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. 1991 Apr;87(4):1467–1469. doi: 10.1172/JCI115154

Reversal of daunorubicin resistance in P388/ADR cells by itraconazole.

S Gupta 1, J Kim 1, S Gollapudi 1
PMCID: PMC295200  PMID: 1849151

Abstract

Itraconazole is a recently developed triazole antifungal agent that inhibits cell membrane sterol biosynthesis. Itraconazole, in a dose-dependent manner, enhanced intracellular accumulation of daunorubicin and reversed the drug resistance in murine leukemia P388/ADR cells. In addition, itraconazole corrected the altered plasma membrane potentials of P388/ADR cells. The concentrations of itraconazole that reversed drug resistance are comparable to the plasma levels achieved by therapeutic dosage used in the treatment of fungal infections. Therefore, itraconazole is a potential candidate for in vivo use to reverse multidrug resistance in cancer with added benefit of its antifungal property.

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Selected References

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  1. Berg D., Plempel M., Büchel K. H., Holmwood G., Stroech K. Sterol biosynthesis inhibitors. Secondary effects and enhanced in vivo efficacy. Ann N Y Acad Sci. 1988;544:338–347. doi: 10.1111/j.1749-6632.1988.tb40418.x. [DOI] [PubMed] [Google Scholar]
  2. Bradley G., Juranka P. F., Ling V. Mechanism of multidrug resistance. Biochim Biophys Acta. 1988 Aug 3;948(1):87–128. doi: 10.1016/0304-419x(88)90006-6. [DOI] [PubMed] [Google Scholar]
  3. Cauwenbergh G., Van Cutsem J. Role of animal and human pharmacology in antifungal drug design. Ann N Y Acad Sci. 1988;544:264–269. doi: 10.1111/j.1749-6632.1988.tb40412.x. [DOI] [PubMed] [Google Scholar]
  4. Dieperink H., Møller J. Ketoconazole and cyclosporin. Lancet. 1982 Nov 27;2(8309):1217–1217. doi: 10.1016/s0140-6736(82)91231-4. [DOI] [PubMed] [Google Scholar]
  5. First International Symposium on Itraconazole. Oaxaca, Mexico, October 7-8, 1985. Proceedings. Rev Infect Dis. 1987 Jan-Feb;9 (Suppl 1):S1–152. [PubMed] [Google Scholar]
  6. Ganapathi R., Grabowski D. Differential effect of the calmodulin inhibitor trifluoperazine in modulating cellular accumulation, retention and cytotoxicity of doxorubicin in progressively doxorubicin-resistant L1210 mouse leukemia cells. Lack of correlation between cellular doxorubicin levels and expression of resistance. Biochem Pharmacol. 1988 Jan 15;37(2):185–193. doi: 10.1016/0006-2952(88)90716-2. [DOI] [PubMed] [Google Scholar]
  7. Ganapathi R., Schmidt H., Grabowski D., Melia M., Ratliff N. Modulation in vitro and in vivo of cytotoxicity but not cellular levels of doxorubicin by the calmodulin inhibitor trifluoperazine is dependent on the level of resistance. Br J Cancer. 1988 Sep;58(3):335–340. doi: 10.1038/bjc.1988.214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gottesman M. M., Pastan I. Resistance to multiple chemotherapeutic agents in human cancer cells. Trends Pharmacol Sci. 1988 Feb;9(2):54–58. doi: 10.1016/0165-6147(88)90117-4. [DOI] [PubMed] [Google Scholar]
  9. Hardin T. C., Graybill J. R., Fetchick R., Woestenborghs R., Rinaldi M. G., Kuhn J. G. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother. 1988 Sep;32(9):1310–1313. doi: 10.1128/aac.32.9.1310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Juranka P. F., Zastawny R. L., Ling V. P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins. FASEB J. 1989 Dec;3(14):2583–2592. doi: 10.1096/fasebj.3.14.2574119. [DOI] [PubMed] [Google Scholar]
  11. Kan V. L., Bennett J. E. Efficacies of four antifungal agents in experimental murine sporotrichosis. Antimicrob Agents Chemother. 1988 Nov;32(11):1619–1623. doi: 10.1128/aac.32.11.1619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lazo J. S., Bahnson R. R. Pharmacological modulators of DNA-interactive antitumor drugs. Trends Pharmacol Sci. 1989 Sep;10(9):369–373. doi: 10.1016/0165-6147(89)90010-2. [DOI] [PubMed] [Google Scholar]
  13. Slater L. M., Sweet P., Stupecky M., Gupta S. Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro. J Clin Invest. 1986 Apr;77(4):1405–1408. doi: 10.1172/JCI112450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Slater L. M., Sweet P., Stupecky M., Wetzel M. W., Gupta S. Cyclosporin A corrects daunorubicin resistance in Ehrlich ascites carcinoma. Br J Cancer. 1986 Aug;54(2):235–238. doi: 10.1038/bjc.1986.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Trenk D., Brett W., Jähnchen E., Birnbaum D. Time course of cyclosporin/itraconazole interaction. Lancet. 1987 Dec 5;2(8571):1335–1336. doi: 10.1016/s0140-6736(87)91232-3. [DOI] [PubMed] [Google Scholar]
  16. Tucker R. M., Williams P. L., Arathoon E. G., Stevens D. A. Treatment of mycoses with itraconazole. Ann N Y Acad Sci. 1988;544:451–470. doi: 10.1111/j.1749-6632.1988.tb40443.x. [DOI] [PubMed] [Google Scholar]
  17. Van Cutsem J., Van Gerven F., Van de Ven M. A., Borgers M., Janssen P. A. Itraconazole, a new triazole that is orally active in aspergillosis. Antimicrob Agents Chemother. 1984 Oct;26(4):527–534. doi: 10.1128/aac.26.4.527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Vayuvegula B., Slater L., Meador J., Gupta S. Correction of altered plasma membrane potentials. A possible mechanism of cyclosporin A and verapamil reversal of pleiotropic drug resistance in neoplasia. Cancer Chemother Pharmacol. 1988;22(2):163–168. doi: 10.1007/BF00257315. [DOI] [PubMed] [Google Scholar]

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