In vitro evaluation of the potential of aclarubicin in the treatment of small cell carcinoma of the lung (SCCL).
The sensitivity of eight cell lines established from treated and untreated patients with small cell carcinoma of the lung (SCCL) was tested in the clonogenic assay with 1 h and continuous exposure to aclarubicin (ACLA), adriamycin (ADR), daunorubicin (DAU) and mitoxantrone (MITO). The sensitivity to ADR, DAU and MITO covariated, and varied with a factor of five. The sensitivity to ACLA was independent of the sensitivity to ADR and varied only within a factor of two. Only ACLA showed pronounced increased potency with continuous incubation, and ACLA was the most potent drug in the three cell lines least sensitive to ADR. Two resistant cell lines were selected by treating NCI-H69 in vitro with DAU. One cell line (9-fold resistant to DAU) expressed large amounts of P-glycoprotein, the other cell line (4-fold resistant to DAU) had barely detectable glycoprotein. Both lines acquired resistance to ADR, ACLA and MITO. The cross-resistance to ACLA and MITO was only partial and ACLA was still the most potent drug on these lines. The sensitivity to ACLA of the cell lines least sensitive to ADR suggest that ACLA partially circumvents mechanisms of multidrug resistance. Together with the pronounced increase in potency with prolonged exposure, these results suggest that ACLA has a mechanism of action different from the 'classical' anthracyclines. In this context mitoxantrone is more similar to the classical anthracyclines although its structure is more dissimilar.
Jensen
P B
PB
Department of Oncology, Finsen Institute, Copenhagen, Denmark.
Vindeløv
L
L
Roed
H
H
Demant
E J
EJ
Sehested
M
M
Skovsgaard
T
T
Hansen
H H
HH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015250:Aclarubicin / Q000627:therapeutic use*; D001798:Blood Proteins / Q000032:analysis; D018288:Carcinoma, Small Cell / Q000032:analysis / Q000188:drug therapy*; D003630:Daunorubicin / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000032:analysis; D008942:Mitoxantrone / Q000627:therapeutic use; D014410:Tumor Stem Cell Assay
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001798:Blood Proteins; D008562:Membrane Glycoproteins; D015250:Aclarubicin; D004317:Doxorubicin; D008942:Mitoxantrone; D003630:Daunorubicin