Induction of cell cycle changes and modulation of apoptogenic/anti-apoptotic and extracellular signalling regulatory protein expression by water extracts of I'm-Yunity™ (PSP)

BMC Complementary and Alternative Medicine

Volumn 6, Issue , 2006, Pages

  Hsieh, Tze Chen ^a   Wu, Peili ^a   Park, Spencer ^a   Wu, Joseph M ^a  

^a NEW YORK MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CORIOLUS VERSICOLOR EXTRACT; CYCLOOXYGENASE 2; CYTOCHROME C; IM YUNITY; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IMMUNOMODULATING AGENT; MITOGEN ACTIVATED PROTEIN KINASE; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; PROTEIN BAX; PROTEIN BCL 2; PROTEIN P50; RETINOBLASTOMA PROTEIN; STAT1 PROTEIN; SURVIVIN; SYNAPTOTAGMIN; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CELL CYCLE; CELL CYCLE G1 PHASE; CELL CYCLE G2 PHASE; CELL CYCLE M PHASE; CELL CYCLE S PHASE; CELL PROLIFERATION; CELL STRAIN HL 60; CELL VIABILITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DOWN REGULATION; EDIBLE MUSHROOM; GROWTH INHIBITION; HUMAN; HUMAN CELL; IMMUNE RESPONSE; IMMUNOMODULATION; INHIBITION KINETICS; LEUKEMIA CELL; PROTEIN EXPRESSION;

APOPTOSIS; BIOLOGICAL AGENTS; CELL CYCLE; CELL PROLIFERATION; COMPLEX MIXTURES; CYCLOOXYGENASE 2; DOSE-RESPONSE RELATIONSHIP, DRUG; DOWN-REGULATION; HL-60 CELLS; HUMANS; INTERFERON-GAMMA; NF-KAPPA B; PHARMACEUTICAL PREPARATIONS; RETINOBLASTOMA PROTEIN; SIGNAL TRANSDUCTION; STAT1 TRANSCRIPTION FACTOR; U937 CELLS;

EID: 33749120511     PISSN: 14726882     EISSN: 14726882     Source Type: Journal    
DOI: 10.1186/1472-6882-6-30     Document Type: Article

References (107)

1. Yang MM, Chen Z, Kwok JS: The anti-tumor effect of a small polypeptide from Coriolus versicolor (SPCV). Am J Chin Med 1992, 20:221-232.
2. Wasser SP, Weis AL: Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms: a modern perspective. Crit Rev Immunol 1999, 19:65-96.
3. Borchers AT, Stern JS, Hackman RM, Keen CL, Gershwin ME: Mushrooms, tumors, and immunity. Proc Soc Exp Biol Med 1999, 221:281-293.
4. Kidd PM: The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev 2000, 5:4-27.
5. Hsieh TC, Wu JM: Cell growth and gene modulatory activities of Yunzhi (Windsor Wunxi) from mushroom Trametes versicolor in androgen-dependent and androgen-insensitive human prostate cancer cells. Int J Oncol 2001, 18:81-88.
6. Chu KK, Ho SS, Chow AH: Coriolus versicolor: a medicinal mushroom with promising immunotherapeutic values. J Clin Pharmacol 2002, 42:976-984.
7. Chang R: Bioactive polysaccharides from traditional Chinese medicine herbs as anticancer adjuvants. J Altern Complement Med 2002, 8:559-565.
8. Chang R, White JD: Asian therapies for cancer - coming of age. J Altern Complement Med 2002, 8:541-543.
9. Zaidman BZ, Yassin M, Mahajna J, Wasser SP: Medicinal mushroom modulators of molecular targets as cancer therapeutics. Appl Microbiol Biotechnol 2005, 67:453-468.
10. Fullerton SA, Samadi AA, Tortorelis DG, Choudhury MS, Mallouh C, Tazaki H, Konno S: Induction of apoptosis in human prostatic cancer cells with beta-glucan (Maitake mushroom polysaccharide). Mol Urol 2000, 4:7-13.
11. Ohno, N, Miura NN, Nakajima M, Yadomae T: Antitumor 1,3-beta-glucan from cultured fruit body of Sparassis crispa. Biol Pharm Bull 2000, 23:866-872.
12. Harada T, Miura N, Adachi Y, Nakajima M, Yadomae T, Ohn N: Effect of SCG, 1,3-beta-D-glucan from Sparassis crispa on the hematopoietic response in cyclophosphamide induced leukopenic mice. Biol Pharm Bull 2002, 25:931-939.
13. Zhang M, Cheung PC, Zhang L: Evaluation of mushroom dietary fiber (nonstarch polysaccharides) from sclerotia of Pleurotus tuber-regium (Fries) singer as a potential antitumor agent. J Agric Food Chem 2001, 49:5059-5062.
14. Ohno N, Furukawa M, Miura NN, Adachi Y, Motoi M, Yadomae T: Antitumor beta glucan from the cultured fruit body of Agaricus blazei. Biol Pharm Bull 2001, 24:820-828.
15. Takaku T, Kimura Y, Okuda H: Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action. J Nutr 2001, 131:1409-1413.
16. Wang HX, Liu WK, Ng TB, Ooi VE, Chang ST: Immunomodulatory and antitumor activities of a polysaccharide-peptide complex from a mycelial culture of Tricholoma sp., a local edible mushroom. Life Sci 1995, 57:269-281.
17. Wang H, Gao J, Ng TB: A new lectin with highly potent antihepatoma and antisarcoma activities from the oyster mushroom Pleurotus ostreatus. Biochem Biophys Res Commun 2000, 275:810-816.
18. Wang HX, Ng TB: Examination of lectins, polysaccharopeptide, polysaccharide, alkaloid, coumarin and trypsin inhibitors for inhibitory activity against human immunodeficiency virus reverse transcriptase and glycohydrolases. Planta Med 2001, 67:669-672.
19. Mayell M: Maitake extracts and their therapeutic potential. Altern Med Rev 2001, 6:48-60.
20. Nanba H, Kubo, K: Effect of Maitake D-fraction on cancer prevention. Ann N Y Acad Sci 1997, 833:204-207.
21. Matsui K, Kodama N, Nanba H: Effects of maitake (Grifola frondosa) D-Fraction on the carcinoma angiogenesis. Cancer Lett 2001, 172:193-198.
22. Finkelstein MP, Aynehchi S, Samadi AA, Drinis S, Choudhury MS, Tazaki H, Konno S: Chemosensitization of carmustine with maitake beta-glucan on androgen-independent prostatic cancer cells: involvement of glyoxalase I. J Altern Complement Med 2002, 8:573-580.
23. Kawamura Y, Manabe M, Kitta K: Antitumor protein (AP) from a mushroom induced apoptosis to transformed human keratinocyte by controlling the status of prb, c-MYC, cyclin E-cdk2, and p21 WAFI in the GI/S transition. Biofactors 2000, 12:157-160.
24. Dong Y, Yang MM, Kwan CY: In vitro inhibition of proliferation of HL-60 cells by tetrandrine and coriolus versicolor peptide derived from Chinese medicinal herbs. Life Sci 1997, 60:PL135-140.
25. Ng TB: A review of research on the protein-bound polysaccharide (polysaccharopeptide, PSP) from the mushroom Coriolus versicolor (Basidiomycetes: Polyporaceae). Gen Pharmacol 1998, 30:1-4.
26. Li XY, Wang JF, Zhu PP, Liu L, Ge JB, Yang SX: Immune enhancement of a polysaccharides peptides isolated from Coriolus versicolor. Zhongguo Yao Li Xue Boo 1990, 11:542-545.
27. Cui J, Chisti Y: Polysaccharopeptides of Coriolus versicolor. physiological activity, uses, and production. Biotechnol Adv 2003, 21:109-122.
28. Hsieh TC, Kunicki J, Darzynkiewicz Z, Wu JM: Effects of extracts of Coriolus versicolor (I'm-Yunity) on cell-cycle progression and expression of interleukins-1 beta,-6, and -8 in promyelocytic HL-60 leukemic cells and mitogenically stimulated and nonstimulated human lymphocytes. J Altern Complement Med 2002, 8:591-602.
29. Zeng F, Hon CC, Sit WH, Chow KY, Hui RK, Law IK, Ng VW, Yang XT, Leung FC, Wan JM: Molecular characterization of Coriolus versicolor PSP-induced apoptosis in human promyelotic leukemic HL-60 cells using cDNA microarray. Int J Oncol 2005, 27:513-523.
30. Hui KP, Sit WH, Wan JM: Induction of S phase cell arrest and caspase activation by polysaccharide peptide isolated from Coriolus versicolor enhanced the cell cycle dependent activity and apoptotic cell death of doxorubicin and etoposide, but not cytarabine in HL-60 cells. Oncol Rep 2005, 14:145-155.
31. Yang X, Sit WH, Chan DK, Wan JM: The cell death process of the anticancer agent polysaccharide-peptide (PSP) in human promyelocytic leukemic HL-60 cells. Oncot Rep 2005, 13:1201-1210.
32. Dipietrantonio A, Hsieh TC, Wu JM: Differential effects of retinoic acid (RA) and N-(4-hydroxyphenyl) retinamide (4-HPR) on cell growth, induction of differentiation, and changes in p34cdc2, Bcl-2, and actin expression in the human promyelocytic HL-60 leukemic cells. Biochem Biophys Res Commun 1996, 224:837-842.
33. DiPietrantonio AM, Hsieh TC, Olson SC, Wu JM: Regulation of GI/S transition and induction of apoptosis in HL-60 leukemia cells by fenretinide (4HPR). Int J Cancer 1998, 78:53-61.
34. Hsieh TC, Wu JM: Mechanism of action of herbal supplement PC-SPES: elucidation of effects of individual herbs of PC-SPES on proliferation and prostate specific gene expression in androgen-dependent LNCaP cells. Int J Oncol 2002, 20:583-588.
35. Hsieh TC, Wang Z, Hamby CV, Wu JM: Inhibition of melanoma cell proliferation by resveratrol is correlated with upregulation of quinone reductase 2 and p53. Biochem Biophys Res Commun 2005, 334:223-230.
36. Hsieh TC, Wu JM: Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines. Exp Cell Res 1999, 249:109-115.
37. Darzynkiewicz Z, Bedner E, Smolewski P: Flow cytometry in analysis of cell cycle and apoptosis. Semin Hematol 2001, 38:179-193.
38. Fu Y, Hsieh TC, Guo J, Kunicki J, Lee MY, Darzynkiewicz Z, Wu JM: Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells. Biochem Biophys Res Commun 2004, 322:263-270.
39. Hsieh TC, Juan G, Darzynkiewicz Z, Wu JM: Resveratrol increases nitric oxide synthase, induces accumulation of p53 and p2l (WAFI/CIP 1), and suppresses cultured bovine pulmonary artery endothelial cell proliferation by perturbing progression through S and G2. Cancer Res 1999, 59:2596-2601.
40. Lu X, Hsieh TC, Wu JM: Equiguard suppresses androgen-dependent LNCaP prostate cancer cell proliferation by targeting cell cycle control via down regulation of the retinoblastoma protein Rb and induction of apoptosis via the release of cytochrome c. Int J Oncol 2004, 25:1801-1807.
41. Lu X, Guo J, Hsieh TC: PC-SPES inhibits cell proliferation by modulating p21, cyclins D, E and B and multiple cell cyclerelated genes in prostate cancer cells. Cell Cycle 2003, 2:59-63.
42. Hsieh TC, Lu X, Guo J, Xiong W, Kunicki J, Darzynkiewicz Z, Wu JM: Effects of herbal preparation Equiguard on hormone-responsive and hormone-refractory prostate carcinoma cells: mechanistic studies. Int J Oncol 2002, 20:681-689.
43. Lu X, Guo J, Hsieh TC, Wu JM: Inhibition of proliferation and expression of AR/PSA by herbal supplement Equiguard in LNCaP cells cultured in androgen-proficient FBS and androgen-deficient charcoal-stripped FBS is correlated with increased serine- 15 phosphorylation of the tumor suppressor gene p53. Anticancer Res 2003, 23:2489-2498.
44. Taya Y: RB kinases and RB-binding proteins: new points of view. Trends Biochem Sci 1997, 22:14-17.
45. Darzynkiewicz Z, Bedner E, Traganos F, Murakami T: Critical aspects in the analysis of apoptosis and necrosis. Hum Cell 1998, 11:3-12.
46. Wu JM, DiPietrantonio AM, Hsieh TC: Mechanism of fenretinide (4-HPR)-induced cell death. Apoptosis 2001, 6:377-388.
47. Darzynkiewicz Z, Smolewski P, Bedner E: Use of flow and laser scanning cytometry to study mechanisms regulating cell cycle and controlling cell death. Clin Lab Med 2001, 21:857-873.
48. Darzynkiewicz Z, Huang X, Okafuji M, King MA: Cytometric methods to detect apoptosis. Methods Cell Biol 2004, 75:307-341.
49. Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science 1995, 267:1456-1462.
50. Duckett CS, Thompson CB: The control and execution of programmed cell death: an update. Biochim Biophys Acta 1997, 1332:R45-47.
51. Tsai SY, Ardelt B, Hsieh TC, Darzynkiewicz Z, Shogen K, Wu JM: Treatment of Jurkat acute T-lymphocytic leukemia cells by onconase (Ranpirnase) is accompanied by an altered nucleo-cytoplasmic distribution and reduced expression of transcription factor NF-kappaB. Int J Oncol 2004, 25:1745-1752.
52. Perkins ND, Gilmore TD: Good cop, bad cop: the different faces of NF-kappaS. Cell Death Differ 2006, 13:759-772.
53. Campbell KJ, Perkins ND: Regulation of NF-kappaB function. Biochem Soc Symp 2006:165-180.
54. Aggarwal BB: Nuclear factor-kappaB: the enemy within. Cancer Cell 2004, 6:203-208.
55. Shishodia S, Aggarwal BB: Nuclear factor-kappaB: a friend or a foe in cancer? Biochem Pharmacol 2004, 68:1071-1080.
56. Kumar A, Takada Y, Boriek AM, Aggarwal BB: Nuclear factor-kappaB: its role in health and disease. J Mol Med 2004, 82:434-448.
57. Shishodia S, Aggarwal BB: Nuclear factor-kappaB activation mediates cellular transformation, proliferation, invasion angiogenesis and metastasis of cancer. Cancer Treat Res 2004, 119:139-173.
58. Horvath CM: The Jak-STAT pathway stimulated by interferon gamma. Sci STKE 2004, 2004:tr8.
59. Qing Y, Stark GR: Alternative activation of STAT1 and STAT3 in response to interferon-gamma. J Biol Chem 2004, 279:41679-41685.
60. Kerr IM, Costa-Pereira AP, Lillemeier BF, Strobl B: Of JAKs, STATs, blind watchmakers, jeeps and trains. FEBS Lett 2003, 546:1-5.
61. Sehgal PB, Guo GG, Shah M, Kumar V, Patel K: Cytokine signaling: STATS in plasma membrane rafts. J Biol Chem 2002, 277:12067-12074.
62. Shah M, Patel K, Fried VA, Sehgal PB: Interactions of STAT3 with caveolin-1 and heat shock protein 90 in plasma membrane raft and cytosolic complexes. Preservation of cytokine signaling during fever. J Biol Chem 2002, 277:45662-45669.
63. Lee CK, Smith E, Gimeno R, Gertner R, Levy DE: STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma. J Immunol 2000, 164:1286-1292.
64. Doll R, Peto R: The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 1981, 66:1191-1308.
65. Hsing AW, Tsao L, Devesa SS: International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 2000, 85:60-67.
66. Hsing AW, Devesa SS: Trends and patterns of prostate cancer: what do they suggest? Epidemiol Rev 2001, 23:3-13.
67. Sporn MB, Suh N: Chemoprevention: an essential approach to controlling cancer. Nat Rev Cancer 2002, 2:537-543.
68. Sporn MB, Newton DL: Chemoprevention of cancer with retinoids. Fed Proc 1979, 38:2528-2534.
69. Sporn MB, Suh N: Chemoprevention of cancer. Carcinogenesis 2000, 21:525-530.
70. Milner JA, McDonald SS, Anderson DE, Greenwald P: Molecular targets for nutrients involved with cancer prevention. Nutr Cancer 2001, 41:1-16.
71. Greenwald P: Cancer prevention clinical trials. J Clin Oncol 2002, 20:14S-22S.
72. Greenwald P: Cancer chemoprevention. Bmj 2002, 324:714-718.
73. Greenwald P: Clinical trials in cancer prevention: current results and perspectives for the future. J Nutr 2004, 134:3507S-3512S.
74. Greenwald P, Clifford CK, Milner JA: Diet and cancer prevention. Eur J Cancer 2001, 37:948-965.
75. Greenwald P, McDonald SS, Anderson DE: An evidence-based approach to cancer prevention clinical trials. Eur J Cancer Prev 2002, 11 (Suppl 2):S43-47.
76. Greenwald P, Milner JA, Anderson DE, McDonald SS: Micronutrients in cancer chemoprevention. Cancer Metastasis Rev 2002, 21:217-230.
77. Hong WK, Sporn MB: Recent advances in chemoprevention of cancer. Science 1997, 278:1073-1077.
78. Kelloff GJ, Hawk ET, Karp JE, Crowell JA, Boone CW, Steele VE, Lubet RA, Sigman CC: Progress in clinical chemoprevention. Semin Oncol 1997, 24:241-252.
79. Kelloff GJ, Lieberman R, Steele VE, Boone CW, Lubet RA, Kopelovich L, Malone WA, Crowell JA, Higley HR, Sigman CC: Agents, biomarkers, and cohorts for chemopreventive agent development in prostate cancer. Urology 2001, 57:46-51.
80. Perkins ND: NF-kappaB: tumor promoter or suppressor? Trends Cell Biol 2004, 14:64-69.
81. Campbell KJ, O'Shea JM, Perkins ND: Differential regulation of NF-kappaB activation and function by topoisomerase II inhibitors. BMC Cancer 2006, 6:101.
82. Campbell KJ, Witty JM, Rocha S, Perkins ND: Cisplatin mimics ARF tumor suppressor regulation of ReIA (p65) nuclear factor-kappaB transactivation. Cancer Res 2006, 66:929-935.
83. Gimonet D, Landais E, Bobichon H, Coninx P, Liautaud-Roger F: Induction of apoptosis by bleomycin in p53-null HL-60 leukemia cells. Int J Oncol 2004, 24:313-319.
84. Shimizu T, Pommier Y: DNA fragmentation induced by protease activation in p53-null human leukemia HL60 cells undergoing apoptosis following treatment with the topoisomerase I inhibitor camptothecin: cell-free system studies. Exp Cell Res 1996, 226:292-301.
85. El-Mahdy MA, Zhu Q, Wang QE, Wani G, Wani AA: Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myeloblastic leukemia HL-60 cells. Int J Cancer 2005, 117:409-417.
86. Houle MG, Kahn RA, Naccache PH, Bourgoin S: ADP-ribosylation factor translocation correlates with potentiation of GTP gamma S-stimulated phospholipase D activity in membrane fractions of HL-60 cells. J Biol Chem 1995, 270:22795-22800.
87. Martin A, Brown FD, Hodgkin MN, Bradwell AJ, Cook SJ, Hart M, Wakelam MJ: Activation of phospholipase D and phosphatidylinositol 4-phosphate 5-kinase in HL60 membranes is mediated by endogenous Arf but not Rho. J Biol Chem 1996, 271:17397-17403.
88. Guillemain I, Exton JH: Effects of brefeldin A on phosphatidylcholine phospholipase D and inositolphospholipid metabolism in HL-60 cells. Eur J Biochem 1997, 249:812-819.
89. Skippen A, Jones DH, Morgan CP, Li M, Cockcroft S: Mechanism of ADP ribosylation factor-stimulated phosphatidylinositol 4,5-bisphosphate synthesis in HL60 cells. J Biol Chem 2002, 277:5823-5831.
90. Denk A, Goebeler M, Schmid S, Berberich I, Ritz O, Lindemann D, Ludwig S, Wirth T: Activation of NF-kappa B via the Ikappa B kinase complex is both essential and sufficient for proinflammatory gene expression in primary endothelial cells. J Biol Chem 2001, 276:28451-28458.
91. Perona R, Montaner S, Saniger L, Sanchez-Perez I, Bravo R, Lacal JC: Activation of the nuclear factor-kappaB by Rho, CDC42, and Rac-1 proteins. Genes Dev 1997, 11:463-475.
92. Nelson WG, De Marzo AM, Isaacs WB: Prostate cancer. N Engl J Med 2003, 349:366-381.
93. Narayanan BA, Narayanan NK, Pittman B, Reddy BS: Regression of mouse prostatic intraepithelial neoplasia by nonsteroidal anti-inflammatory drugs in the transgenic adenocarcinoma mouse prostate model. Clin Cancer Res 2004, 10:7727-7737.
94. Narayanan BA, Narayanan NK, Pttman B, Reddy BS: Adenocarcina of the mouse prostate growth inhibition by celecoxib: Down-regulation of transcription factors involved in COX-2 inhibition. Prostate 2005.
95. Kashfi K, Rigas B: Is COX-2 a 'collateral' target in cancer prevention? Biochem Soc Trans 2005, 33:724-727.
96. Ranger GS, Thomas V, Jewell A, Mokbel K: Elevated cyclooxygenase-2 expression correlates with distant metastases in breast cancer. Anticancer Res 2004, 24:2349-2351.
97. Spano JP, Chouahnia K, Morere JF: [Cyclooxygenase 2 inhibitors and lung carcinoma]. Bull Cancer 2004, 91 (Suppl 2):S109-112.
98. Monro JA: Treatment of cancer with mushroom products. Arch Environ Health 2003, 58:533-537.
99. Wasser SP: Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides. Appl Microbiol Biotechnol 2002, 60:258-274.
100. Fisher M, Yang LX: Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Anticancer Res 2002, 22:1737-1754.
101. Howard KA, Li XW, Somavarapu S, Singh J, Green N, Atuah KN, Ozsoy Y, Seymour LW, Alpar HO: Formulation of a microparticle carrier for oral polyplex-based DNA vaccines. Biochim Biophys Acta 2004, 1674:149-157.
102. Ross BP, Toth I: Gastrointestinal absorption of heparin by lipidization or coadministration with penetration enhancers. Curr Drug Deliv 2005, 2:277-287.
103. Kim SK, Lee EH, Vaishali B, Lee S, Lee YK, Kim CY, Moon HT, Byun Y: Tricaprylin microemulsion for oral delivery of low molecular weight heparin conjugates. J Control Release 2005, 105:32-42.
104. Kim SK, Vaishali B, Lee E, Lee S, Lee YK, Kumar TS, Moon HT, Byun Y: Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation. Thromb Res 2005.
105. Bernkop-Schnurch A, Kast CE, Guggi D: Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: thiomer/GSH systems. J Control Release 2003, 93:95-103.
106. Tsai MF, Chiang YL, Wang LF, Huang GW, Wu PC: Oral sustained delivery of diclofenac sodium using calcium chondraitin sulfate matrix. J Biomater Sci Polym Ed 2005, 16:1319-1331.
107. Sinha VR, Kumria R: Polysaccharides in colon-specific drug delivery. Int J Pharm 2001, 224:19-38.