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Effect of amifostine on the cytotoxicity of daunorubicin and daunoxome in tumor and normal cells

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Abstract

Anthracyclines are powerful cytotoxic agents, used as first-line treatment of leukemias and many other tumors, but host-tissue toxicity is their main dose-limiting factor. However, their therapeutic effects depend not only on the toxicity, hence on the dose, but also on drug resistance. Among the mechanisms that can account for cell sensitivity to anthracyclines, there is an overexpression of drug transport proteins, like the transmembrane P-glycoprotein (PGP), the multidrug- resistance-related protein (MRP) and the lung-resistance-related protein (LRP). Attempts to reduce the toxicity of chemotherapeutic agents without affecting their efficacy have been made using liposomal anthracyclines or cytoprotective agents, as Amifostine. The aim of this study was to evaluate and compare the toxic effects of Daunorubicin, in normal or liposomal formulation, used in combination with WR1065, the active metabolite of Amifostine, against normal and tumor cells. In conclusion these data show that the preincubation with WR-1065 does not inhibit the drug toxic effect on blast cells and on tumor cell lines, independently by their multidrug resistance phenotype, but has a cytoprotective effect on stem cells causing a drug cytotoxicity reduction of 10–20%. This advantage is even higher using the liposomal formulation of DNR. Therefore, Amifostine can offer a chance of protecting normal cells from the toxicity of anthracyclines, in normal or liposomal formulation. The combination of liposomal anthracyclines with Amifostine can confer further advantages in management of leukemic patients, especially the elderly where treatment toxicity is a main problem. These patients may be candidates for alternative therapeutic strategies and the combination of DNX and Amifostine is an attractive treatment for these cases where a low nonhematological toxicity is required.

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References

  1. Alberts DS, Speicher LA, Krutzsch M, Wymer J, Capizzi RL, Conlon J, Barrett A, Aickin M (1996) WR-1065, the active metabolite of amifostine (ethiol), does not inhibit the cytotoxic effects of a broad range of standard anticancer drug against human ovarian and breast cancer cells. Eur J Cancer 32A(Suppl 4):S17–S20

    Article  Google Scholar 

  2. Allen TM, Hansen CB, Lopes de Menezes DE (1995) Pharmacokynetics of long-circulating liposomes. Adv Drug Deliv Rev 16:267–269

    Article  CAS  Google Scholar 

  3. Allen TM (1997) Liposomes: opportunities in drug delivery. Drugs 54(Suppl 4):8–12

    PubMed  CAS  Google Scholar 

  4. Beck WT (1990) Mechanisms of multidrug resistance in human tumor cells. The roles of P-glycoprotein, DNA topoisomerase II, and other factors. Cancer Treatm Rev 17(Suppl A):11–20

    Article  CAS  Google Scholar 

  5. Bloomfield CD, Shuma C, Regal L, Philip PP, Hossefeld DK, Hagemeijer AM, Garson OM, Peterson BA, Sakurai M, Alimena G, Berger R, Rowley JD, Ruutu T, Mitelman F, Dewald GW, Swansbury J (1997) Long-term survival of patients with acute myeloid leukemia: a third follow-up of the Fourth International Workshop on Chromosomes in Leukemia. Cancer 80(Suppl 11):2191–2198

    Article  PubMed  CAS  Google Scholar 

  6. Cairo MS, Siegel S, Anas N, Sender L (1989) Clinical trial of continuous infusion verapamil, bolus vinblastine, and continuous infusion VP-16 in drug resistant pediatric tumors. Cancer Res 49:1063–1066

    PubMed  CAS  Google Scholar 

  7. Calabro-Jones PM, Aguilera JA, Ward JF, Smoluk GD, Fahey RC (1988) Uptake of WR-2721 derivatives by cells in culture: identification of the transported form of the drug. Cancer Res 48:3634–3640

    PubMed  CAS  Google Scholar 

  8. Campos L, Guyotat D, Archimbaud E, Almard-Oriol P, Tsuruo T, Troncy J, Treille D, Fiere D (1992) Clinical significance of multidrug resistance P-glycoprotein expression on acute non lymphoblastic leukemia cells at diagnosis. Blood 89:473–476

    Google Scholar 

  9. Capizzi RL, Scheffler BJ, Schein PS (1993) Amifostine-mediated protection of normal bone marrow from cytotoxic chemotherapy. Cancer 72(Suppl 11):3495–3501

    Article  PubMed  CAS  Google Scholar 

  10. Capizzi RL (1999) The preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies by amifostine. Semin Oncol 26(Suppl 7):3–21

    PubMed  CAS  Google Scholar 

  11. Cassileth PA, Harrington DP, Appelbaum FR, Lazarus HM, Rowe JM, Paietta E, Willman C, Hurd DD, Bennett JM, Blume KG, Head DR, Wiernik PH (1998)Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 339:1649–1656

    Article  PubMed  CAS  Google Scholar 

  12. Damiani D, Michieli M, Michelutti A, Geromin A, Raspadori D, Fanin R, Savignano C, Giacca M, Pileri S, Mallardi F, Baccarani M (1993) Expression of multidrug resistance gene (mdr-1) in human normal leucocytes. Haematologica 78:12–17

    PubMed  CAS  Google Scholar 

  13. Damiani D, Michieli M, Ermacora A, Candoni A, Raspadori D, Geromin A, Stocchi R, Grimaz S, Masolini P, Michelutti A, Scheper RJ, Baccarani M (1998) P-glycoprotein (PGP) and not lung resistance-related protein (LRP), is a negative prognostic factor in secondary leukemias. Haematologica 83:290–297

    PubMed  CAS  Google Scholar 

  14. Dorr RT, Lagel KE (1994) Anthracycline cardioprotection by amifostine (WR-2721) and its active metabolite (WR-1065) in vitro (abstract). Proc Am Soc Clin Oncol 13:435–439

    Google Scholar 

  15. Estey E, Thall P, Beran M, Kantarijian H, Pierce S, Keating M (1997) Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia, AML) on outcome of AML-type chemotherapy. Blood 90:2969–2977

    PubMed  CAS  Google Scholar 

  16. Forssen EA, Coulter DM, Proffitt RT(1992) Selective in vivo localization of daunorubicin small unilamellar vesicles in solid tumors. Cancer Res 52:3255–3261

    PubMed  CAS  Google Scholar 

  17. Foster-Nora JA, Siden R (1997) Amifostine for protection from antineoplastic drug toxicity. Am J Health Syst Pharm 54:787–800

    PubMed  CAS  Google Scholar 

  18. Fulda S, Oster W, Berthold F (1997) WR-2721 (amifostine) and its metabolite WR-1065 on the antiproliferative activity of chemotherapeutic agents on neuroblastoma cells in vitro. Anticancer Drugs 8:34–41

    Article  PubMed  CAS  Google Scholar 

  19. Grosso D, Filicko J, Garcia-Manero G, Beardell F, Brunner J, Cohn J, Ferber A, Martinez J, Mookerjee B, Rose L, Tice D, Wagner JL, Capizzi R, Flomenberg N (2004) Cytoprotection in acute myelogenous leukemia (AML) therapy. Semin Oncol 31(Suppl 18):67–73

    Article  PubMed  CAS  Google Scholar 

  20. Hwang WJK, Koh L-P, Ng HJ, Tan PHC, Chuah CTH, Fook SC, Chow H, Tan KW, Wong C, Tan CH, Goh Y-T (2004) A randomized trial of amifostine as a cytoprotectant for patients receiving myeloablative therapy for allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 34:51–56

    Article  PubMed  CAS  Google Scholar 

  21. Jonsson B, Nilsson K, Nygren P, Larsson R (1992) SDZ PSC 833 a novel potent in vitro chemosensitizer in multiple myeloma. Anti Cancer Drugs 3:641–646

    PubMed  CAS  Google Scholar 

  22. Kaye S, Merry S (1985) Tumour cell resistance to anthracyclines. A review. Cancer Chemother Pharmacol 14:96–103

    Article  PubMed  CAS  Google Scholar 

  23. Keller RP, Alterman HJ, Nooter K, Poschmann G, Laissue JA, Bollinger P, Hiestand PC (1992) SDZ PSC 833, a non immunosuppressive cyclosporine: its potency in overcoming P-glycoprotein-mediated multidrug resistance of murine leukemia. Int J Cancer 50:593–597

    Article  PubMed  CAS  Google Scholar 

  24. Leith C, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, Head DR, Appelbaun ER, William CL (1997) Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group Study. Blood 89:3323–3329

    PubMed  CAS  Google Scholar 

  25. Licht T, Pastan I, Gottesman M, Hermann F (1994) P-glycoprotein-mediated multidrug resistance in normal and neoplastic hematopoietic cells. Ann Hematol 69:159–171

    Article  PubMed  CAS  Google Scholar 

  26. Linn SC, Van Kalken CK, Van Tellingen O, van der Valk P, van Groningen CJ, Kuiper CM, Pinedo HM, Giaccone G (1994) Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil. J Clin Oncol 12:812–819

    PubMed  CAS  Google Scholar 

  27. List AF, Spier C, Greer J, Wolff S, Hutter J, Dorr R, Salmon S, Futscher B, Baier M, Dalton W (1993) Phase I/II trial of cyclosporin as a chemotherapy resistance modifier in acute leukemia. J Clin Oncol 11:1629–1635

    PubMed  Google Scholar 

  28. List AF, Heaton R and Glinsman-Gibson B, Capizzi RL (1996) Amifostine protects primitive human hematopoietic progenitors against cytotoxicity from diverse antineoplastics. Semin Oncol 23:58–63

    PubMed  CAS  Google Scholar 

  29. Lum BL, Fisher GA, Brophy NA, Yahanda AM, Adler KM, Kaubisch S, Halsey J, Sikic BI (1993) Clinical trials of modulation of multidrug resistance. Cancer 72:3502–3514

    Article  PubMed  CAS  Google Scholar 

  30. Mandelli F, Petti MC, Lo Coco F (1988) Therapy of acute myeloid leukemia: towards a patient-oriented, risk adapted approach. Haematologica 83:1015–1023

    Google Scholar 

  31. Marie JP, Zittoun R, Sikic BI (1991) Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlation with treatment outcome and in vitro drug sensitivity. Blood 78:586–592

    PubMed  CAS  Google Scholar 

  32. Marie JP, Legrand O, Russo D, Zhou D, Suberville AM, Zittoun R (1992) Multidrug resistance (MDR) gene expression in acute non lymphoblastic leukemia: sequential analysis. Leuk Lymphoma 8:261–265

    Article  PubMed  CAS  Google Scholar 

  33. Michieli M, Damiani D, Geromin A, Michelutti A, Fanin R, Raspadori D, Russo D, Visani G, Dinota A, Pileri S, Tsuruo T, Grandi M, Baccarani M (1992) Overexpression of multidrug resistance-associated p170-glycoprotein in acute-non-lymphocytic leukemia. Eur J Haematol 48:87–92

    Article  PubMed  CAS  Google Scholar 

  34. Michieli M, Damiani D, Michelutti A, Melli C, Russo D, Fanin R, Baccarani M (1994) P170-dependent multidrug resistance. Restoring full sensitivity to idarubicin with verapamil and cyclosporin A derivatives. Haematologica 79:119–126

    PubMed  CAS  Google Scholar 

  35. Michieli M, Damiani D, Masolini P, Michelutti A, Grimaz S, Geromin A, Fanin R, Russo D, Baccarani M (1996) Screening of multidrug resistance in leukemia: cell reactivity to MRK-16 correlates with anthracycline retention and sensitivity of leukemic cells. Leuk Lymphoma 23:99–105

    Article  PubMed  CAS  Google Scholar 

  36. Michieli M, Damiani D, Ermacora A, Raspadori D, Michelutti A, Grimaz S, Fanin R, Russo D, Lauria F, Masolini P, Baccarani M (1997) P-glycoprotein and lung resistance-related protein (LRP) expression and function in leukemic blast cells. Br J Haematol 96:356–365

    Article  PubMed  CAS  Google Scholar 

  37. Michieli M, Damiani D, Ermacora A, Masolini P, Raspadori D, Visani G, Scheper RJ, Baccarani M (1999) P-glycoprotein, lung resistance-related protein and multidrug resistance associated protein in de novo acute non-lymphocytic leukemias: biological and clinical implications. Br J Haematol 104:328–335

    Article  PubMed  CAS  Google Scholar 

  38. Michieli M, Damiani D, Ermacora A, Masolini P, Michelutti A, Michelutti T, Russo D, Pea F, Baccarani M (1999) Liposome-encapsulated daunorubicin for PGP-related multidrug resistance. Br J Haematol 106:92–99

    Article  PubMed  CAS  Google Scholar 

  39. Michieli M, Michelutti A, Damiani D, Ermacora A, Masolini P, Stocchi R, Russo D (2001) Amifostine does not inhibits the toxic effects of anthracycline derivates or mitoxantrone in MDR tumor cell lines. Leuk Lymhoma 42:721–729

    Article  CAS  Google Scholar 

  40. Mickisch GH, Rahman A, Pastan J, Gottesman MM (1992) Increased effectiveness of liposome-encapsulated doxorubicin in multidrug resistant transgenic mice compared with free doxorubicin. J Natl Cancer Inst 84:804–809

    Article  PubMed  CAS  Google Scholar 

  41. Miller TP, Grogan TM, Dalton WS, Spier CM, Scheper RJ, Salmon SE (1991) P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high dose verapamil. J Clin Oncol 9:17–24

    PubMed  CAS  Google Scholar 

  42. Ormerod MG (1998) The study of apoptotic cells by flow cytometry. Leukemia 12:1013–1025

    Article  PubMed  CAS  Google Scholar 

  43. Paine G, Taylor CW, Lopez MH, Johnson CS, Capizzi RL (1996) Effects of Amifostine and paclitaxel on growth of human ovarian carcinoma xenografts in the severe combined immuno deficient mouse: preliminary results. Semin Oncol 23(Suppl 8):35–39

    PubMed  CAS  Google Scholar 

  44. Pastan I, Gottesman M (1987) Multiple-drug resistance in human cancer. N Engl J Med 316:1388–1393

    Article  PubMed  CAS  Google Scholar 

  45. Pea F, Russo D, Michieli M, Baraldo M, Ermacora A, Damiani D, Baccarani M, Furlanut M (2000) Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia. Cancer Chemother Pharmacol 46:279–286

    Article  PubMed  CAS  Google Scholar 

  46. Pileri SA, Sabbatini E, Falini B, Tazzarri PL, Gherlinzoni F, Michieli MG, Damiani D, Zucchini L, Gobbi M, Tsuruo T, Baccarani M (1991) Immunohistochemical detection of the multidrug transport protein P170 in human normal tissues and malignant lymphomas. Histopathology 19:131–140

    Article  PubMed  CAS  Google Scholar 

  47. Romanul FCA, Bannister RG (1962) Localized areas of high alkaline phosphatase activity in endothelium of arteries. Nature 195:611–612

    Article  PubMed  CAS  Google Scholar 

  48. Russo D, Marie JP, Zhou DC, Faussat AM, Delmer A, Maisonneuve L, Ngoc LH, Baccarani M, Zittoun R (1994) Coexpression of anionic glutathione-s-transferase (GSTπ) and multidrug resistance (mdr-1) genes in acute myeloid and lymphoid leukemias. Leukemia 8:881–884

    PubMed  CAS  Google Scholar 

  49. Russo D, Marie JP, Zhou DC, Faussat AM, Melli C, Damiani D, Michelutti A, Michieli M, Fanin R, Baccarani M, Zittoun R (1994) Evaluation of the clinical relevance of the anionic glutathione-s-transferase (GSTp) and multidrug resistance (mdr-1) gene coexpression in leukemias and lymphomas. Leuk Lymphoma 15:453–468

    Article  PubMed  CAS  Google Scholar 

  50. Salmon SE, Dalton WS, Grogan TM, Plezia P, Lehnert M, Roe DJ, Miller TP (1991) Multidrug resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer. Blood 78:44–50

    PubMed  CAS  Google Scholar 

  51. Sato H, Preisler H, Day R, Raza A, Larson R, Browman G, Goldberg J, Vogler R, Grunwald H, Gottlieb A (1990) Mdr1 transcript levels as an indication of resistant disease in acute myelogenous leukaemia. Br J Haematol 75:340–345

    PubMed  CAS  Google Scholar 

  52. Shaw LM, Bonner HS, Brown DQ (1994) Metabolic pathway of WR-2721 (ethiol, amifostine) in BALB/c mouse. Drug Metab Dispos 22:895–902

    PubMed  CAS  Google Scholar 

  53. Sonneveld P, Durie BGM, Lokhorst HM, Marie JP, Solbu G, Suciu S, Zittoun R, Lowenberg B, Nooteer K (1992) Modulation of multidrug resistant multiple myeloma by Cyclosporin. Lancet 340:255–259

    Article  PubMed  CAS  Google Scholar 

  54. Spath-Shwalbe E, Lange C, Genvresse I, Kruger L, Eucker J, Schweigert M, Sezer O, Budach V, Possinger K (2002) Influence of amifostine on toxicity of CHOP in elderly patients with aggressive non-Hodgkin’s lymphoma—a phase II study. Anticancer Drugs 13:395–403

    Article  PubMed  Google Scholar 

  55. Spencer CM, Goa KL (1995) Amifostine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as radioprotector and cytotoxic chemoprotector. Drugs 50:1001–1031

    PubMed  CAS  Google Scholar 

  56. Stocchi R, Damiani D, Masolini P, Michelutti A, Baccarani M, Tosi P, Fanin R (2004) Amifostine feasibility and efficacy in autologous stem cell transplantation for multiple myeloma. Haematologica 89:ELT02

    PubMed  Google Scholar 

  57. Suntharalingam M, Jaboin J, Taylor R, Wolf J, Banglore M, Van Echo D, Ord R (2004) The evaluation of amifostine for mucosal protection in patients with advanced loco-regional squamous cell carcinomas of the head and neck (SCCHN) treated with concurrent weekly carboplatin, paclitaxel, and daily radiotherapy (RT). Semin Oncol 31(Suppl 18):2–7

    Article  PubMed  CAS  Google Scholar 

  58. Thierry AR, Vige D, Coughlin SS, Belli JA, Dritschilo A, Rahman A (1993) Modulation of doxorubicin resistance in multidrug resistant cells by liposomes. FASEB J 7:572–579

    PubMed  CAS  Google Scholar 

  59. Wu NZ, Da D, Rudoll TL, Needham D, Whorton AR, Dewhirst MW (1993) Increased microvascular permeability contributes to preferential accumulation of Stealth liposomes in tumor tissue. Cancer Res 53:3765–3770

    PubMed  CAS  Google Scholar 

  60. Yuhas JM, Spellman JM, Culo F (1980) The role of WR-2721 in radiotherapy and or chemotherapy. Cancer Clin Trials 3:211–216

    PubMed  CAS  Google Scholar 

  61. Yuhas JM (1979) Differential protection of normal and malignant tissues against the cytotoxic effects of mechlorethamine. Cancer Treat Rep 63:971–976

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by COFIN 2001, 2001055984_003.

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Authors and Affiliations

  1. Division of Hematology, Department of Medical and Morphological Research, University Hospital, P.le S. Maria della Misericordia, 33100, Udine, Italy

    Michelutti Angela, Stocchi Raffaella, Candoni Anna, Tiribelli Mario, Calistri Elisabetta, Fanin Renato & Damiani Daniela

  2. Chair of Hematology, University of Brescia,  , Italy

    Russo Domenico

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  1. Michelutti Angela
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Angela, M., Raffaella, S., Anna, C. et al. Effect of amifostine on the cytotoxicity of daunorubicin and daunoxome in tumor and normal cells. Cancer Chemother Pharmacol 57, 517–524 (2006). https://doi.org/10.1007/s00280-005-0043-2

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