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In vitro analysis of drug resistance in tumor cells from patients with acute myelocytic leukemia

  • Jörgen Kristensen
  • Bertil Jonsson
  • Christer Sundström
  • Peter Nygren
  • Rolf Larsson
Article
  • 17 Downloads

Abstract

A 72 hours fluorometric microculture cytotoxicity assay (FMCA) was used for the study of chemotherapeutic drug resistance in tumor cell suspensions from patients with acute myelocytic leukemia (AML). A marked heterogeneity with respect to sensitivity was observed for a panel of cytotoxic drugs tested in 76 samples from 60 patients with treated or untreated AML. Primary resistance to vincristine (Vcr) and prednisolone in untreated AML was observed as well as ‘acquired’ resistance to several other antileukemic drugs. Cross resistance patterns for AML active drugs revealed significant positive relationships between anthracyclines, VP 16 and amsacrine (Amsa), whereas mitoxantrone (Mitox) was more weakly correlated. Sensitivity to cytosine arabinoside was unrelated to the anthracyclines, VP16, Amsa and Mitox butshowed a significant relationship to 6-thioguanine. Several resistance modifying agents, including the novel non-imrnunosuppressive cyclosporin A analogue PSC 833, were able to potentiate the effects of doxorubicin and Vcr at concentrations achievable in the clinic. However, the pattern of activity was heterogenous and the frequency of responsive samples was higher in relapse compared tode novo cases. Individualin vitro/in vivo correlations based on quartile distributions of ail accumulated drug sensitivity data from AML patients indicated a high specifity with respect to the identification of drug resistance. The results suggest that the FMCA may provide clinically valuable information on chemotherapeutic drug resistance in AML.

Key Words

Drug resistance Acute non-lymphocytic leukemia Acute myelocytic leukemia Drug sensitivity assay 

Abbreviations

AML

acute myelocytic leukemia

ALL

acute lymphocytic leukemia

FDA

fluorescein diacetate

FMCA

fluorometric microculture cytotoxicity assay

MTT

3- (4, 5 dimethylthiazol-2-yi)-2, 5-diphenyl tetrazolium bromide

Disc

Differential staining cytotoxicity

EDCC

empirically derived cut-off concentration

SI

survival index

DMSO

dimethyl sulfoxide

AraC

cytosin arabinoside

Vcr

vincristine

Dnr

daunorubicin

Dox

doxorubicin

Pred

prednisolone

Amsa

amsacrine

Mitox

mitoxantrone

Mel

melphalan

VP16

etoposide

Ver

verapamil

Quin

quinine

CsA

cyclosporin A

PBS

phosphate buffered saline

CV

coefficient of variation

FCS

fetal calf serum

CR

complete remission

MDR

multidrug resistance

pgp 170

170 kDa P-glycoprotein

RMA

resistance modifying agents

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Copyright information

© Humana Press Inc. 1992

Authors and Affiliations

  • Jörgen Kristensen
    • 1
    • 2
  • Bertil Jonsson
    • 2
  • Christer Sundström
    • 3
  • Peter Nygren
    • 4
  • Rolf Larsson
    • 1
  1. 1.Division of Clinical PharmacologyUppsala UniversityUppsalaSweden
  2. 2.Departments of MedicineUppsala UniversityUppsalaSweden
  3. 3.PathologyUppsala UniversityUppsalaSweden
  4. 4.Oncology, University HospitalUppsala UniversityUppsalaSweden

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