Abstract
We have studied the growth inhibition, DNA synthesis inhibition and cell incorporation of the new anthracycline 4'-iodo-4'-deoxydoxorubicin (4'-iododoxorubicin) and of its 13-dihydroderivative in a model of doxorubicin-sensitive and -resistant rat C6 glioblastoma cells; results were compared to those obtained with doxorubicin and doxorubicinol in the same model. 4'-Iododoxorubicin was 7.5 times more potent than doxorubicin on the wild cell line and 45 times on the doxorubicin-resistant line, indicating that cross-resistance was only partial between the two drugs. Whereas doxorubicinol presented only a very faint cytotoxic activity, 4'-iododoxorubicinol retained the same activity as the parent drug against sensitive cells and a lower activity against resistant cells. DNA synthesis inhibition occurred for much higher doses than growth inhibition in the sensitive cells, but for similar doses in resistant cells. In both cell lines, 4'-iododoxorubicin and its metabolite were incorporated to a higher extent than doxorubicin and doxorubicinol respectively. Incorporation of metabolites was always lower than that of their parent compound. We have studied the metabolism of doxorubicin and 4'-iododoxorubicin by sensitive and resistant cells; only traces (less than 5%) of metabolites were identified in the cells as well as in the culture medium. A new cell line was selected for resistance in the presence of low amounts of 4'-iododoxorubicin. It presented a 6-fold resistance to 4'-iododoxorubicin and an 85-fold resistance to doxorubicin. Doxorubicin incorporation was markedly reduced in this cell line while 4'-iododoxorubicin was incorporated to the same extent as in the sensitive line. Measurements of drug efflux were performed in the three cell lines. No significant difference was exhibited between the efflux of doxorubicin and that of 4'-iododoxorubicin in each cell line; these effluxes were very rapid in the doxorubicin-selected resistant line, slow in the wild line and intermediate in the 4'-iododoxorubicin-selected line.
Highlights
Southern blots revealed a faint amplification of the Pglycoprotein gene (2- 3 times) in the C6 line selected in doxorubicin (C6 0.5 E), whereas the line selected in 4'iododoxorubicin presented no amplification at all of the gene
Northern blots revealed in both lines an overexpression of the P-glycoprotein gene; it could be evaluated semi-quantitatively as 10-fold the level of the wild line in doxorubicinresistant cells (C6 0.5 E) and as 5-fold in 4'-iododoxorubicinresistant (C6 IDX-R)
Studies of growth inhibition by vincristine revealed that both anthracycline-resistant lines
Summary
4'-Iodo-4'-deoxydoxorubicin and its 13-dihydroderivative, as well as doxorubicinol, were provided by Farmitalia-Carlo Erba; doxorubicin and vincristine were provided by Laboratoire Roger-Bellon. It had been possible to obtain the doxorubicin-resistant line with steps of 10 passages each at the successive concentrations of 0.03, 0.1, 0.3 and 0.5 or 1.0 ig of doxorubicin per ml medium (Vrignaud et al, 1986b). It was necessary with 4'-iododoxorubicin to begin with 0.005 lg ml-'; one increment to 0.01 jg ml was possible after 20 passages, but no further increase of the selection dose was possible thereafter. This line is called thereafter C6 IDX-R
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
