L1210 CELLS SELECTED FOR RESISTANCE TO METHOXYMORPHOLINYL DOXORUBICINAPPEAR SPECIFICALLY RESISTANT TO THIS CLASS OF MORPHOLINYL DERIVATIVES

We investigated the mechanism of resistance in murine L1210 leukaemia cells selected after treatment with FCE 23762 methoxymorpholinyl doxor ubicin; (MMRDX), a methoxymorpholinyl derivative of doxorubicin active in vitro and in vivo on multidrug-resistant (mdr) cells, currently un dergoing 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 cyanomorph olinyl doxorubicin, but shows resistance to morpholinyl derivatives on ly in vivo or following their activation with rat S9-liver fractions i n vitro. L1210/MMRDX cells are sensitive to classic mdr- and altered t opoisomerase (AT)-mdr-associated drugs. These cells do not appear to o verexpress the mdr1 gene, nor do they exhibit impaired intracellular d rug accumulation and efflux or altered levels of glutathione and gluta thione 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 subl ine. The mechanism of resistance in L1210/MMRDX cells remains to be id entified but may prove a novel one, highly specific for this class of mdr-active anthracyclines.