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Cancer Chemotherapy and Pharmacology

, Volume 78, Issue 4, pp 661–671 | Cite as

The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy

  • Martina Ahlmann
  • Georg HempelEmail author
Review Article
Part of the following topical collections:
  1. Cytotoxic Reviews

Abstract

Cyclophosphamide is an alkylating agent belonging to the group of oxazaphosporines. As cyclophosphamide is in clinical use for more than 40 years, there is a lot of experience using this drug for the treatment of cancer and as an immunosuppressive agent for the treatment of autoimmune and immune-mediated diseases. Besides antimitotic and antireplicative effects, cyclophosphamide has immunosuppressive as well as immunomodulatory properties. Cyclophosphamide shows selectivity for T cells and is therefore now frequently used in tumour vaccination protocols and to control post-transplant allo-reactivity in haplo-identical unmanipulated bone marrow after transplantation. The schedule of administration is of special importance for the immunological effect: while cyclophosphamide can be used in high-dose therapy for the complete eradication of haematopoietic cells, lower doses of cyclophosphamide are relatively selective for T cells. Of special interest is the fact that a single administration of low-dose cyclophosphamide is able to selectively suppress regulatory T cells (Tregs). This effect can be used to counteract immunosuppression in cancer. However, cyclophosphamide can also increase the number of myeloid-derived suppressor cells. Combination of cyclophosphamide with other immunomodulatory agents could be a promising approach to treat different forms of advanced cancer.

Keywords

T cells Oxazaphosphorines Immune reactivation Immunosuppression 

References

  1. 1.
    Brock N, Wilmanns H (1958) Effect of a cyclic nitrogen mustard-phosphamidester on experimentally induced tumors in rats; chemotherapeutic effect and pharmacological properties of B518 ASTA [German]. Dtsch Med Wochenschr 83:453–458CrossRefPubMedGoogle Scholar
  2. 2.
    Emadi A, Jones RJ, Brodsky RA (2009) Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 6:638–647CrossRefPubMedGoogle Scholar
  3. 3.
    Baxter Oncology. German Product Summary Endoxan®. http://www.fachinfo.de/suche/fi/000728. Accessed Jan 2015
  4. 4.
    Santos GW, Sensenbrenner LL, Burke PJ, Mullins GM, Blas WB, Tutschka PJ, Slavin RE (1972) The use of cyclophosphamide for clinical marrow transplantation. Transpl Proc 4:559–564Google Scholar
  5. 5.
    Wang JY, Prorok G, Vaughan WP (1993) Cytotoxicity, DNA cross-linking, and DNA single-strand breaks induced by cyclophosphamide in a rat leukemia in vivo. Cancer Chemother Pharmacol 31:381–386CrossRefPubMedGoogle Scholar
  6. 6.
    Fleer R, Brendel M (1981) Toxicity, interstrand cross-links and DNA fragmentation induced by ‘activated’ cyclophosphamide in yeast. Chem Biol Interact 37:123–140CrossRefPubMedGoogle Scholar
  7. 7.
    Van Putten LM, Lelieveld P, Kram-Idsenga LKJ (1972) Cell-cycle specificity and therapeutic effectiveness of cytostatic agents. Cancer Chemother Rep 56:691–700PubMedGoogle Scholar
  8. 8.
    Candeias SM, Gaipl US (2016) The immune system in cancer prevention, development and therapy. Anticancer Agents Med Chem 16:101–107CrossRefPubMedGoogle Scholar
  9. 9.
    Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33:1974–1982CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Tsung K, Norton JA (2015) An immunological view of chemotherapy. Immunotherapy. 7:941–943CrossRefPubMedGoogle Scholar
  11. 11.
    Yule SM, Boddy AV, Cole M, Price L, Wyllie R, Tasso MJ, Pearson AD, Idle JR (1995) Cyclophosphamide metabolism in children. Cancer Res 55:803–809PubMedGoogle Scholar
  12. 12.
    Bohnenstengel F, Hofmann U, Eichelbaum M, Kroemer HK (1996) Characterization of the cytochrome P450 involved in side-chain oxidation of cyclophosphamide in humans. Eur J Clin Pharmacol 51:297–301CrossRefPubMedGoogle Scholar
  13. 13.
    Brüggemann SK, Kisro J, Wagner T (1997) Ifosfamide cytotoxicity on human tumor and renal cells: role of chloroacetaldehyde in comparison to 4-hydroxyifosfamide. Cancer Res 57:2676–2680PubMedGoogle Scholar
  14. 14.
    Sood C, O’Brien PJ (1996) 2-Chloroacetaldehyde-induced cerebral glutathione depletion and neurotoxicity. Br J Cancer Suppl 27:S287–S293PubMedPubMedCentralGoogle Scholar
  15. 15.
    Audemard-Verger A, Martin Silva N, Verstuyft C, Costedoat-Chalumeau N, Hummel A, Le Guern V, Sacré K, Meyer O, Daugas E, Goujard C, Sultan A, Lobbedez T, Galicier L, Pourrat J, Le Hello C, Godin M, Morello R, Lambert M, Hachulla E, Vanhille P, Queffeulou G, Potier J, Dion JJ, Bataille P, Chauveau D, Moulis G, Farge-Bancel D, Duhaut P, Saint-Marcoux B, Deroux A, Manuzak J, Francès C, Aumaitre O, Bezanahary H, Becquemont L, Bienvenu B (2016) Glutathione S transferases polymorphisms are independent prognostic factors in lupus nephritis treated with cyclophosphamide. PLoS One 11:e0151696. doi: 10.1371/journal.pone.0151696 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    de Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH (2005) Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 44:1135–1164CrossRefPubMedGoogle Scholar
  17. 17.
    Yule SM, Price L, Cole M, Pearson AD, Boddy AV (2001) Cyclophosphamide metabolism in children following a 1-h and a 24-h infusion. Cancer Chemother Pharmacol 47:222–228CrossRefPubMedGoogle Scholar
  18. 18.
    Svensson HM, Ljungman P, Björkstrand B, Olsson H, Bielenstein M, Abdel-Rehim M, Nilsson C, Johansson M, Karlsson MO (1999) A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients. Br J Clin Pharmacol 48:669–677PubMedPubMedCentralGoogle Scholar
  19. 19.
    McCune JS, Batchelder A, Guthrie KA, Witherspoon R, Appelbaum FR, Phillips B, Vicini P, Salinger DH, McDonald GB (2009) Personalized dosing of cyclophosphamide in the total body irradiation-cyclophosphamide conditioning regimen: a phase II trial in patients with hematologic malignancy. Clin Pharmacol Ther 85:615–622CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hipkens JH, Struck RF, Gurtoo HL (1981) Role of aldehyde dehydrogenase in the metabolism-dependent biological activity of cyclophosphamide. Cancer Res 41:3571–3583PubMedGoogle Scholar
  21. 21.
    Jones RJ, Barber JP, Vala MS, Collector MI, Kaufmann SH, Ludeman SM, Colvin OM, Hilton J (1995) Assessment of aldehyde dehydrogenase in viable cells. Blood 85:2742–2746PubMedGoogle Scholar
  22. 22.
    Pinto N, Ludeman SM, Dolan ME (2009) Drug focus: pharmacogenetic studies related to cyclophosphamide-based therapy. Pharmacogenomics 10:1897–1903CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zhong S, Huang M, Yang X, Liang L, Wang Y, Romkes M, Duan W, Chan E, Zhou SF (2006) Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus. Br J Clin Pharmacol 62:457–472CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Penel N, Adenis A, Bocci G (2012) Cyclophosphamide-based metronomic chemotherapy: after 10 years of experience, where do we stand and where are we going? Crit Rev Oncol Hematol 82:40–50CrossRefPubMedGoogle Scholar
  25. 25.
    Potel J, Brock N (1965) The influence of anticarcinogenic substances on immunologic reactions. 2. The influence of N, N-bis-(2-chlorethyl)-N’, O-propylenephosphoric acid ester diamide on antibody formation. Arzneimittelforschung 15:659–666PubMedGoogle Scholar
  26. 26.
    Müller US, Wirth W, Junge-Hülsing G, Hauss WH (1973) Suppressive effects in mesenchyme and immunosuppressive effects of cytostatics. Int J Clin Pharmacol 7:228–233PubMedGoogle Scholar
  27. 27.
    Potel J (1969) Immunsuppression durch kanzerotoxische Substanzen. Organtransplantation Immunologie und Klinik. F.K.Schattauer Verlag StuttgartGoogle Scholar
  28. 28.
    Müller US, Wirth W, Thöne F, Junge-Hülsing G, Hauss WH (1973) Animal experiments on the anti-inflammatory and immunosuppressive effect of cytostatic agents. Arzneimittelforschung 23:487–491PubMedGoogle Scholar
  29. 29.
    Brock N, Kuhlmann J (1974) Pharmacological studies with alkylsulfonyloxyalkyl substituted and chloroethyl substituted oxazaphosphorine-2-oxides. 1. Communication: relationship between chemical structure and pharmacological action. Arzneimittelforschung 24:1139–1149PubMedGoogle Scholar
  30. 30.
    Polak L, Turk JL (1974) Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity. Nature 249:654–656CrossRefPubMedGoogle Scholar
  31. 31.
    Röllinghoff M, Starzinski-Powitz A, Pfizenmaier K, Wagner H (1977) Cyclophosphamide-sensitive T lymphocytes suppress the in vivo generation of antigen-specific cytotoxic T lymphocytes. J Exp Med 145:455–459CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Awwad M, North RJ (1988) Cyclophosphamide (Cy)-facilitated adoptive immunotherapy of a Cy-resistant tumour. Evidence that Cy permits the expression of adoptive T-cell mediated immunity by removing suppressor T cells rather than by reducing tumour burden. Immunology 65:87–92PubMedPubMedCentralGoogle Scholar
  33. 33.
    Le DT, Jaffee EM (2012) Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res 72:3439–3444CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Liu Z, Huang Q, Liu G, Dang L, Chu D, Tao K, Wang W (2014) Presence of FoxP3(+)Treg cells is correlated with colorectal cancer progression. Int J Clin Exp Med 7:1781–1785PubMedPubMedCentralGoogle Scholar
  35. 35.
    Li K, Chen F, Xie H (2016) Decreased FoxP3+ and GARP+ Tregs to neoadjuvant chemotherapy associated with favorable prognosis in advanced gastric cancer. Onco Targets Therapy 9:3525–3533CrossRefGoogle Scholar
  36. 36.
    Engels CC, Charehbili A, van de Velde CJ, Bastiaannet E, Sajet A, Putter H, van Vliet EA, van Vlierberghe RL, Smit VT, Bartlett JM, Seynaeve C, Liefers GJ, Kuppen PJ (2015) The prognostic and predictive value of Tregs and tumor immune subtypes in postmenopausal, hormone receptor-positive breast cancer patients treated with adjuvant endocrine therapy: a Dutch TEAM study analysis. Breast Cancer Res Treat 149:587–596CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Anderson BJ, Holford N (2008) Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48:303–332CrossRefPubMedGoogle Scholar
  38. 38.
    Peng S, Lyford-Pike S, Akpeng B, Wu A, Hung CF, Hannaman D, Saunders JR, Wu TC, Pai SI (2013) Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine. Cancer Immunol Immunother 62:171–182CrossRefPubMedGoogle Scholar
  39. 39.
    Son CH, Shin DY, Kim SD, Park HS, Jung MH, Bae JH, Kang CD, Yang K, Park YS (2012) Improvement of antitumor effect of intratumoral injection of immature dendritic cells into irradiated tumor by cyclophosphamide in mouse colon cancer model. J Immunother 35:607–614CrossRefPubMedGoogle Scholar
  40. 40.
    Tongu M, Harashima N, Yamada T, Harada T, Harada M (2010) Immunogenic chemotherapy with cyclophosphamide and doxorubicin against established murine carcinoma. Cancer Immunol Immunother 59:769–777CrossRefPubMedGoogle Scholar
  41. 41.
    Salem ML, Kadima AN, El-Naggar SA, Rubinstein MP, Chen Y, Gillanders WE, Cole DJ (2007) Defining the ability of cyclophosphamide preconditioning to enhance the antigen-specific CD8+ T-cell response to peptide vaccination: creation of a beneficial host microenvironment involving type I IFNs and myeloid cells. J Immunother 30:40–53CrossRefPubMedGoogle Scholar
  42. 42.
    Salem ML, Al-Khami AA, El-Naggar SA, Díaz-Montero CM, Chen Y, Cole DJ (2010) Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells. J Immunol 184:1737–1747CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Angulo I, de las Heras FG, García-Bustos JF, Gargallo D, Muñoz-Fernández MA, Fresno M (2000) Nitric oxide-producing CD11b(+)Ly-6G(Gr-1)(+)CD31(ER-MP12)(+) cells in the spleen of cyclophosphamide-treated mice: implications for T-cell responses in immunosuppressed mice. Blood 95:212–220PubMedGoogle Scholar
  44. 44.
    Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine selectively eliminate splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhance antitumor immune activity. Clin Cancer Res 11:6713–6721CrossRefPubMedGoogle Scholar
  45. 45.
    Tongu M, Harashima N, Monma H, Inao T, Yamada T, Kawauchi H, Harada M (2013) Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo. Cancer Immunol Immunother 62:383–391CrossRefPubMedGoogle Scholar
  46. 46.
    Cao Y, Zhao J, Yang Z, Cai Z, Zhang B, Zhou Y, Shen GX, Chen X, Li S, Huang B (2010) CD4+ FOXP3+ regulatory T cell depletion by low-dose cyclophosphamide prevents recurrence in patients with large condylomata acuminata after laser therapy. Clin Immunol 136:21–29CrossRefPubMedGoogle Scholar
  47. 47.
    Ge Y, Domschke C, Stoiber N, Schott S, Heil J, Rom J, Blumenstein M, Thum J, Sohn C, Schneeweiss A, Beckhove P, Schuetz F (2012) Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol Immunother 61:353–362CrossRefPubMedGoogle Scholar
  48. 48.
    Ellebaek E, Engell-Noerregaard L, Iversen TZ, Froesig TM, Munir S, Hadrup SR, Andersen MH (2012) Svane IM metastatic melanoma patients treated with dendritic cell vaccination, interleukin-2 and metronomic cyclophosphamide: results from a phase II trial. Cancer Immunol Immunother 61:1791–1804CrossRefPubMedGoogle Scholar
  49. 49.
    Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, Hilf N, Schoor O, Fritsche J, Mahr A, Maurer D, Vass V, Trautwein C, Lewandrowski P, Flohr C, Pohla H, Stanczak JJ, Bronte V, Mandruzzato S, Biedermann T, Pawelec G, Derhovanessian E, Yamagishi H, Miki T, Hongo F, Takaha N, Hirakawa K, Tanaka H, Stevanovic S, Frisch J, Mayer-Mokler A, Kirner A, Rammensee HG, Reinhardt C, Singh-Jasuja H (2012) Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 18:1254–1261CrossRefPubMedGoogle Scholar
  50. 50.
    Viaud S, Flament C, Zoubir M, Pautier P, LeCesne A, Ribrag V, Soria JC, Marty V, Vielh P, Robert C, Chaput N, Zitvogel L (2011) Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res 71:661–665CrossRefPubMedGoogle Scholar
  51. 51.
    Noguchi M, Moriya F, Koga N, Matsueda S, Sasada T, Yamada A, Kakuma T, Itoh K (2016) A randomized phase II clinical trial of personalized peptide vaccination with metronomic low-dose cyclophosphamide in patients with metastatic castration-resistant prostate cancer. Cancer Immunol Immunother 65:151–160CrossRefPubMedGoogle Scholar
  52. 52.
    Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59CrossRefPubMedGoogle Scholar
  53. 53.
    Luznik L, O’Donnell PV, Fuchs EJ (2012) Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol 39:683–693CrossRefPubMedGoogle Scholar
  54. 54.
    Kasamon YL, Jones RJ, Gocke CD, Blackford AL, Seifter EJ, Davis-Sproul JM, Gore SD, Ambinder RF (2011) Extended follow-up of autologous bone marrow transplantation with 4-hydroperoxy-cyclophosphamide (4-HC) purging for indolent or transformed non-Hodgkin lymphomas. Biol Blood Marrow Transpl 17:365–367CrossRefGoogle Scholar
  55. 55.
    Kanakry CG, Ganguly S, Zahurak M, Bolaños-Meade J, Thoburn C, Perkins B, Fuchs EJ, Jones RJ, Hess AD, Luznik L (2013) Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med 5:211ra157CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Ninomiya S, Narala N, Huye L, Yagyu S, Savoldo B, Dotti G, Heslop HE, Brenner MK, Rooney CM, Ramos CA (2015) Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood 125:3905–3916CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yoshikawa T, Hara T, Tsurumi H, Goto N, Hoshi M, Kitagawa J, Kanemura N, Kasahara S, Ito H, Takemura M, Saito K, Seishima M, Takami T, Moriwaki H (2010) Serum concentration of L-kynurenine predicts the clinical outcome of patients with diffuse large B-cell lymphoma treated with R-CHOP. Eur J Haematol 84:304–309CrossRefPubMedGoogle Scholar
  58. 58.
    Ninomiya S, Hara T, Tsurumi H, Hoshi M, Kanemura N, Goto N, Kasahara S, Shimizu M, Ito H, Saito K, Hirose Y, Yamada T, Takahashi T, Seishima M, Takami T, Moriwaki H (2011) Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol 90:409–416CrossRefPubMedGoogle Scholar
  59. 59.
    Vacchelli E, Aranda F, Bloy N, Buqué A, Cremer I, Eggermont A, Fridman WH, Fucikova J, Galon J, Spisek R, Zitvogel L, Kroemer G, Galluzzi L (2015) Trial Watch—immunostimulation with cytokines in cancer therapy. Oncoimmunology 5:e1115942CrossRefPubMedGoogle Scholar
  60. 60.
    Vacchelli E, Aranda F, Eggermont A, Sautès-Fridman C, Tartour E, Kennedy EP, Platten M, Zitvogel L, Kroemer G, Galluzzi L (2014) Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology 3(10):e957994CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Niemeyer U, Pohl J (2011) Einmalig dosierte Oxazaphosphorine zur Therapie von Krankheiten. German Patent Application DE102011085695 A1, 3rd November, 2011Google Scholar
  62. 62.
    Ninomiya S, Narala N, Huye L, Yagyu S, Savoldo B, Dotti G, Heslop HE, Brenner MK, Rooney CM, Ramos CA (2015) Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood 125(25):3905–3916CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Dimeloe S, Frick C, Fischer M, Gubser PM, Razik L, Bantug GR, Ravon M, Langenkamp A, Hess C (2014) Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis. Eur J Immunol 44:3614–3620CrossRefPubMedGoogle Scholar
  64. 64.
    Szakács G, Váradi A, Özvegy-Laczka C, Sark B (2008) The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME–Tox). Drug Discov Today 13:379–393CrossRefPubMedGoogle Scholar
  65. 65.
    Zhang J, Tian Q, Yung Chan S, Chuen Li S, Zhou S, Duan W, Zhu YZ (2005) Metabolism and transport of oxazaphosphorines and the clinical implications. Drug Metab Rev. 37:611–703CrossRefPubMedGoogle Scholar
  66. 66.
    Hsu FT, Chen TC, Chuang HY, Chang YF, Hwang JJ (2015) Enhancement of adoptive T cell transfer with single low dose pretreatment of doxorubicin or paclitaxel in mice. Oncotarget 6:44134–44150PubMedPubMedCentralGoogle Scholar
  67. 67.
    Zhao J, Cao Y, Lei Z, Yang Z, Zhang B, Huang B (2010) Selective depletion of CD4+ CD25+ Foxp3+ regulatory T cells by low-dose cyclophosphamide is explained by reduced intracellular ATP levels. Cancer Res 70:4850–4858CrossRefPubMedGoogle Scholar
  68. 68.
    Viaud S, Daillère R, Boneca IG, Lepage P, Pittet MJ, Ghiringhelli F, Trinchieri G, Goldszmid R, Zitvogel L (2014) Harnessing the intestinal microbiome for optimal therapeutic immunomodulation. Cancer Res 74:4217–4221CrossRefPubMedGoogle Scholar
  69. 69.
    Francescone R, Hou V, Grivennikov SI (2014) Microbiome, inflammation, and cancer. Cancer J 20:181–189CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Bérard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, Elson CO, Doré J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L (2013) The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342:971–976CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Madondo MT, Quinn M, Plebanski M (2016) Low dose cyclophosphamide: mechanisms of T cell modulation. Cancer Treat Rev 42:3–9CrossRefPubMedGoogle Scholar
  72. 72.
    van der Most RG, Currie AJ, Mahendran S, Prosser A, Darabi A, Robinson BW, Nowak AK, Lake RA (2009) Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother 58:1219–1228CrossRefPubMedGoogle Scholar
  73. 73.
    Kohyama M, Sugahara D, Sugiyama S, Yagita H, Okumura K, Hozumi N (2004) Inducible costimulator-dependent IL-10 production by regulatory T cells specific for self-antigen. Proc Natl Acad Sci USA 101:4192–4197CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Kanakry CG, Ganguly S, Luznik L (2015) Situational aldehyde dehydrogenase expression by regulatory T cells may explain the contextual duality of cyclophosphamide as both a pro-inflammatory and tolerogenic agent. Oncoimmunology 4:e974393CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    van der Most RG, Currie AJ, Robinson BW, Lake RA (2008) Decoding dangerous death: how cytotoxic chemotherapy invokes inflammation, immunity or nothing at all. Cell Death Differ 15:13–20CrossRefPubMedGoogle Scholar
  76. 76.
    Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G (2015) Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28:690–714CrossRefPubMedGoogle Scholar
  77. 77.
    Kawano M, Tanaka K, Itonaga I, Iwasaki T, Miyazaki M, Ikeda S, Tsumura H (2016) Dendritic cells combined with doxorubicin induces immunogenic cell death and exhibits antitumor effects for osteosarcoma. Oncol Lett 11:2169–2175PubMedPubMedCentralGoogle Scholar
  78. 78.
    Sistigu A, Viaud S, Chaput N, Bracci L, Proietti E, Zitvogel L (2011) Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. Semin Immunopathol 33:369–383CrossRefPubMedGoogle Scholar
  79. 79.
    Patutina OA, Mironova NL, Logashenko EB, Popova NA, Nikolin VP, Vasil’ev GV, Kaledin VI, Zenkova MA, Vlasov VV (2012) Cyclophosphamide metabolite inducing apoptosis in RLS mouse lymphosarcoma cells is a substrate for P-glycoprotein. Bull Exp Biol Med 152:348–352CrossRefPubMedGoogle Scholar
  80. 80.
    Grishanova AY, Melnikova EV, Kaledin VI, Nikolin VP, Lyakhovich VV (2005) Possible role of P-glycoprotein in cyclophosphamide resistance of transplanted mouse RLS lymphosarcoma. Bull Exp Biol Med 139:611–614CrossRefPubMedGoogle Scholar
  81. 81.
    Brayboy LM, Oulhen N, Witmyer J, Robins J, Carson S, Wessel GM (2013) Multidrug-resistant transport activity protects oocytes from chemotherapeutic agents and changes during oocyte maturation. Fertil Steril 100:1428–1435CrossRefPubMedGoogle Scholar
  82. 82.
    Joy MS, La M, Wang J, Bridges AS, Hu Y, Hogan SL, Frye RF, Blaisdell J, Goldstein JA, Dooley MA, Brouwer KL, Falk RJ (2012) Cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics in patients with glomerulonephritis secondary to lupus and small vessel vasculitis. Br J Clin Pharmacol 74:445–455CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Kim IW, Yun HY, Choi B, Han N, Kim MG, Park S, Oh JM (2013) Population pharmacokinetics analysis of cyclophosphamide with genetic effects in patients undergoing hematopoietic stem cell transplantation. Eur J Clin Pharmacol 69:1543–1551CrossRefPubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Pädiatrische Hämatologie und Onkologie, Klinik für Kinder- und JugendmedizinUniversitätsklinikum MünsterMünsterGermany
  2. 2.PharmaCampus, Klinische PharmazieWestfälische Wilhelms-Universität MünsterMünsterGermany

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