Abstract
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.
Highlights
We have previously shown that the sensitivity of the small cell carcinoma of the lung (SCCL) cell lines to ADR, DAU and MITO with 1-h incubation is dependent on the size of the S-phase fraction at the time of drug exposure and that reduced variation in the clonogenic assay can be obtained by standardisation of the cell culture conditions (Jensen et al, 1989)
The sensitivity of the DAU resistant cell lines NCI-H69/ DAU4 and NCI-H69/DAU8 was assessed with continuous incubation (Figure 3)
Likewise the use of immunohistochemistry did not recognise P-glycoprotein on the wild type cell lines or on NCI-H69/DAU8 and confirmed the Western blot detection of P-glycoprotein in NCI-H69/DAU4. In this panel of eight SCCL cell lines established from treated and untreated patients the sensitivities to the four drugs vary within a factor of only five
Summary
ADR (Carlo Erba), DAU (Rhone Poulenc) and ACLA (Lundbeck) were dissolved in sterile water just before use. The human SCCL cell lines used were NCI-H69, NCI-N592, NCI-H249CL5, NCI-N417, OC-NYH ( designated GLC2), OC-TOL (GLC-3), GLC-16 and SCLC-86M1. The surviving cells were pooled and passaged three times in medium with 0.1 lg ml-' DAU. H69 /DAU4 was maintained in drug-free medium for 4 weeks before testing. Cell line NCI-H69/DAU8 was maintained in drug-free medium for 8 weeks before testing. In experiments with 1 h drug exposure the growth conditions before sensitivity testing were standardised, i.e. 5 x 105 cells were passed to 15 ml of medium and left untouched in flasks for 5 days
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