Cannabinoids: Potential anticancer agents

Nature Reviews Cancer

Volumn 3, Issue 10, 2003, Pages 745-755

  Guzmán, Manuel ^a  

^a UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

2 ARACHIDONOYLGLYCEROL; 2,3 DIHYDRO 5 METHYL 3 (MORPHOLINOMETHYL) 6 (1 NAPHTHOYL)PYRROLO[1,2,3 DE][1,4]BENZOXAZINE; 5 (4 CHLORO 3 METHYLPHENYL) 1 (4 METHYLBENZYL) N (1,3,3 TRIMETHYLBICYCLO[2.2.1]HEPTAN 2 YL) 3 PYRAZOLECARBOXAMIDE; AJULEMIC ACID; ANANDAMIDE; ANTIEMETIC AGENT; ANTINEOPLASTIC AGENT; APREPITANT; CANNABINOID DERIVATIVE; CANNABIS; CARBOPLATIN; CARMUSTINE; DEXANABINOL; DOMPERIDONE; DRONABINOL; FENRETINIDE; LY 109514; METOCLOPRAMIDE; NABILONE; NEUROKININ 1 RECEPTOR ANTAGONIST; O 1057; ONDANSETRON; PROCHLORPERAZINE; RIMONABANT; TEMOZOLOMIDE; TETRAHYDROCANNABINOL DERIVATIVE; THALIDOMIDE; UNCLASSIFIED DRUG; CANNABINOID;

AMNESIA; ANIRIDIA; ANTINEOPLASTIC ACTIVITY; BRONCHODILATATION; CANCER INHIBITION; CANCER PAIN; CANCER PALLIATIVE THERAPY; CARDIOTOXICITY; CELL DEATH; CHEMOTHERAPY INDUCED EMESIS; CLINICAL TRIAL; COGNITIVE DEFECT; CONFUSION; DEPRESSION; DISORIENTATION; DROWSINESS; DRUG ACTIVITY; DRUG APPROVAL; DRUG EFFECT; DRUG EXCRETION; DRUG FATALITY; DRUG MECHANISM; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG TOLERANCE; EUPHORIA; GASTROINTESTINAL SYMPTOM; GROWTH INHIBITION; HOT FLUSH; HUMAN; INSOMNIA; IRRITABILITY; META ANALYSIS; METASTASIS INHIBITION; MITOSIS INHIBITION; MOOD DISORDER; MOTOR COORDINATION; MOTOR DYSFUNCTION; MUSCLE RELAXATION; NAUSEA; NEUROTOXICITY; NONHUMAN; PATHOLOGICAL LAUGHTER; PERCEPTION DISORDER; PRIORITY JOURNAL; RESPIRATORY DISTRESS; RESTLESSNESS; REVIEW; SENSORY DYSFUNCTION; SIDE EFFECT; TACHYCARDIA; TUMOR CELL; TUMOR GROWTH; VERTIGO; WITHDRAWAL SYNDROME; ANIMAL; DISEASE MODEL; MOUSE; NEOPLASM; PALLIATIVE THERAPY; SIGNAL TRANSDUCTION;

CANNABIS SATIVA;

ANIMALS; CANNABINOIDS; DISEASE MODELS, ANIMAL; HUMANS; MICE; NEOPLASMS; PALLIATIVE CARE; SIGNAL TRANSDUCTION;

EID: 0142166330     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1188     Document Type: Review

References (113)

1. Gaoni, Y. & Mechoulam, R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am. Chem. Soc. 86, 1646-1647 (1964).
2. Howlett, A. C. et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54, 161-202 (2002). A comprehensive update on cannabinoid receptors and their biochemistry and pharmacology.
3. Herkenham, M. et al. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci. 11, 563-583 (1991).
4. Porter, A. C. & Felder, C. C. The endocannabinoid nervous system Unique opportunities for therapeutic intervention. Pharmacol. Ther. 90, 45-60 (2001).
5. Pertwee, R. G. Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin. Investig. Drugs 9, 1553-1571 (2000).
6. Di Carlo, G. & Izzo, A. A. Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert Opin. Investig. Drugs 12, 39-49 (2003).
7. Croxford, J. L. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 17, 179-2202 (2003).
8. Robson, P. Therapeutic aspects of cannabis and cannabinoids. Br. J. Psychiatry 178, 107-115 (2001).
9. Tramer, M. R. et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 323, 16-21 (2001). A detailed review on the best palliative action of cannabinoids in cancer therapy that has been established so far.
10. Walsh, D., Nelson, K. A. & Mahmoud, F. A. Established and potential therapeutic applications of cannabinoids in oncology. Support Care Cancer 11, 137-143 (2003).
11. Barann, M. et al. Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site. Br. J. Pharmacol. 137, 589-596 (2002).
12. Tisdale, M. J. Cachexia in cancer patients. Nature Rev. Cancer 2, 862-871 (2002).
13. Berry, E. M. & Mechoulam, R. Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol. Ther. 95, 185-190 (2002). An authoritative review on the physiological role and therapeutic potential of cannabinoids in appetite stimulation.
14. Cota, D. et al. Endogenous cannabinoid system as a modulator of food intake. Int. J. Obes. Relat. Metab. Disord. 27, 289-301 (2003).
15. Gomez, R. et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J. Neurosci. 22, 9612-9617 (2002).
16. 1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol. Pharmacol. 63, 908-914 (2003).
17. Cota, D. et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J. Clin. Invest. 112, 423-431 (2003).
18. Nelson, K., Walsh, D., Deeter, P. & Sheehan, F. A phase II study of δ-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia. J. Palliat. Care 10, 14-18 (1994).
19. Jatoi, A. et al. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J. Clin. Oncol. 20, 567-573 (2002).
20. Mantyh, P. W., Clohisy, D. R., Koltzenburg, M. & Hunt, S. P. Molecular mechanisms of cancer pain. Nature Rev. Cancer 2, 201-209 (2002).
21. Pertwee, R. G. Cannabinoid receptors and pain. Prog. Neurobiol. 63, 569-611 (2001).
22. Walker, J. & Huang, S. Cannabinoid analgesia. Pharmacol. Ther. 95, 127-135 (2002).
23. Calignano, A., LaRana, G., Giuffrida, A. & Piomelli, D. Control of pain initiation by endogenous cannabinoids. Nature 394, 277-281 (1998).
24. Campbell, F. A. et al. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 323, 13-16 (2001). A lively discussion on the possible therapeutic value of cannabinoids as analgesic agents.
25. Noyes, R. Jr, Brunk, S. F., Avery, D. A. H. & Canter, A. C. The analgesic properties of delta-g-tetrahydrocannabinol and codeine. Clin. Pharmacol. Ther. 18, 84-89 (1975).
26. Iversen, L. & Chapman, V. Cannabinoids: a real prospect for pain relief. Curr. Opin. Pharmacol. 2, 50-55 (2002).
27. Manzanares, J. et al. Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol. Sci. 20, 287-294 (1999).
28. Baker, D. & Pryce, G. The therapeutic potential of cannabis in multiple sclerosis. Expert Opin. Investig. Drugs 12, 561-567 (2003).
29. Munson, A. E., Harris, L. S., Friedman, M. A., Dewey, W. L. & Carchman, R. A. Antineoplastic activity of cannabinoids. J. Natl Cancer Inst. 55, 597-602 (1975). The seminal demonstration that THC inhibits tumour-cell growth in culture and in mice.
30. Guzman, M., Sanchez, C. & Galve-Roperh, I. Cannabinoids and cell fate. Pharmacol. Ther. 95, 175-184 (2002).
31. Bouaboula, M. et al. Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem. J. 312, 637-641 (1995).
32. Bouaboula, M. et al. Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression. Eur. J. Biochem. 237, 704-711 (1996).
33. 1 cannabinoid receptors in human vascular endothelial cells. Biochem. J. 346. 835-840 (2000).
34. 1 cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase. Mol. Pharmacol. 58, 814-820 (2000).
35. Derkinderen, P., Ledent, C., Parmentier, M. & Girault, J. A. Cannabinoids activate p38 mitogen-activated protein kinases through CB1 receptors in hippocampus. J. Neurochem. 77, 957-960 (2001).
36. Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37-40 (2001).
37. Rueda, D., Navarro, B., Martinez-Serrano, A., Guzman, M. & Galve-Roperh, I. The endocannabinoid anandamide inhibits neuronal progenitor cell differentiation through attenuation of the Rap1/B-Raf/ERK pathway. J. Biol. Chem. 277, 46645-46650 (2002).
38. 1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem. J. 347, 369-373 (2000).
39. 2 cannabinoid receptors expressed in prostate PC-3 cells. Involvement in Raf-1 stimulation and NGF induction. Cell. Signal. 15, 851-859 (2003).
40. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489-501 (2002).
41. Samson, M. T. et al. Differential roles of CB1 and CB2 cannabinoid receptors in mast cells. J. Immunol. 170, 4953-4962 (2003).
42. Gomez del Pulgar, T., Velasco, G., Sanchez, C., Haro, A. & Guzman, M. De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem. J. 363, 189-188 (2002).
43. Bouaboula, M. et al. A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions. J. Biol. Chem. 272, 22330-22339 (1997).
44. 1 cannabinoid receptor. Mol. Pharmacol. 62, 1385-1392 (2002).
45. Derkinderen, P. et al. Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J. Neurosci. 23, 2371-2382 (2003).
46. 9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. Mol. Pharmacol. 54, 834-843 (1998).
47. Hannun, Y. A. & Obeid, L. M. The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J. Biol. Chem. 277, 25847-25850 (2002).
48. Kolesnick, R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J. Clin. Invest. 110, 3-8 (2002).
49. 1 cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan. Mol. Pharmacol. 59, 955-959 (2001).
50. Galve-Roperh, I. et al. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nature Med. 6, 313-319 (2000). The first identification of a signalling mechanism for the apoptotic action of cannabinoids on tumour cells.
51. 9-Tetrahydrocannapinol induces apoptosis in C6 glioma cells. FEBS Lett. 436, 6-10 (1998).
52. Guzman, M., Galve-Roperh, I. & Sanchez, C. Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol. Sci. 22, 19-22 (2001).
53. 2 cannabinoid receptor. Cancer Res. 61, 5784-5789 (2001).
54. Mimeault, M., Pommery, N., Wattez, N., Bailly, C. & Henichart, J. P. Anti-proliferative and apoptotic effects of anandamide in human prostatic cancer cell lines: implication of epidermal growth factor receptor down-regulation and ceramide production. Prostate 56, 1-12 (2003).
55. Sarker, K. P., Obara, S., Nakata, M., Kitajima, I. & Maruyama, I. Anandamide induces apoptosis of PC-12 cells: involvement of superoxide and caspase-3. FEBS Lett. 472, 39-44 (2000).
56. Sarker, K. P. et al. ASK1-p38 MAPK/JNK signaling cascade mediates anandamide-induced PC12 cell death. J. Neurochem. 85, 50-61 (2003).
57. De Petrocellis, L. et al. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc. Natl Acad. Sci. USA 95, 8375-8380 (1998).
58. Melck, D. et al. Involvement of the cAMP/protein kinase A pathway and of mitogen-activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells. FEBS Lett. 463, 235-240 (1999).
59. Melck, D. et al. Suppression of nerve growth factor trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 141, 118-126 (2000).
60. Bifulco, M. et al. Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth. FASEB J. 15, 2745-2747 (2001).
61. Casanova, M. L. et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J. Clin. Invest. 111, 43-50 (2003).
62. Kerbel, R. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nature Rev. Cancer 2, 727-739 (2002).
63. Blazquez, C. et al. Inhibition of tumor angiogenesis by cannabinoids. FASEB J. 17, 529-531 (2003). The first paper showing that cannabinoid administration to mice impairs tumour angiogenesis.
64. 1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J. 3 Jul 2003 (doi:10.1096/fj. 02-1129fje).
65. Gomez Del Pulgar, T., De Ceballos, M. L., Guzman, M. & Velasco, G. Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 277, 36527-36533 (2002).
66. Molina-Holgado, E. et al. Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J. Neurosci. 22, 9742-9753 (2002).
67. Blazquez, C., Galve-Roperh, I. & Guzman, M. De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase. FASEB J. 14, 2315-2322 (2000).
68. Glass, M. & Felder C. C. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J. Neurosci. 17, 5327-5333 (1997).
69. Vasquez, C. & Lewis, D. L. The CB1 cannabinoid receptor can sequester G-proteins, making them unavailable to couple to other receptors. J. Neurosci. 19, 9271-9280 (1999).
70. 1 cannabinoid receptor juxtamembrane C-terminal peptide confers activation to specific G proteins in brain. Mol. Pharmacol. 57, 162-170 (2000).
71. Mechoulam, R., Panikashvili, D. & Shohami, E. Cannabinoids and brain injury: therapeutic implications. Trends Mol. Med. 8, 58-61 (2002).
72. van der Stelt, M. et al. Acute neuronal injury, excitotoxicity, and the endocannabinoid system. Mol. Neurobiol. 26, 317-346 (2002).
73. Maccarrone, M., Lorenzon, T., Bari, M., Melino, G. & Finazzi-Agro, A. Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J. Biol. Chem. 275, 31938-31945 (2000).
74. Guzman, M., Sanchez, C. & Galve-Roperh, I. Control of the cell survival/death decision by cannabinoids. J. Mol. Med. 78, 613-625 (2001).
75. Schwarz, H., Blanco, F. J. & Lotz, M. Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis. J. Neuroimmunol. 55, 107-115 (1994).
76. 9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1. J. Pharmacol. Exp. Ther. 286, 1103-1109 (1998).
77. Zhu, L. X. et al. Δ-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J. Immunol. 165, 373-380 (2000).
78. Derocq, J. M., Segui, M., Marchand, J., Le Fur, G. & Casellas, P. Cannabinoids enhance human B-cell growth at low nanomolar concentrations. FEBS Lett. 369, 177-182 (1995).
79. Valk, P. et al. Anandamide, a natural ligand for the peripheral cannabinoid receptor is a novel synergistic growth factor for hematopoietic cells. Blood 90, 1448-1457 (1997).
80. Tashkin, D. R., Baldwin, G. C., Sarafian, T., Dubinett, S. & Roth, M. D. Respiratory and immunologic consequences of marijuana smoking. J. Clin. Pharmacol. 42, 71S-81S (2002).
81. Adams, I. B. & Martin, B. R. Cannabis: pharmacology and toxicology in animals and humans. Addiction 91, 1585-1614 (1996).
82. Grotenhermen, F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin. Pharmacokinet. 42, 327-360 (2003).
83. 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. Fund. Appl. Toxicol. 30, 109-117 (1996).
84. 2 cannabinoid receptor agonists: pain relief without psychoactive effects? Curr. Opin. Pharmacol. 3, 62-67 (2003).
85. Jacobsson, S. O., Rongard, E., Stridh, M., Tiger, G. & Fowler, C. J. Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability. Biochem. Pharmacol. 60, 1607-1613 (2000).
86. Mechoulam, R., Parker, L. A. & Gallily, R. Cannabidiol: an overview of some pharmacological aspects. J. Clin. Pharmacol. 42, 11S-19S (2002).
87. Pop, E. Dexanabinol Pharmos. Curr. Opin. Investig. Drugs 1, 494-503 (2000).
88. Recht, L. D. et al. Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid. Biochem. Pharmacol. 62, 755-763 (2001).
89. Rhee, M. H. et al. Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase. J. Med. Chem. 40, 3228-3233 (1997).
90. Bifulco, M. & Di Marzo, V. Targeting the endocannabinoid system in cancer therapy: a call for further research. Nature Med. 8, 547-550 (2002). An enjoyable commentary about the possible antitumour action of the endogenous cannabinoid system.
91. Gallily, R. et al. γ-Irradiation enhances apoptosis induced by cannabidiol, a non-psychotropic cannabinoid, in cultured HL-60 myeloblastic leukemia cells. Leukemia Lymphoma 44, 1767-1773 (2003).
92. Radin, N. S. Killing tumours by ceramide-induced apoptosis: a critique of available drugs. Biochem. J. 371, 243-256 (2003).
93. 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, 1897-1909 (2000).
94. Maher, E. A. et al. Malignant glioma: genetics and biology of a grave matter. Genes Dev. 15, 1311-1333 (2001).
95. Louis, D. N., Pomeroy, S. L. & Caimcross, J. G. Focus on central nervous system neoplasia. Cancer Cell 1, 125-128 (2002).
96. McKallip, R. J. et al. Targeting CB2 cannabinoid receptors as a novel therapy to treat malignant lymphoblastic disease. Blood 100, 627-634 (2002).
97. 9-tetrahydrocannabinol on cell proliferation and macromolecular biosynthesis in human cells. Biochem. Pharmacol. 27, 1759-1765 (1978).
98. Blevins, R. D. & Smith, D. P. Effects of Δ -9-tetrahydrocannabinol on cultured HeLa cell growth and development. Growth 44, 133-138 (1980).
99. 9-tetrahydrocannebinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Lett. 458, 400-404 (1999).
100. Devane, W. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946-1949 (1992). The discovery of anandamide, the first endogenous ligand of cannabinoid receptors.
101. Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83-90 (1995).
102. Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89-97 (1995).
103. 1 - the first specific cannabinoid receptor.
104. Munro, S., Thomas, K. L. & Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61-65 (1993).
105. Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide. Nature 372, 686-691 (1994). The discovery of the currently accepted molecular mechanism of endocannabinoid biosynthesis.
106. Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 368, 773-778 (1997).
107. Beltramo, M. et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277, 1094-1097 (1997).
108. Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83-87 (1996).
109. Piomelli, D., Giuffrida, A., Calignano, A. & Rodriguez de Fonseca, F. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol. Sci. 21, 218-224 (2000).
110. Wilson, R. I. & Nicoll, R. A. Endogenous cannabinoids mediate retrograde signaling at hippocampal synapses. Nature 410, 588-592 (2001).
111. Schlicker, E. & Kathmann, M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci. 22, 565-572 (2001).
112. Maldonado, R. & Rodriguez de Fonseca, F. Cannabinoid addiction: behavioral models and neural correlates. J. Neurosci. 22, 3326-3331 (2002).
113. Calhoun, S. R., Galloway, G. P. & Smith, D. E. Abuse potential of dronabinol (Marinol). J. Psychoactive Drugs 30, 187-196 (1998).