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Correlation between Growth Inhibition and Intranuclear Doxorubicin and 4'-Deoxy-4'-iododoxorubicin Quantitated in Living K562 Cells by Microspectrofluorometry

Laboratory of Biomolecular Spectroscopy [T. W. D. R., J-M. M., M. M.] and Biochemistry Laboratory [P. J., J-C. J.], Faculty of Pharmacy, 51, rue Cognacq Jay, 51096 Reims Cedex, France; and Farmitalia-C. Erba, R & D-Erbamont Group [V. R., F. A.], via dei Gracchi 35, 20146 Milan, Italy

Intranuclear drug concentration in cells treated with doxorubicin (DXR) or with 4'-deoxy-4'-iododoxorubicin (IDX) was measured by means of a quantitative microspectrofluorometric technique recently developed by us. Resolution of free and bound drug contributions in fluorescence emission spectra, as collected from a microvolume of single living cell nuclel, provided concentration data with about 10% indetermination. Uptake of DXR and IDX into the nucleus of K562 cells and DXR-resistant K562/DXR cells could then be studied with a sensitive, nondestructive technique. Growth inhibitory concentrations of K562 and K562/DXR cells, when measured with respect to drug content in the medium, differed by a factor of 25 in the case of DXR and by a factor of three in the case of IDX. By contrast, intranuclear drug concentrations measured at corresponding growth inhibitory concentrations are found to be nearly constant, i.e., independent of cellular-resistant phenotype and of anthracycline structure. This result supports an identical mechanism of action for the two drugs, most probably targeted to the nucleus, and ascribes to intracellular transport the different potency of the two drugs in the two cell lines.

¹ Temporarily on staff at the Laboratory of Biomolecular Spectroscopy. Permanent address: Farmitalia-C. Erba R & D-Erbamont Group, via dei Gracchi 35, I-20146 Milan, Italy.

² Present address: Menarini Ricerche Sud, via Tito Speri 10, 00040 Pomezia, Roma, Italy.

Received 5/25/88. Revised 10/ 6/88. Accepted 10/13/88.

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