Abstract
Itraconazole is a triazole antifungal agent that inhibits cell membrane serol biosynthesis. Currently, itraconazole is a potent candidate for in vivo use to revert multidrug resistance in acute leukemias, with the added benefit of its antifungal effect. As previously reported, itraconazole, as well as verapamil, reversed adriamycin-resistant K562 cells (K562/ADR) and HL60 cells (HL60/ADR) in dosages compatible to the plasma levels achieved by the therapeutic dosages used for the treatment of fungal infections. By RT-PCR analysis of mdrl, mdr3, and mrp mRNA, these adriamycin-resistant cells showed a higher expression of the transcript of these genes than those of the parent cells. By FACS analysis, both the adriamycin-resistant cells showed a higher expression of P-glycoprotein on their cell surfaces. These results suggested the involvement of itraconazole in the mdr gene and/or mrp gene product-associated resistance. Furthermore, itraconazole partially reversed etoposide resistance in both the K562 and K562/ADR cells. The present study suggests that itraconazole may reverse multidrug resistance, at least in part, via a classical MDR-associated mechanism.
Similar content being viewed by others
References
Schinkel AH, Borst P (1991) Multidrug resistance mediated by P-glycoproteins. Semin Cancer Biol 2:213–226
Nooter K, Sonneveld P (1994) Clinical relevance of P-glycoprotein expression in hematological malignancies. Leukemia Res 18:233–243
Gupta S, Kim J, Gollapudi S (1991) Reversal of daunorubicin resistance in P388/ADR cells by itraconazole. J Clin Invest 87:1467–1469
Vreugdenhil G, Raemaekers JMM, van Dijke BJ, de Pauw BE (1993) Itraconazole and multidrug resistance: possible effects on remission rate and disease-free survival in acute leukemia. Ann Hematol 67:107–109
Okabe M, Matsushima S, Morioka M, Kobayashi M, Abe S, Sakurada K, Kakinuma M, Miyazaki T (1987) Establishment and characterization of a cell line, TOM-1, derived from a patient with Philadelphia chromosome-positive acute lymphocytic leukemia. Blood 69:990–998
Higa T, Okabe M, Kunieda Y, Kodama S, Itaya T, Kurosawa M, Sakurada K, Maekawa I, Shoji M, Kasai M, Miyazaki T (1994) Establishment and characterization of a new Ph1l-positive ALL cell line (ALL/MIK) presenting bcr rearrangement on bcr-2and ALL-type bcr/abl transcript: suggestion of in vitro differentiation to monocytoid lineage. Leuk Lymphoma 12:287–296
Okabe M, Kunieda Y, Nakane S, Kurosawa M, Itaya T, Vogler WR, Shoji M, Miyazaki T (1995) Establishment and characterization of a new Ph'-positive chronic myeloid leukemia cell line MC3 with trilineage phenotype and an altered p53 gene. Leuk Lymphoma 16:493–503
Bodner AJ, Tsai S, Ting RC, Collins SJ, Gallo RC (1980) Isolation and characterization of thioguanosine resistant human promyelocytic leukemia cells. Leuk Res 4:151–154
Okabe M, Uehara Y, Miyagishima T, Itaya T, Tanaka M, Kunieda Y, Kurosawa M, Miyazaki T (1992) Effect of herbimycin A, an antagonist of tyrosine kinase, on bcr/abl oncoprotein-associated cell proliferations: abrogative effect on the transformation of murine hematopoietic cells by transfection of a retroviral vector expressing oncoprotein P210bcr/abl and preferential inhibition on Ph1-positive leukemia cell growth. Blood 80:1330–1338
Kunieda Y, Okabe M, Kurosawa M, Itaya T, Kakinuma M, Miyazaki T (1994) Chronic myeloid leukemia presenting ALL-type BCR/ABL transcript. Ann Hematol 69:189–193
Noonan KE, Beck C, Holzmayer TA, Chin JE, Wunder JS, Andrulis IL, Gazdar AF, Willman CL, Griffith B, Von Hoff DD, Roninson IB (1990) Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci U S A 87:7160–7164
Sugawara I, Watanabe M, Masunaga A, Itoyama S, Ueda K (1992) Primer-dependent amplification of mdr1m RNA by polymerase chain reaction. Jpn J Cancer Res 83:131–133
Abbazadegan MR, Futsher BW, Klimecki WT, List A, Dalton WS (1994) Analysis of multidrug resistance-associated protein (MRP) messenger RNA in normal and malignant hematopoietic cells. Cancer Res 54:4676–4679
Harker WG, Slade DL, Parr RL, Feldhoff PW, Sullivan DM, Holguin MH (1995) Alteration in the topoisomerase IIα gene, messenger RNA, and subcellular protein distribution as well as reduced expression of the DNA topoisomeras IIβ enzyme in a mitoxantrone-resistant HL-60 human leukemia cell line. Cancer Res 55:1707–1716
Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vitro and in vivo through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41:1967–1972
Nooter K, Oostrum R, Jonker R, Dekken H van, Stokdiji W, Engh G van den (1989) Effect of cyclosporin A on daunorubicin accumulation in multidrug-resistant P388 leukemia cells measured by real-time flow cytometry. Cancer Chemother Pharmacol 23:296–300
Cimoli G, Valenti M, Parodi S, De Sessa F, Russo P (1994) Circumvention of atypical multidrug resistance with tumor necrosis factor. Jpn J Cancer Res 85:135–138
Author information
Authors and Affiliations
Additional information
This work was supported in part by a grant-in-aid for scientific research on priority areas — Cancer — from the Ministry of Education, Science and Culture of Japan
Rights and permissions
About this article
Cite this article
Kurosawa, M., Okabe, M., Hara, N. et al. Reversal effect of itraconazole on adriamycin and etoposide resistance in human leukemia cells. Ann Hematol 72, 17–21 (1996). https://doi.org/10.1007/BF00663011
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00663011