Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth

Neoplasia

Volumn 10, Issue 10, 2008, Pages 1105-1119

  Das, Bikul ^a,b,c   Antoon, Roula ^a,b,c   Tsuchida, Rika ^b   Lotfi, Shamim ^a,b   Morozova, Olena ^b   Farhat, Walid ^a,b   Malkin, David ^b,c   Koren, Gideon ^b,c   Yeger, Herman ^a,b,d   Baruchel, Sylvain ^b,c  

^a HOSPITAL FOR SICK CHILDREN RESEARCH INSTITUTE   (Canada)

^b HOSPITAL FOR SICK CHILDREN   (Canada)

^c UNIVERSITY OF TORONTO   (Canada)

^d UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

CARBOPLATIN; CISPLATIN; GLUTATHIONE; GLUTATHIONE PEROXIDASE; REACTIVE OXYGEN METABOLITE; SQUALENE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIOXIDANT ACTIVITY; ARTICLE; BONE MARROW CELL; BONE MARROW TOXICITY; CELL PROTECTION; COLONY FORMING UNIT F; COLONY FORMING UNIT GM; CONTROLLED STUDY; CYTOTOXICITY; DRUG SELECTIVITY; EXPERIMENTAL MODEL; FEMALE; MEDULLOBLASTOMA; MESENCHYMAL STEM CELL; MOUSE; NEUROBLASTOMA; NONHUMAN; PRIORITY JOURNAL; SMALL CELL CARCINOMA; TUMOR GROWTH; TUMOR XENOGRAFT; WEIGHT REDUCTION;

EID: 54249135351     PISSN: 15228002     EISSN: 14765586     Source Type: Journal    
DOI: 10.1593/neo.08466     Document Type: Article

References (94)

1. DanielDand Crawford J (2006).Myelotoxicity from chemotherapy. Semin Oncol 33 (1), 74-85.
2. Weycker D, Malin J, Edelsberg J, Glass A, Gokhale M, and Oster G (2008). Cost of neutropenic complications of chemotherapy. Ann Oncol 19 (3), 454-460.
3. Go RS and Adjei AA (1999). Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 17 (1), 409-422.
4. BC Cancer Agency (2006). Cancer Drug Manual. British Columbia Agency.
5. Zahra MA, Taylor A, Mould G, Coles C, Crawford R, and Tan LT (2008). Concurrent weekly cisplatin chemotherapy and radiotherapy in a haemodialysis patient with locally advanced cervix cancer. Clin Oncol (R Coll Radiol) 20 (1), 6-11.
6. de Jongh FE, van Veen RN, Veltman SJ, de Wit R, van der Burg ME, van den Bent MJ, Planting AS, Graveland WJ, Stoter G, and Verweij J (2003). Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. Br J Cancer 88 (8), 1199-1206.
7. Frappaz D, Bouffet E, Perel Y, Stephan JL, Alos N, Grabois M, Berger C, Brunat Mentigny M, and Philip T (1998). Phase II study of cisplatinum and carboplatinum (CACIS) combination in advanced stage neuroblastomas. Med Pediatr Oncol 30 (1), 9-14.
8. Zwelling LA, Michaels S, Schwartz H, Dobson PP, and Kohn KW (1981). DNA cross-linking as an indicator of sensitivity and resistance of mouse L1210 leukemia to cis-diamminedichloroplatinum(II) and L-phenylalanine mustard. Cancer Res 41 (2), 640-649.
9. Lu Y and Cederbaum A (2007). The mode of cisplatin-induced cell death in CYP2E1-overexpressing HepG2 cells: modulation by ERK, ROS, glutathione, and thioredoxin. Free Radic Biol Med 43 (7), 1061-1075.
10. Martins NM, Santos NA, Curti C, Bianchi ML, and Santos AC (2008). Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver. J Appl Toxicol 28 (3), 337-344.
11. Evans RG, Wheatley C, Engel C, Nielsen J, and Ciborowski LJ (1984). Modification of the bone marrow toxicity of cis-diamminedichloroplatinum(II) in mice by diethyldithiocarbamate. Cancer Res 44 (9), 3686-3690.
12. Nowrousian MR and Schmidt CG (1982). Effects of cisplatin on different haemopoietic progenitor cells in mice. Br J Cancer 46 (3), 397-402.
13. Das B, Yeger H, Baruchel H, Freedman M, Koren G, and Baruchel S (2003). In vitro cytoprotective activity of squalene on a bone marrow versus neuroblastoma model of cisplatin-induced toxicity. Implications in cancer chemotherapy. Eur J Cancer 39 (17), 2556-2565.
14. Lelieveld P, Van der Vijgh WJ, Veldhuizen RW, Van Velzen D, Van Putten LM, Atassi G, and Danguy A (1984). Preclinical studies on toxicity, antitumour activity and pharmacokinetics of cisplatin and three recently developed derivatives. Eur J Cancer Clin Oncol 20 (8), 1087-1104.
15. Su WC, Chang SL, Chen TY, Chen JS, and Tsao CJ (2000). Comparison of in vitro growth-inhibitory activity of carboplatin and cisplatin on leukemic cells and hematopoietic progenitors: the myelosuppressive activity of carboplatin may be greater than its antileukemic effect. Jpn J Clin Oncol 30 (12), 562-567.
16. Weijl NI, Elsendoorn TJ, Lentjes EG, Hopman GD, Wipkink-Bakker A, Zwinderman AH, Cleton FJ, and Osanto S (2004). Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study. Eur J Cancer 40 (11), 1713-1723.
17. Husain K, Whitworth C, and Rybak L (2004). Time response of carboplatin-induced nephrotoxicity in rats. Pharmacol Res 50 (3), 291-300.
18. Abd-Allah AR, Al-Majed AA, Al-Yahya AA, Fouda SI, and Al-Shabana OA (2005). L-Carnitine halts apoptosis and myelosuppression induced by carboplatin in rat bone marrow cell cultures (BMC). Arch Toxicol 79 (7), 406-413.
19. Budd GT, Ganapathi R, Bukowski RM, and Murthy S (1996). Clinical effects of amifostine (Ethyol) in patients treated with carboplatin. Eur J Cancer 32A (Suppl 4), S43-S45.
20. Muldoon LL, Walker-Rosenfeld SL, Hale C, Purcell SE, Bennett LC, and Neuwelt EA (2001). Rescue from enhanced alkylator-induced cell death with low molecular weight sulfur-containing chemoprotectants. J Pharmacol Exp Ther 296 (3), 797-805.
21. Neuwelt EA, Pagel MA, Kraemer DF, Peterson DR, and Muldoon LL (2004). Bone marrow chemoprotection without compromise of chemotherapy efficacy in a rat brain tumor model. J Pharmacol Exp Ther 309 (2), 594-599.
22. Pratibha R, Sameer R, Rataboli PV, Bhiwgade DA, and Dhume CY (2006). Enzymatic studies of cisplatin induced oxidative stress in hepatic tissue of rats. Eur J Pharmacol 532 (3), 290-293.
23. Rose PG (1996). Amifostine cytoprotection with chemotherapy for advanced ovarian carcinoma. Semin Oncol 23 (4 Suppl 8), 83-89.
24. Bukowski RM (1996). The need for cytoprotection. Eur J Cancer 32A (Suppl 4), S2-S4.
25. Muggia FM (1994). Cytoprotection: concepts and challenges. Support Care Cancer 2 (6), 377-379.
26. Gandara DR, Perez EA, Weibe V, and De Gregorio MW (1991). Cisplatin chemoprotection and rescue: pharmacologic modulation of toxicity. Semin Oncol 18 (1 Suppl 3), 49-55.
27. Pierelli L, Scambia G, Fattorossi A, Bonanno G, Battaglia A, Perillo A, Menichella G, Panici PB, Leone G, and Mancuso S (1998). In vitro effect of amifostine on haematopoietic progenitors exposed to carboplatin and non-alkylating antineoplastic drugs: haematoprotection acts as a drug-specific progenitor rescue. Br J Cancer 78 (8), 1024-1029.
28. Blakley BW, Cohen JI, Doolittle ND, Muldoon LL, Campbell KC, Dickey DT, and Neuwelt EA (2002). Strategies for prevention of toxicity caused by platinum-based chemotherapy: Review and Summary of the AnnualMeeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001. Laryngoscope 112 (11), 1997-2001.
29. Das B (2000). Human Antioxidant Squalene, p. 81. Toronto: Toronto Medical Publishing, ISBN 1-890412-95-3.
30. Storm HM, Oh SY, Kimler BF, and Norton S (1993). Radioprotection of mice by dietary squalene. Lipids 28 (6), 555-559.
31. Hashim YZ, Eng M, Gill CI, McGlynn H, and Rowland IR (2005). Components of olive oil and chemoprevention of colorectal cancer.Nutr Rev 63 (11), 374-386.
32. Murakoshi M, Nishino H, Tokuda H, Iwashima A, Okuzumi J, Kitano H, and Iwasaki R (1992). Inhibition by squalene of the tumor-promoting activity of 12-O-tetradecanoylphorbol-13-acetate in mouse-skin carcinogenesis. Int J Cancer 52 (6), 950-952.
33. Smith TJ (2000). Squalene: potential chemopreventive agent. Expert Opin Investig Drugs 9 (8), 1841-1848.
34. Smith TJ, Yang GY, Seril DN, Liao J, and Kim S (1998). Inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis by dietary olive oil and squalene. Carcinogenesis 19 (4), 703-706.
35. Desai KN, Wei H, and Lamartiniere CA (1996). The preventive and therapeutic potential of the squalene-containing compound, Roidex, on tumor promotion and regression. Cancer Lett 101 (1), 93-96.
36. Ikekawa T, Umeji M, Manabe T, Yanoma S, Irinoda K, Mizunuma H, and Ikekawa N (1986). Studies on antitumor activity of squalene and its related compounds. Yakugaku Zasshi 106 (7), 578-582.
37. Nakagawa M, Yamaguchi T, Fukawa H, Ogata J, Komiyama S, Akiyama S, and Kuwano M (1985). Potentiation by squalene of the cytotoxicity of anticancer agents against cultured mammalian cells and murine tumor. Jpn J Cancer Res 76 (4), 315-320.
38. Yamaguchi T, Nakagawa M, Hidaka K, Yoshida T, Sasaki T, Akiyama S, and Kuwano M (1985). Potentiation by squalene of antitumor effect of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-nitrosourea in a murine tumor system. Jpn J Cancer Res 76 (10), 1021-1026.
39. Wang X, Fjerdingstad H, Strom-Gundersen I, and Benestad HB (1999). Maturation rate of mouse neutrophilic granulocytes: acceleration by retardation of proliferation, but no detectable influence from G-CSF or stromal cells. Stem Cells 17 (5), 253-264.
40. Relas H, Gylling H, and Miettinen TA (2001). Fate of intravenously administered squalene and plant sterols in human subjects. J Lipid Res 42 (6), 988-994.
41. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, and Tang DG (2005). Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res 65 (14), 6207-6219.
42. Treskes M, Boven E, Holwerda U, Piendo HM, and van der Vijh WJ (1992). Time dependence of the selective modulation of cisplatinum-induced nephrotoxicity by WR2721 in the mouse. Cancer Res 52, 2257-2260.
43. Hou L, Cao H, Wang D, Wei G, Bai C, Zhang Y, and Pei X (2003). Induction of umbilical cord blood mesenchymal stem cells into neuron-like cells in vitro. Int J Hematol 78 (3), 256-261.
44. Phinney DG, Kopen G, Issacson RL, and Prockop DJ (1999). Plastic adherent stromal cells from the bone marrow of commonly used strains of inbred mice: variations in yield, growth, and differentiation. J Cell Biochem 38, 7-12.
45. Das B, Tsuchida R, Malkin D, Baruchel S, and Yeger H (2008). Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side-population fraction. Stem Cells 26 (7), 1818-1830.
46. Junn E, Taniguchi H, Jeong BS, Zhao X, Ichijo H, and Mouradian MM (2005). Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc Natl Acad Sci USA 102 (27), 9691-9696.
47. Spanggord RJ, Wu B, Sun M, Lim P, and Ellis WY (2002). Development and application of an analytical method for the determination of squalene in formulations of anthrax vaccine adsorbed. J Pharm Biomed Anal 29 (1-2), 183-193.
48. Das B, Stempak D, Koren G, Yeger H, Baruchel S. A rapid and simple HPLC method for the measurement of dietary squalene in tissues and its pharmacokinetic application. 32nd International Symposium on High Performance Liquid Phase Separations and Related Techniques; May 10, 2008; Baltimore, MD.
49. Lamoury F, Croitoru-Lamoury J, and Brew B (2006). Undifferentiated mouse mesenchymal stem cells spontaneously express neural and stem cell markers Oct-4 and Rex-1. Cytotherapy 8 (3), 228-242.
50. Short B, Brouard N, Occhiodoro-Scott T, Ramakrishnan A, and Simmons PJ (2003). Mesenchymal stem cells. Arch Med Res 34 (6), 565-571.
51. Tsuchida R, Das B, Yeger H, Koren G, Masabhumi S, Thorner SP, Baruchel S, and Malkin D (2008). Cisplatin treatment increases survival and expansion of a highly tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling. Oncogene 27 (28), 3923-3934.
52. Mackillop W, Ciampi A, Till J, and Buick R (1983). A stem cell model of human tumor growth: implications for tumor cell clonogenic assay. J Natl Cancer Inst 70 (1), 9-16.
53. Tsuchida R, Das B, Baruchel S, Yeger H, and Malkin D (2006). VEGF/Flt1 signaling is involved in the drug-resistance and stemness in osteosarcoma. Proc Am Assoc Cancer Res 47, 1567.
54. Das B, Yeger H, Baruchel S. Bone marrow cytoprotective activity of a triterpenoid antioxidant squalene: its implications in Pediatric Cancer Chemotherapy. Pediatric Oncology Group of Ontario (POGO) Annual Multidisciplinary Symposium, November 2002, Toronto.
55. Wink DA, Cook JA, Christodoulou D, Krishna MC, Pacelli R, Kim S, DeGraff W, Gamson J, Vodovotz Y, Russo A, et al. (1997). Nitric oxide and some nitric oxide donor compounds enhance the cytotoxicity of cisplatin. Nitric Oxide 1 (1), 88-94.
56. Mansour HH, Hafez HF, and Fahmy NM (2006). Silymarin modulates cisplatin-induced oxidative stress and hepatotoxicity in rats. J Biochem Mol Biol 39 (6), 656-661.
57. Greggi Antunes LM, Darin JD, and Bianchi MD (2000). Protective effects of vitamin C against cisplatin-induced nephrotoxicity and lipid peroxidation in adult rats: a dose-dependent study. Pharmacol Res 41 (4), 405-411.
58. Ishikawa T and Ali-Osman F (1993). Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem 268 (27), 20116-20125.
59. Miyajima A, Nakashima J, Yoshioka K, Tachibana M, Tazaki H, and Murai M (1997). Role of reactive oxygen species in cis-dichlorodiammineplatinum- induced cytotoxicity on bladder cancer cells. Br J Cancer 76 (2), 206-210.
60. Sadzuka Y, Shoji T, and Takino Y (1992). Effect of cisplatin on the activities of enzymes which protect against lipid peroxidation. Biochem Pharmacol 43 (8), 1872-1875.
61. Von Drygalski A, Alespeiti G, Ren L, and Adamson JW (2004). Murine bone marrow cells cultured ex vivo in the presence of multiple cytokine combinations lose radioprotective and long-term engraftment potential. Stem Cells Dev 13 (1), 101-111.
62. von Drygalski A, Savatski L, Eastwood D, Klein J, and Adamson JW (2005). The rate of marrow recovery and extent of donor engraftment following transplantation of ex vivo-expanded bone marrow cells are independently influenced by the cytokines used for expansion. Stem Cells Dev 14 (5), 564-575.
63. Kohono Y, Egawa Y, Itoh S, Nagaoka S, Takahashi M, and Mukai K (1995). Kinetic study of quenching reaction of singlet oxygen and scavenging reaction of free radical by squalene in n-butanol. Biochim Biophys Acta 1256, 52-56.
64. Cathcart R, Schwiers E, and Ames BN (1983). Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay. Anal Biochem 134 (1), 111-116.
65. Crow JP (1997). Dichlorodihydrofluorescein and dihydrorhodamine 123 are sensitive indicators of peroxynitrite in vitro: implications for intracellular measurement of reactive nitrogen and oxygen species. Nitric Oxide 1 (2), 145-157.
66. Mohan IK, Khan M, Shobha JC, Naidu MU, Prayag A, Kuppusamy P, and Kutala VK (2006). Protection against cisplatin-induced nephrotoxicity by Spirulina in rats. Cancer Chemother Pharmacol 58 (6), 802-808.
67. Cetin R, Devrim E, Kilicoglu B, Avci A, Candir O, and Durak I (2006). Cisplatin impairs antioxidant system and causes oxidation in rat kidney tissues: possible protective roles of natural antioxidant foods. J Appl Toxicol 26 (1), 42-46.
68. Rhoden EL, Lucas ML, Pereira-Lima L, Rhoden CR, and Souto CA (2001). Effects of L-arginine on the kidney levels of malondialdehyde in rats submitted to renal ischaemia-reperfusion. BJU Int 88 (3), 273-277.
69. Das B, Tsuchida R, Morozova O, Yeger H, Malkin D, and Baruchel S (2005). The role of VEGF signaling during oxidative stress. Dig Dis Sci 50 (10), 1978-1979.
70. Cetin T, Arpaci F, Yilmaz M, Saglam K, Ozturk B, Komurcu S, Gunay M, Ozet A, Akay C, Kilic S, et al. (2004). Oxidative stress in patients undergoing highdose chemotherapy plus peripheral blood stem cell transplantation. Biol Trace Elem Res 97 (3), 237-247.
71. Mishima K, Baba A, Matsuo M, Itoh Y, and Oishi R (2006). Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity. Free Radic Biol Med 40 (9), 1564-1577.
72. de Haan JB, Cristiano F, Iannello R, Bladier C, Kelner M, and Kola I (1996). Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. Hum Mol Genet 5 (2), 283-292.
73. Sies H (1993). Strategies of antioxidant defense. Eur J Biochem 215, 213-219.
74. Imlay JA, Chin SM, and Linn S (1988). Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science 240, 640-642.
75. Ono M, Kohda H, Kawaguchi T, and Ohhira M (1994). High-dose superoxide dismutase suggests that superoxide can both initiate and terminate lipid peroxidation in the reperfused heart. Free Radic Biol Med 16, 195-200.
76. Sabeena Farvin KH, Anandan R, Kumar SH, Shiny KS, Sankar TV, and Thankappan TK (2004). Effect of squalene on tissue defense system in isoproterenol-induced myocardial infarction in rats. Pharmacol Res 50 (3), 231-236.
77. Li HY, Wu SY, and Shi N (2007). Transcription factor Nrf2 activation by deltamethrin in PC12 cells: involvement of ROS. Toxicol Lett 171 (1-2), 87-98.
78. Wang XJ, Hayes JD, and Wolf CR (2006). Generation of a stable antioxidant response element-driven reporter gene cell line and its use to show redoxdependent activation of nrf2 by cancer chemotherapeutic agents. Cancer Res 66 (22), 10983-10994.
79. Baruchel S, Wang T, Farah R, Jamali M, and Batist G (1995). In vivo selective modulation of tissue glutathione in a rat mammary carcinoma model. Biochem Pharmacol 50, 1505-1508.
80. Duffield-Lillico AJ and Begg CB (2004). Reflections on the landmark studies of beta-carotene supplementation. J Natl Cancer Inst 96 (23), 1729-1731.
81. Klaunig JE and Kamendulis LM (2004). The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 44, 239-267.
82. Cook JA, Gius D, Wink DA, Krishna MC, Russo A, and Mitchell JB (2004). Oxidative stress, redox, and the tumor microenvironment. Semin Radiat Oncol 14 (3), 259-266.
83. Schwartz JL (1996). The dual roles of nutrients as antioxidants and prooxidants: their effects on tumor cell growth. J Nutr 126 (4 Suppl), 1221S-1227S.
84. Ajith TA, Usha S, and Nivitha V (2007). Ascorbic acid and alpha-tocopherol protect anticancer drug cisplatin induced nephrotoxicity in mice: a comparative study. Clin Chim Acta 375 (1-2), 82-86.
85. Block KI and Gyllenhaal C (2005). Commentary: the pharmacological antioxidant amifostine - implications of recent research for integrative cancer care. Integr Cancer Ther 4 (4), 329-351.
86. Newmark HL (1999). Squalene, olive oil, and cancer risk. Review and hypothesis. Ann N Y Acad Sci 889, 193-203.
87. Brusselmans K, Timmermans L, Van de Sande T, Van Veldhoven PP, Guan G, Shechter I, Claessens F, Verhoeven G, and Swinnen JV (2007). Squalene synthase, a determinant of Raft-associated cholesterol and modulator of cancer cell proliferation. J Biol Chem 282 (26), 18777-18785.
88. Montero J, Morales A, Llacuna L, Lluis JM, Terrones O, Basanez G, Antonsson B, Prieto J, Garcia-Ruiz C, Colell A, et al. (2008). Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res 68 (13), 5246-5256.
89. Rades D, Fehlauer F, Bajrovic A, Mahlmann B, Richter E, and Alberti W (2004). Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients. Radiother Oncol 70 (3), 261-264.
90. Boccia R, Anne PR, Bourhis J, Brizel D, Daly C, Holloway N III, Hymes S, Koukourakis M, Kozloff M, Turner M, et al. (2004). Assessment and management of cutaneous reactions with amifostine administration: findings of the Ethyol (amifostine) Cutaneous Treatment Advisory Panel (ECTAP). Int J Radiat Oncol Biol Phys 60 (1), 302-309.
91. Meropol NJ, Miller LL, Korn EL, Braitman LE, MacDermott ML, and Schuchter LM (1992). Severe myelosuppression resulting from concurrent administration of granulocyte colony-stimulating factor and cytotoxic chemotherapy. J Natl Cancer Inst 84 (15), 1201-1203.
92. Chan P, Tomlinson B, Lee CB, and Lee YS (1996). Effectiveness and safety of low-dose pravastatin and squalene, alone and in combination, in elderly patients with hypercholesterolemia. J Clin Pharmacol 36 (5), 422-427.
93. Hamilton J, Byrene R, and Whitty G (2000). Particulate adjuvants can induce marcophage survival, DNA synthesis, and a synergistic proliferative response to GM-CSF and CSF-1. Leukocyte Biol 67, 226-232.
94. Das B. The role of VEGF autocrine signaling in the hypoxia and oxidative-stress driven stemness switch. PhD thesis, Institute of Medical Sciences, University of Toronto, 2007.