p170-dependent multidrug resistance. Restoring full sensitivity to idarubicin with verapamil and cyclosporin A derivatives

M. Michieli, D. Damiani, A. Michelutti, C. Melli, D. Russo, R. Fanin, M. Baccarani

Research output: Contribution to journalArticle

Abstract

Background. Cell sensitivity to anthracyclines and other drugs depends on several factors, including overexpression of a 170 Kd transmembrane glycoprotein (p170) that enhances drug efflux from the cells. Since the result of treatment is negatively related to the expression of p170 in leukemia, malignant lymphoma and other tumors, it is important to investigate drugs and methods that can modify multidrug resistance (MDR). Materials and Methods. Using an MTT-microcultured tetrazolium colorimetric method, we assayed sensitivity to daunorubicin (DNR) and to its 4-demethoxy derivative idarubicin (IDA) in two MDR cell lines (CEM VLB and LOVO DX) and in their respective non-MDR parental lines (CEM and LOVO 109), with and without three MDR modifiers, namely the D-isomer of verapamil (DVRP), cyclosporin A (CyA) and the new CyA derivative SDZ PSC 833. Results. We showed that down-modulation of resistance with MDR modifiers was greater for DNR than for IDA in MDR cells. However, we also demonstrated that restoration of full sensitivity could only be achieved for IDA, not for DNR. DVRP and CyA in combination were more effective than either compound alone and could abolish p170-related resistance to IDA at concentrations of 1-2 μM and 1.6 μM, respectively. SDZ PSC 833 alone was even more effective and set MDR to zero at a concentration ranging between 0.8 and 1.6 μM. Conclusions. These data suggest that combinations of IDA and MDR modifiers may improve the results of cancer and leukemia treatment and that they are worth investigating in vivo, with attention to possible effects on drug pharmacokinetics and on normal tissue damage.

Original languageEnglish
Pages (from-to)119-126
Number of pages8
JournalHaematologica
Volume79
Issue number2
Publication statusPublished - 1994

Fingerprint

Idarubicin
Multiple Drug Resistance
Verapamil
Cyclosporine
Daunorubicin
Pharmaceutical Preparations
Leukemia
Anthracyclines
Lymphoma
Neoplasms
Glycoproteins
Pharmacokinetics
Cell Line

Keywords

  • idarubicin
  • MDR modifiers
  • multidrug resistance

ASJC Scopus subject areas

  • Hematology

Cite this

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(2), 119-126.

p170-dependent multidrug resistance. Restoring full sensitivity to idarubicin with verapamil and cyclosporin A derivatives. / Michieli, M.; Damiani, D.; Michelutti, A.; Melli, C.; Russo, D.; Fanin, R.; Baccarani, M.

In: Haematologica, Vol. 79, No. 2, 1994, p. 119-126.

Research output: Contribution to journalArticle

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, vol. 79, no. 2, pp. 119-126.
Michieli, M. ; Damiani, D. ; Michelutti, A. ; Melli, C. ; Russo, D. ; Fanin, R. ; Baccarani, M. / p170-dependent multidrug resistance. Restoring full sensitivity to idarubicin with verapamil and cyclosporin A derivatives. In: Haematologica. 1994 ; Vol. 79, No. 2. pp. 119-126.
@article{16e471b6206845d397d4bedef6b9ead6,
title = "p170-dependent multidrug resistance. Restoring full sensitivity to idarubicin with verapamil and cyclosporin A derivatives",
abstract = "Background. Cell sensitivity to anthracyclines and other drugs depends on several factors, including overexpression of a 170 Kd transmembrane glycoprotein (p170) that enhances drug efflux from the cells. Since the result of treatment is negatively related to the expression of p170 in leukemia, malignant lymphoma and other tumors, it is important to investigate drugs and methods that can modify multidrug resistance (MDR). Materials and Methods. Using an MTT-microcultured tetrazolium colorimetric method, we assayed sensitivity to daunorubicin (DNR) and to its 4-demethoxy derivative idarubicin (IDA) in two MDR cell lines (CEM VLB and LOVO DX) and in their respective non-MDR parental lines (CEM and LOVO 109), with and without three MDR modifiers, namely the D-isomer of verapamil (DVRP), cyclosporin A (CyA) and the new CyA derivative SDZ PSC 833. Results. We showed that down-modulation of resistance with MDR modifiers was greater for DNR than for IDA in MDR cells. However, we also demonstrated that restoration of full sensitivity could only be achieved for IDA, not for DNR. DVRP and CyA in combination were more effective than either compound alone and could abolish p170-related resistance to IDA at concentrations of 1-2 μM and 1.6 μM, respectively. SDZ PSC 833 alone was even more effective and set MDR to zero at a concentration ranging between 0.8 and 1.6 μM. Conclusions. These data suggest that combinations of IDA and MDR modifiers may improve the results of cancer and leukemia treatment and that they are worth investigating in vivo, with attention to possible effects on drug pharmacokinetics and on normal tissue damage.",
keywords = "idarubicin, MDR modifiers, multidrug resistance",
author = "M. Michieli and D. Damiani and A. Michelutti and C. Melli and D. Russo and R. Fanin and M. Baccarani",
year = "1994",
language = "English",
volume = "79",
pages = "119--126",
journal = "Haematologica",
issn = "0390-6078",
publisher = "NLM (Medline)",
number = "2",

}

TY - JOUR

T1 - p170-dependent multidrug resistance. Restoring full sensitivity to idarubicin with verapamil and cyclosporin A derivatives

AU - Michieli, M.

AU - Damiani, D.

AU - Michelutti, A.

AU - Melli, C.

AU - Russo, D.

AU - Fanin, R.

AU - Baccarani, M.

PY - 1994

Y1 - 1994

N2 - Background. Cell sensitivity to anthracyclines and other drugs depends on several factors, including overexpression of a 170 Kd transmembrane glycoprotein (p170) that enhances drug efflux from the cells. Since the result of treatment is negatively related to the expression of p170 in leukemia, malignant lymphoma and other tumors, it is important to investigate drugs and methods that can modify multidrug resistance (MDR). Materials and Methods. Using an MTT-microcultured tetrazolium colorimetric method, we assayed sensitivity to daunorubicin (DNR) and to its 4-demethoxy derivative idarubicin (IDA) in two MDR cell lines (CEM VLB and LOVO DX) and in their respective non-MDR parental lines (CEM and LOVO 109), with and without three MDR modifiers, namely the D-isomer of verapamil (DVRP), cyclosporin A (CyA) and the new CyA derivative SDZ PSC 833. Results. We showed that down-modulation of resistance with MDR modifiers was greater for DNR than for IDA in MDR cells. However, we also demonstrated that restoration of full sensitivity could only be achieved for IDA, not for DNR. DVRP and CyA in combination were more effective than either compound alone and could abolish p170-related resistance to IDA at concentrations of 1-2 μM and 1.6 μM, respectively. SDZ PSC 833 alone was even more effective and set MDR to zero at a concentration ranging between 0.8 and 1.6 μM. Conclusions. These data suggest that combinations of IDA and MDR modifiers may improve the results of cancer and leukemia treatment and that they are worth investigating in vivo, with attention to possible effects on drug pharmacokinetics and on normal tissue damage.

AB - Background. Cell sensitivity to anthracyclines and other drugs depends on several factors, including overexpression of a 170 Kd transmembrane glycoprotein (p170) that enhances drug efflux from the cells. Since the result of treatment is negatively related to the expression of p170 in leukemia, malignant lymphoma and other tumors, it is important to investigate drugs and methods that can modify multidrug resistance (MDR). Materials and Methods. Using an MTT-microcultured tetrazolium colorimetric method, we assayed sensitivity to daunorubicin (DNR) and to its 4-demethoxy derivative idarubicin (IDA) in two MDR cell lines (CEM VLB and LOVO DX) and in their respective non-MDR parental lines (CEM and LOVO 109), with and without three MDR modifiers, namely the D-isomer of verapamil (DVRP), cyclosporin A (CyA) and the new CyA derivative SDZ PSC 833. Results. We showed that down-modulation of resistance with MDR modifiers was greater for DNR than for IDA in MDR cells. However, we also demonstrated that restoration of full sensitivity could only be achieved for IDA, not for DNR. DVRP and CyA in combination were more effective than either compound alone and could abolish p170-related resistance to IDA at concentrations of 1-2 μM and 1.6 μM, respectively. SDZ PSC 833 alone was even more effective and set MDR to zero at a concentration ranging between 0.8 and 1.6 μM. Conclusions. These data suggest that combinations of IDA and MDR modifiers may improve the results of cancer and leukemia treatment and that they are worth investigating in vivo, with attention to possible effects on drug pharmacokinetics and on normal tissue damage.

KW - idarubicin

KW - MDR modifiers

KW - multidrug resistance

UR - http://www.scopus.com/inward/record.url?scp=0028225623&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028225623&partnerID=8YFLogxK

M3 - Article

C2 - 7914881

AN - SCOPUS:0028225623

VL - 79

SP - 119

EP - 126

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 2

ER -