Immunomodulating role of bisphosphonates on human gamma delta T cells: An intriguing and promising aspect of their antitumour activity

Expert Opinion on Therapeutic Targets

Volumn 11, Issue 7, 2007, Pages 941-954

  Galluzzo, S ^a   Santini, D ^a   Vincenzi, B ^a   Caccamo, N ^b   Meraviglia, S ^b   Salerno, A ^b   Dieli, F ^b   Tonini, G ^a  

^a UNIVERSITY CAMPUS BIO MEDICO   (Italy)

^b UNIVERSITY OF PALERMO   (Italy)

Author keywords

Antitumour; Bisphophonate; Human gamma delta T cells; Immunomodulatory; Immunotherapy

Indexed keywords

ALENDRONIC ACID; ANTINEOPLASTIC AGENT; BISPHOSPHONIC ACID DERIVATIVE; CLODRONIC ACID; CORTICOSTEROID; CYTOKINE; ETIDRONIC ACID; IBANDRONIC ACID; INCANDRONATE; INTERLEUKIN 2; NERIDRONIC ACID; PAMIDRONIC ACID; PYROPHOSPHORIC ACID DERIVATIVE; RISEDRONIC ACID; TILUDRONIC ACID; UNCLASSIFIED DRUG; ZOLEDRONIC ACID;

ANTINEOPLASTIC ACTIVITY; BACTERICIDAL ACTIVITY; BONE CANCER; BONE DISEASE; BONE METASTASIS; BREAST CANCER; CANCER IMMUNOTHERAPY; CELL INTERACTION; CELLULAR IMMUNITY; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOLYSIS; DENDRITIC CELL; DRUG MECHANISM; DRUG POTENTIATION; DRUG STRUCTURE; HUMAN; HUMAN CELL; IMMUNE SYSTEM; IMMUNOMODULATION; INFECTION; INNATE IMMUNITY; KIDNEY CARCINOMA; LOW DRUG DOSE; LUNG NON SMALL CELL CANCER; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE PROLIFERATION; MONOCYTE; MONOTHERAPY; MULTIPLE MYELOMA; NONHODGKIN LYMPHOMA; OSTEOPOROSIS; PROSTATE CANCER; REVIEW; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TUMOR IMMUNITY;

ANIMALS; ANTINEOPLASTIC AGENTS; BONE DISEASES; DENDRITIC CELLS; DIPHOSPHONATES; HUMANS; IMMUNOLOGIC FACTORS; INTERLEUKIN-2; MONOCYTES; NEOPLASMS; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES;

EID: 34447317227     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.11.7.941     Document Type: Review

References (99)

1. SHINODA H, ADAMEK G, FELIX R, FLESCH H, SCHENK R, HAGAN P: Structure-activity relationship of various bisphosphonates. Calcif. Tissue Int. (1983) 35:87-99.
2. SIETSEMA WK, EBETINO FH, SALVAGNO AM, BEVAN JA: Antiresorptive dose-response relationship across three generations of bisphosphonates. Drugs Exp. Clin. Res. (1989) 15:389-396.
3. GREEN JR, MULLER K, JAEGGI KA: Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound. J. Bane Miner. Res. (1994) 9:745-751.
4. WATTS NB, HARRIS ST, GENANT HK et al.: Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N. Engl. J. Med. (1990) 323:73-79.
5. REID IR, KING AR, ALEXANDER CJ, IBBERTSON HK: Prevention of steroid-induced osteoporosis with (3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate (APD). Lancet (1988) 1:143-146.
6. MILLER PD, BROWN JP, SIRIS ES, HOSEYNI MS, AXELROD DW, BEKKER PJ: A randomized, double blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Paget's Risedronate/Etidronate Study Group. Am. J. Med. (1999) 106:513-520.
7. COLEMAN RE: Bisphosphonates: clinical experience. Oncologist (2004) 9(Suppl. 4): 14-27.
8. CLEZARDIN P: The antitumor potential of bisphosphonates. Semin. Oncol. (2002) 29(Suppl. 21):33-42.
9. THOMPSON K, ROGERS MJ, COXON FP, CROCKETT JC: Cytosolic entry of bisphosphonate drugs requires acidification of vesicles following fluid-phase endocytosis. Mol. Pharmacol. (2006) 69:1624-1632.
10. ROELOFS AJ, THOMPSON K, GORDON S, ROGERS MJ: Molecular mechanisms of action of bisphosphonates: current status. Clin. Cancer Res. (2006) 12:6222-6230.
11. FRITH JC, MONKKONEN J, BLACKBURN GM, RUSSELL RG, ROGERS MJ: Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5'-(β,γ-dichloromethylene) triphosphate, by mammalian cells in vitro. J. Bone Miner. Res. (1997) 12:1358-1367.
12. FRITH JC, MONKKONEN J, AURIOLA S, MONKKONEN J, ROGERS MJ: The molecular mechanism of action of the anti-resorptive and anti-inflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum. (2001) 44:2201-2210.
13. LEHENKARI PP, KELLINSALMI M, NAPANKANGAS JP et al.: Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol. Pharmacol. (2002) 61:1255-1262.
14. GOBER HJ, KISTOWSKA M, ANGMAN L, JENO P, MORI L, DE LIBERO G: Human T cell receptor γyδ cells recognize endogenous mevalonate metabolites in tumor cells. J. Exp. Med. (2003) 197:163-168.
15. RUSSELL RG, ROGERS MJ, FRITH JC et al.: The pharmacology of bisphosphonates and new insights into their mechanisms of action. J. Bone Miner. Res. (1999) 14:53-65.
16. KAVANAGH KL, GUO K, DUNFORD JE et al.: The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc. Natl. Acad Sci. USA (2006) 16:7829-7834.
17. VAN BEEK E, PIETERMAN E, COHEN L, LOWIK C, PAPAPOULOS S: Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem. Biophys. Res. Commun. (1999) 264:108-111.
18. BERGSTROM JD, BOSTEDOR RG, MASARACHIA PJ, RESZKA AA, RODAN G: Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch. Biochem. Biophys. (2000) 373:231-241.
19. DUNFORD JE, THOMPSON K, COXON FP et al.: Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J. Pharmacol. Exp. Ther. (2001) 296:235-242.
20. LUCKMAN SP, HUGHES DE, COXON FP, RUSSELL RGG, ROGERS MJ: Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J. Bone Miner. Res. (1998) 13:581-589.
21. VAN BEEK E, LOWIK C, VAN DER PLUIJM G, PAPAPOULOS S: The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: a clue to the mechanism of action of nitrogen-containing bisphosphonates. J. Bone Miner. Res. (1999) 14:722-729.
22. COXON FP, ROGERS MJ: The role of prenylated small GTP-binding proteins in the regulation of osteoclast function. Calcif. Tissue Int. (2003) 72:80-84.
23. COXON FP, EBETINO FH, MULES EH, SEABRA MC, MCKENNA CE, ROGERS MJ: Phosphonocarboxylate inhibitors of Rab geranylgeranyl transferase disrupt the prenylation and membrane localization of Rab proteins in osteoclasts in vitro and in vivo. Bone (2005) 37:349-358.
24. DUNFORD JE, ROGERS MJ, EBETINO FH, PHIPPS RJ, COXON FP: Inhibition of protein prenylation by bisphosphonates causes sustained activation of Rac, Cdc42, and Rho GTPases. J. Bone Miner. Res. (2006) 21:684-694.
25. MONKKONEN H, AURIOLAS, LEHENKARI PJ et al.: A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br. J. Pharmacol. (2006) 147:437-445.
26. MAYER, OBERBAUER R: Mitochondrial regulation of apoptosis News Physiol. Sci. (2003) 18:89-94.
27. STAAL A, FRITH JC, FRENCH MH et al.: The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. J. Bone Miner. Res. (2003) 18:88-96.
28. CROUCHER PI, DE HENDRIK R, PERRY MJ et al.: Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J. Bone Miner. Res. (2003) 18:482-492.
29. GIRAUDO E, INOUE M, HANAHAN D: An amino-bisphosphonate targets MM P-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J. Clin. Invest. (2004) 114:623-633.
30. WOOD J, BONJEAN K, RUETZ S et al.: Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J. Pharmacol. Exp. Ther. (2002) 302:1055-1061.
31. BEZZI M, HASMIM M, BIELER G, DORMOND O, RUEGG C: Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt. J. Biol. Chem. (2003) 278:(4) 3603-3614.
32. YACCOBY S, PEARSE RN, JOHNSON CL, BARLOGIE B, CHOI Y, EPSTEIN J: Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteodast activity. Br. J. Haematol. (2002) 116:278-290.
33. KURODA J, KIMURA S, SEGAWA H et al.: The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate. Blood (2003) 15:2229-2235.
34. KABELITZ D, WESCH D, PITTERS E, ZOLLER M: Characterization of tumor reactivity of human Vγ9Vδ2 γδ T cells in vitro and in SCID mice in vivo. J. Immunol. (2004) 173:6767-6776.
35. HIRAGA T, WILLIAMS PJ, UEDA A, TAMURA D, YONEDA T: Zoledronic acid inhibits visceral metastases in the 4T 1/luc mouse breast cancer model. Clin. Cancer Res. (2004) 10:4559-4567.
36. KUNZMANN V, BAUER E, FEURLE J, WEISSINGER F, TONY HP, WILHELM M: Stimulation of γδ T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood (2000) 96:384-392.
37. DIELI F, GEBBIA N, POCCIA F et al.: Induction of γδ T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood (2003) 102:2310-2311.
38. MARIANI S, MURARO M, PANTALONI F et al.: Effector γδ T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma. Leukemia (2005) 19:664-670.
39. THOMPSON K, DUNFORD JE, EBETINO FH, ROGERS MJ: Identification of a bisphosphonate that inhibits isopentenyl diphosphate isomerase and farnesyl diphosphate synthase. Biochem. Biophys. Res. Commun. (2002) 290:869-873.
40. BENFORD HL, FRITH JC, AURIOLA S, MONKKONEN J, ROGERS MJ: Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. Mol. Pharmacol. (1999) 56:131-140.
41. FISHER JE, ROGERS MJ, HALASY JM et al.: Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc. Natl. Acad. Sci. USA (1999) 96:133-138.
42. SAWADA K, MORISHIGE K, TAHARA M et al.: Alendronate inhibits lysophosphatidic acid-induced migration of human ovarian cancer cells by attenuating the activation of rho. Cancer Res. (2002) 62:6015-6020.
43. DENOYELLE C, HONG L, VANNIER JP, SORIA J, SORIA C: New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects. Br. J. Cancer (2003) 88:1631-1640.
44. OADES GM, SENARATNE SG, CLARKE IA, KIRBY RS, COLSTON KW: Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing Ras membrane localization in prostate cancer cells. J. Urol. (2003) 170:246-252.
45. SENARATNE SG, MANSI JL, COLSTON KW: The bisphosphonate zoledronic acid impairs Ras membrane localisation and induces cytochrome c release in breast cancer cells. Br. J. Cancer (2002) 86:1479-1486.
46. VIRTANEN SS, VAANANEN HK, HARKONEN PL, LAKKAKORPI PT: Alendronate inhibits invasion of PC-3 prostate cancer cells by affecting the mevalonate pathway. Cancer Res. (2002) 62:2708-2714.
47. TANAKA Y, MORITA CT, TANAKA Y, NIEVES E, BRENNER MB, BLOOM BR: Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature (1995) 37:155-158.
48. KUNZMANN V, BAUER E, WILHELM M: γδ T-cell stimulation by pamidronate. N. Engl. J. Med. (1999) 340:737-738.
49. DAS H, WANG L, KAMATH A, BUKOWSKI JF: Vγ9Vδ2 T-cell receptor-mediated recognition of aminobisphosphonates. Blood (2001) 98:1616-1618.
50. MALKOVSKA V, CIGEL FK, ARMSTRONG N, STORERE B, HONG R: Antilymphoma activity of human γδ T-cells in mice with severe combined immune deficiency. Cancer Res. (1992) 52:5610-5616.
51. PENNINGER JM, WEN T, TIMMS E et al.: Spontaneous resistance to acute T-cell leukaemias in TCRV γ1. 1J γ4C γ4 transgenic mice. Nature (1995) 18:241-244.
52. SALERNO A, DIELI F: Role of γδ T lymphocytes in immune responses in humans and mice. Crit. Rev. Immunol. (1998) 18:327-357.
53. HAYDAY A: γδT cells: a right time and a right place for a conserved third way of protection. Ann. Rev. Immunol. (2000) 18:975-1026.
54. CACCAMO N, MERAVIGLIA S, FERLAZZO V et al.: Differential requirements for antigen or homeostatic cytokines for proliferation and differentiation of human Vγ9Vδ2 naive, memory and effector T cell subsets. Eur. J. Immunol. (2005) 35:1764-1772.
55. PORCELLI S, BRENNER MB, BAND H: Biology of the human γδT-cell receptor. Immunol. Rev. (1999) 120:137-183.
56. CONSTANT P, DAVODEAU F, PEYRAT MA et al.: Stimulation of human γδT-cells by nonpeptidic mycobacterial ligands. Science (1994) 264:267-270.
57. SPADA FM, GRANT EP, PETERS PJ et al.: Self recognition of CD 1 by γδT cells: implications for innate immunity. J. Exp. Med. (2000) 191:937-948.
58. MORITA CT, BECKMAN EM, BUKOWSKY JF et al.: Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδT cells, Immunity (1995) 3:495-507.
59. FISCH P, MALKOVSKY M, KOVATS S et al.: Recognition by human Vγ9Vδ2 T cells of a GroEL homolog on Daudi Burkitt's lymphoma cells. Science (1990) 250:1269-1273.
60. JOMAA H, FEURLE J, LUHS K et al.: Vγ9/Vδ2 T cell activation induced by bacterial low molecular mass compounds depends on the 1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid biosynthesis. FEMS Immunol. Med. Microbiol. (1999) 25:371-378.
61. BEGLEYM, GAHAN CG, KOLLAS AK et al.: The interplay between classical and alternative isoprenoid biosynthesis controls γδ T cell bioactivity of Listeria monocytogenes. FEBS Lett. (2004) 561:99-104.
62. HALARY F, PEYRAT MA, CHAMPAGNE E et al.: Control of self-reactive cytotoxic T lymphocytes expressing γδT cell receptors by natural killer inhibitory receptors. Eur. J. Immunol. (1997) 27:2812-2821.
63. RAULET DH: Roles of the NKG2D immunoreceptor and its ligands. Nat. Rev. Immunol. (2003) 3:781-790.
64. FISCH P, MALKOVSKY M, BRAAKMAN E et al.: γδ T cell clones and natural killer cell clones mediate distinct patterns of non-major histocompatibility complex-restricted cytolysis. J. Exp. Med. (1990) 1:1567-1579.
65. POCCIA F, CIPRIANI B, VENDETTI S et al.: CD94/NKG2 inhibitory receptor complex modulates both anti-viral and anti-tumoral responses of polyclonal phosphoantigen-reactive Vγ9Vδ2 T lymphocytes. J. Immunol. (1997) 15:6009-6017.
66. BUKOWSKI JF, MORITA CT, BRENNER MB: Human γδ T cells recognize alkylamines derived from microbes, edible plants and tea: implications for innate immunity. Immunity (1999) 11:57-65.
67. THOMPSON K, ROGERS MJ: Statins prevent bisphosphonate-induced γ,δ-T-cell proliferation and acdvation in vitro. J. Bone Miner. Res. (2004) 19:278-288.
68. CONTI L, CASETTI R, CARDONE M et al.: Reciprocal activating interaction between dendritic cells and pamidronate-stimulated γ-δ-T cells: role of CD86 and inflammatory cytokines. J. Immunol. (2005) 174:252-260.
69. ISMAILI J, OLISLAGERS V, POUPOT R, FOURNIE JJ, GOLDMAN M: Human γδ T cells induce dendritic cell maturation. Clin. Immunol. (2002) 103:296-302.
70. DEVILDER MC, MAILLET S, BOUYGE-MOREAU I, DONNADIEU E, BONNEVILLE M, SCOTET E: Potentiation of antigen-stimulated Vγ9Vδ2 T cell cytokine production by immature dendritic cells (DC) and reciprocal effect on DC maturation. J. Immunol. (2006) 176:1386-1393.
71. DIELI F, POCCIA F, LIPP M et al.: Differentiation of effector/ memory Vδ2 T cells and migratory routes in lymph nodes or inflammatory sites. J. Exp. Med. (2003) 198:391-397.
72. SALLUSTO F, LENIG D, MACKAY CR, LANZAVECCHIA A: Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes J. Exp. Med. (1998) 187:875-883.
73. GARCIA-LOPEZ MA, SANCHEZ-MADRID F, RODRIGUEZ-FRADE JM et al.: CXCR3 chemokine receptor distribution in normal and inflamed tissues: expression on activated lymphocytes, endothelial cells, and dendritic cells. Lab. Invest. (2001) 81:409-418.
74. CACCAMO N, BATTISTINI L, BONNEVILLE M et al.: CXCR5 identifies a subset of Vγ9Vδ2 T cells which secrete IL-4 and IL-10 and help B cells for antibody production. J. Immunol. (2006) 177:5290-5295.
75. + αβT cell and γδT cell responses to Mycabacterium tuberculosis. J. Immunol. (1995) 154:1786-1796.
76. COOPER AM, DALTON DK, STEWART TA, GRIFFIN JP, RUSSELL DG, ORME IM: Disseminated tuberculosis in IFN-γ gene-disrupted mice. J. Exp. Med. (1993) 178:2243-2247.
77. FLYNN JL, CHAN J, TRIEBOLD KJ, DALTON DK, STEWART TA, BLOOM BR: An essential role for IFN-γ in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. (1993) 178:2249-2254.
78. OTTENHOFF TH, KUMARARATNE D, CASANOVA JL: Novel human immunodeficiencies reveal the essential role of type-I cytokines in immunity to intracellular bacteria. Immunol. Today (1998) 19:491-494.
79. ANFOSSI N, PASCAL V, VIVIER E, UGOLINI S: Biology of T memory Type 1 cells. Immunol. Rev. (2001) 181:269-278.
80. WILHELM M, KUNZMANN V, ECKSTEIN S et al.: γδ T cells for immune therapy of patients with lymphoid malignancies. Blood (2003) 102:200-206.
81. FERLAZZO V, SFERRAZZA C, CACCAMO N et al.: In vitro effects of aminobisphosphonates on Vγ9Vδ2 T cell activation and differentiation. Int. J. Immunopathol. Pharmacol. (2006) 19:309-317.
82. WATANABE N, NARITA M, YOKOYAMA A et al.: Type I IFN-mediated enhancement of anti-leukemic cytotoxicity of γδ T cells expanded from peripheral blood cells by stimulation with zoledronate. Cytotherapy (2006) 8:118-129.
83. NARAZAKI H, WATARI E, SHIMIZU M et al.: Perforin-dependent killing of tumor cells by Vγ1Vδ1-bearing T-cells. Immunol. Lett. (2003) 86:113-119.
84. SATO K, KIMURA S, SEGAWA H et al.: Cytotoxic effects of γδ T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy. Int. J. Cancer (2005) 116: 94-99.
85. LOZUPONE F, PENDE D, BURGIO VL et al.: Effect of human natural killer and γδT cells on the growth of human autologous melanoma xenograft in SCID mice. Cancer Res. (2004) 64:378-385.
86. BERENSON JR, LICHTENSTEIN A, PORTER L et al.: Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N. Engl. J. Med. (1996) 334:488-493.
87. KATO Y, TANAKA Y, MIYAGAWA F, YAMASHITA S, MINATO N: Targeting of tumor cells for human γδT cells by nonpeptide antigens, J. Immunol. (2001) 167:5092-5098.
88. MATSUMOTO S, KIMURAS, SEGAWA H et al.: Efficacy of the third-generadon bisphosphonate, zoledronic acid alone and combined with anti-cancer agents against small cell lung cancer cell lines. Lung Cancer (2005) 47:31-39.
89. RISCHER M, PSCHERER S, DUWE S, VORMOOR J, JURGENS H, ROSSIG C: Human γδ T cells as mediators of chimaeric-receptor redirected anti-tumour immunity. Br. J. Haematol. (2004) 126:583-592.
90. MIYAGAWA F, TANAKA Y, YAMASHITA S, MINATO N: Essential requirement of antigen presentation by monocyte lineage cells for the activation of primary human γδ T cells by aminobisphosphonate antigen. J. Immunol. (2001) 166:5508-5514.
91. FLORE F, CASTELLA B, NUSCHAK B et al.: Enhanced ability of dendritic cells to stimulate innate and adaptive
92. VON LILIENFELD-TOAL M, SIEVERS E, BODEMULLER V et al.: Coculture with dendritic cells promotes proliferation but not cytotoxic activity of γδ T cells. Immunol. Lett. (2005) 15:103-108.
93. APARICIO A, GARDNER A, TU Y, SAVAGE A, BERENSON J, LICHTENSTEIN A: In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia (1998) 12:220-229.
94. SICARD H, INGOURE S, LUCIANI B et al.: In vivo immunomanipulation of Vγ9Vδ2 T cells with a synthetic phosphoandgen in a preclinical nonhuman primate model. J. Immunol. (2005) 175:5471-5480.
95. CASETTI R, PERRETTA G, TAGLIONI A et al.: Drug-induced expansion and differendation of Vγ9Vδ2 T cells in vivo: the role of exogenous IL-2. J. Immunol. (2005) 175:1593-1598.
96. KOBAYASHI H, TANAKA Y, YAGI J, TOMA H, UCHIYAMA T: γ/δT cells provide innate immunity against renal cell carcinoma. Cancer Immunol. Immunother. (2001) 50:115-124.
97. GIRARDI M, OPPENHEIM DE, STEELE CR et al.: Regulation of cutaneous malignancy by γδT cells. Science (2001) 294:605-609.
98. YANG JC, SHERRY RM, STEINBERG SM et al.: Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J. Clin. Oncol. (2003) 15:3127-3132.
99. FDA approves ZOMETA for treatment of cancer-related bone complications. Expert Rev. Anti-Cancer Ther. (2002) 2:137-138.