L1210 cells selected for resistance to methoxymorpholinyl doxorubicin appear specifically resistant to this class of morpholinyl derivatives

Abstract

We investigated the mechanism of resistance in murine L1210 leukaemia cells selected after treatment with FCE 23762 methoxymorpholinyl doxorubicin: (MMRDX), a methoxymorpholinyl derivative of doxorubicin active in vitro and in vivo on multidrug-resistant (mdr) cells, currently undergoing phase I clinical trials. The resistant subline obtained after repeated in vitro treatments, L1210/MMRDX, is resistant in vitro and in vivo to all tested methoxymorpholinyl derivatives and to cyanomorpholinyl doxorubicin, but shows resistance to morpholinyl derivatives only in vivo or following their activation with rat S9-liver fractions in vitro. L1210/MMRDX cells are sensitive to classic mdr- and altered topoisomerase (AT)-mdr-associated drugs. These cells do not appear to overexpress the mdr1 gene, nor do they exhibit impaired intracellular drug accumulation and efflux or altered levels of glutathione and glutathione S-transferase. The extent of DNA single-strand break formation and, after microsomal activation, of DNA interstrand cross-links after treatment with MMRDX was similar in the parent and the resistant subline. The mechanism of resistance in L1210/MMRDX cells remains to be identified but may prove a novel one, highly specific for this class of mdr-active anthracyclines.

Down-regulation of the Nucleotide Excision Repair gene XPG as a new mechanism of drug resistance in human and murine cancer cells

“…In the same isogenic system used for the experiments presented here, doxorubicin was found to be equally or only marginally more active in NER defective cells compared to wt, NER proficient cells (ratio of IC50 s in cells with NER defects and wt cells ranging from 1.2 to 1.4) [24]. The evidences reported here, together with the published lack of cross resistance with doxorubicin [19] make nemorubicin a compound clearly acting with a mechanism different from that of classical anthracyclines. The requirement of an intact NER system for nemorubicin activity has been demonstrated in murine and human cell lines.…”

“…We employed a murine L1210-derived cell line resistant to nemorubicin (L1210/MMDX) [ 19 ], and further characterised the sensitivity of parental and resistant cells to agents whose activity is influenced by NER. Nemorubicin-resistant cells were cross-resistant to the marine compound trabectedin, whose activity is NER-dependent [ 8 , 9 ], (Figure 1C ) and the resistance index was similar to the one for nemorubicin.…”

“…A murine cell line resistant to nemorubicin has been isolated and did not show cross-resistance to doxorubicin, topoisomerase I and II inhibitors, 5-FU, or vinblastine [ 19 ]. Interestingly, nemorubicin-resistant cells were hypersensitive to alkylating agents including melphalan, mitomycin C, platinum derivatives and nitrosoureas.…”

Generation and characterization of MEK and ERK inhibitors- resistant non-small-cells-lung-cancer (NSCLC) cells

“…These cells, which show class-specific resistance, will be important for the development of new agents and combination able to circumvent resistance to MEK and ERK inhibitors. Although we did not test yet if the in resistance obtained in vitro can be confirmed in vivo too, we have several examples showing that MDR-1 unrelated drug resistance (as in this case) is maintained when cells are implanted in vivo [ 18 , 31 , 32 ]. Being ERK inhibitors at their initial clinical testing [ 5 ], the availability of models to study resistance in vitro and in vivo is of particular relevance.…”

Antitumor Activity of Methoxymorpholinyl Doxorubicin: Potentiation by Cytochrome P450 3A Metabolism

“…P450-activated MMDX induces DNA-DNA interstrand cross-links, in contrast to MMDX, which primarily induces protein-associated DNA single-strand breaks (Lau et al, 1989(Lau et al, , 1994. Other studies suggest that activated MMDX differs from the parent drug in terms of its spectrum of antitumor activity and pattern of resistance (Kuhl et al, 1993;Geroni et al, 1994;van der Graaf et al, 1995).…”