mixed apoptosis/necrosis in neuroblastoma cell lines. J. Natl Cancer Inst. 91:1999;1138-1146.
69. Sani B.P., Shealy Y.F., Hill D.L. N-(4-hydroxyphenyl)retinamide: interactions with retinoid- binding proteins/receptors. Carcinogenesis. 16:1995;2531-2534.
70. Sheikh M.S., Shao Z.M., Li X.S., Ordonez J.V., Conley B.A., Wu S., Dawson M.I., Han O.X., Chao W.R., Quick T. N-(4-hydroxyphenyl)retinamide (4-HPR)-mediated biological actions involve retinoid receptor-independent pathways in human breast carcinoma. Carcinogenesis. 16:1995;2477-2486.
71. Delia D., Aiello A., Meroni L., Nicolini M., Reed J.C., Pierotti M.A. Role of antioxidants and intracellular free radicals in retinamide-induced cell death. Carcinogenesis. 18:1997;943-948.
72. Oridate N., Suzuki S., Higuchi M., Mitchell M.F., Hong W.K., Lotan R. Involvement of reactive oxygen species in N-(4- hydroxyphenyl) retinamide-induced apoptosis in cervical carcinoma cells. J. Natl Cancer Inst. 89:1997;1191-1198.
73. Keshelava N., Seeger R.C., Groshen S., Reynolds C.P. Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res. 58:1998;5396-5405.
74. O'Donnell P.H., Guo W.X., Reynolds C.P., Maurer B.J. N-(4-hydroxyphenyl) retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes. Leukemia. 16:2002;902-910.
75. Batra S., Maurer B.J., Reynold C.P. Fenretinide cytotoxicity in Ewing's sarcoma (ES) and primitive neuroectodermal (PNET) cell lines is blunted by hypoxia but synergistically enhanced by safingol. Proc. Am. Assoc. Cancer Res. 2002;43.
76. Wang H., Maurer B.J., Reynolds C.P., Cabot M.C. N-(4-hydroxyphenyl) retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase. Cancer Res. 61:2001;5102-5105.
77. Reynolds C.P., Lemons R.S. Retinoid therapy of childhood cancer. (Review) (283 refs). Hematol. Oncol. Clin. North Am. 15:2001;867-910.
78. Villablanca J.G., Ames M.M., Reid J.M., Bagniewski P.G., Krailo M., Reynolds C.P. Phase I trial of oral N-(4-hydroxyphenyl)retinamide (4-HPR) in children with resistant/recurrent solid tumors: a Children's Cancer Group study (CCG 09709). Proc. Am. Soc. Clin. Oncol. 21:2002;. Ref. type: Abstract.
79. Jasti B.R., Lo Ruso P.M., Parchment R.E., Wozniak A.J., Flaherty L.E., Shields A.F., et al. Phase I clinical trial of fenretinide (NSC 374551) in advanced solid tumors. Proc. Am. Soc. Clin. Oncol. 20:(122A):2001;. Ref. type: Abstract.
80. Reynolds C.P., Wang Y., Melton L.J., Einhorn P.A., Slamon D.J., Maurer B.J. Retinoic-acid-resistant neuroblastoma cell lines show altered MYC regulation and high sensitivity to fenretinide. Med. Pediatr. Oncol. 35:2000;597-602.
81. Garzotto M., Haimovitz-Friedman A., Liao W.C., White-Jones M., Huryk R., Heston W.D., et al. Reversal of radiation resistance in LNCaP cells by targeting apoptosis through ceramide synthase. Cancer Res. 59:1999;5194-5201.
82. Chmura S.J., Nodzenski E., Beckett M.A., Kufe D.W., Quintans J., Weichselbaum R.R. Loss of ceramide production confers resistance to radiation-induced apoptosis. Cancer Res. 57:1997;1270-1275.
83. Santana P., Pena L.A., Haimovitz-Friedman A., Martin S., Green D., McLoughlin M., et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell. 86:1996;189-199.
84. Chmura S.J., Nodzenski E., Kharbanda S., Pandey P., Quintans J., Kufe D.W., Weichselbaum R.R. Down-regulation of ceramide production abrogates ionizing radiation-induced cytochrome c release and apoptosis. Mol. Pharmacol. 57:2000;792-796.
85. Kimura K., Markowski M., Edsall L.C., Spiegel S., Gelmann E.P. Role of ceramide in mediating apoptosis of irradiated LNCaP prostate cancer cells. Cell Death Differ. 10:2003;240-248.
86. Lin X., Fuks Z., Kolesnick R. Ceramide mediates radiation-induced death of endothelium. Crit. Care Med. 28:2000;N87-N93.
87. Chmura S.J., Mauceri H.J., Advani S., Heimann R., Beckett M.A., Nodzenski E., et al. Decreasing the apoptotic threshold of tumor cells through protein kinase C inhibition and sphingomyelinase activation increases tumor killing by ionizing radiation. Cancer Res. 57:1997;4340-4347.
88. Nava V.E., Cuvillier O., Edsall L.C., Kimura K., Milstien S., Gelmann E.P., Spiegel S. Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells. Cancer Res. 60:2000;4468-4474.
89. Rodriguez-Lafrasse C., Alphonse G., Aloy M.T., Ardail D., Gerard J.P., Louisot P., Rousson R. Increasing endogenous ceramide using inhibitors of sphingolipid metabolism maximizes ionizing radiation-induced mitochondrial injury and apoptotic cell killing. Int. J. Cancer. 101:2002;589-598.
90. Wang H., Giuliano A.E., Cabot M.C. Enhanced de novo ceramide generation through activation of serine palmitoyltransferase by the P-glycoprotein antagonist SDZ PSC 833 in breast cancer cells. Mol. Cancer Ther. 1:2002;719-726.
91. Goulding C.W., Giuliano A.E., Cabot M.C. SDZ PSC 833 the drug resistance modulator activates cellular ceramide formation by a pathway independent of P-glycoprotein. Cancer Lett. 149:2000;143-151.
92. Abe A., Radin N.S., Shayman J.A., Wotring L.L., Zipkin R.E., Sivakumar R. Structural and stereochemical studies of potent inhibitors of glucosylceramide synthase and tumor cell growth. J. Lipid Res. 36:1995;611-621.
93. Lee L., Abe A., Shayman J.A. Improved inhibitors of glucosylceramide synthase. J. Biol. Chem. 274:1999;14662-14669.
94. Platt F.M., Neises G.R., Dwek R.A., Butters T.D. N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J. Biol. Chem. 269:1994;8362-8365.