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Mechanisms of Resistance of Confluent Human and Rat Colon Cancer Cells to Anthracyclines: Alteration of Drug Passive Diffusion¹

Research Group on Digestive Tumors, INSERM U252, Faculty of Medicine, 7 Bd Jeanne d'Arc, 21033 Dijon Cedex [H. P., B. C., P. G., F. M.], and Laboratory of Biomolecular Spectroscopy, Faculty of Pharmacy, 51 rue Cognacq Jay, 51096 Reims Cedex [J. M. M., M. M.], France

Two colon cancer cell lines, HT-29 (human) and DHD/K12/TRb (rat), were grown as monolayer cultures to various confluence degrees. The cytotoxic efficacies of doxorubicin and 4'-deoxydoxorubicin, evaluated by a survival assay, and the nuclear drug concentrations, measured by microspectrofluorometry, were shown to progressively decrease with the augmentation of confluence. This confluence dependent resistance (CDR) to anthracyclines was demonstrated independent of the multidrug resistance drug efflux mechanism. The cellular uptake of three compounds (sodium [⁵¹Cr]chromate, D-[¹⁴C]alanine, L-[¹⁴C]glucose) known to passively diffuse across the cell membrane as anthracyclines do was also reduced in confluent cells. After trypsin cell detachment, the kinetics of reversion of the sodium [⁵¹Cr]chromate uptake decrease and that of CDR were similar. Therefore, CDR may be attributed to a reduction of anthracycline cell intake due to a general alteration of passive diffusion across the cell membrane. However, CDR is only partly explained by this phenomenon since a reduced sensitivity of confluent cells was observed compared with nonconfluent cells for a similar amount of drug in their nuclei. CDR could explain the high resistance to anthracyclines of some solid tumors, such as colon tumors, in which cancer cells are tightly aggregated.

¹ Supported by Contract 86023 with GLAXO-France Laboratories.

² To whom requests for reprints should be addressed.

Received 12/12/89. Accepted 7/ 5/90.

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