Genetic transfer of non-P-glycoprotein-mediated multidrug resistance (MDR) in somatic cell fusion: Dissection of a compound MDR phenotype

A non-P-glycoprotein-mediated mechanism of multidrug resistance (non-Pgp MDR) bas been identified in doxorubicin-selected sublines of the human non-small cell lung carcinoma cell lines SW-1573. These sublines are cross-resistant to daunorubicin, VP16-213, Vinca alkaloids, colchicine, gramicidin D, and 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA). They accumulate less drug than the parental cells and their resistance is not due to the MDR1-encoded P-glycoprotein, as the resistant cell lines have lost the low amount of MDR1 mRNA detectable in parental cells. Here we show that the resistant cell lines also contain less topoisomerase II mRNA and enzyme activity than the parental cells. This might contribute to the resistance of these lines to drugs interacting with topoisomerase II, such as doxorubicin, daunorubicin, and VP16-213, but cannot account for the resistance to the other drugs. We have tested whether all properties of the non-Pgp MDR cell lines cosegregate in somatic cell fusions between lethally gamma-irradiated, resistant donor cells and drug-sensitive acceptor cells. Whereas a MDR phenotype with reduced drug accumulation and the loss of MDR1 P-glycoprotein mRNA were cotransferred to the acceptor cells, the decrease in topoisomerase II gene expression was not. We conclude that the MDR phenotype, the reduced drug accumulation, and the loss of MDR1 P-glycoprotein MRNA are genetically linked. They might be due to a single dominant mutation, which does not cause the alteration in topoisomerase II

Mobilisation of haemopoietic progenitors in CML: a second course of intensive chemotherapy does not improve Ph-negativity in stem cell harvests

We collected peripheral blood stem cells (PBSC) in 19 early chronic phase CML patients following each of two consecutive cycles of intensive chemotherapy (CT) to evaluate whether an additional cycle of CT would increase Philadelphia (Ph)-negativity of the PBSC harvest. Autologous SCT (autoSCT) was performed if a major cytogenetic response (MCR) of the PBSC harvest was obtained, CT consisted of cytarabine 200 mg/m(2)/day (days 1-7)/idarubicin 12 mg/m(2)/day (days 1-2) (cycle one) and cytarabine 2000 mg/m(2)/day (days 1-6)/amsacrine 120 mg/m(2)/day (days 1-3) (cycle two), One patient died of fungal pneumonia after the first cycle. Stem cells were harvested in 18 patients after cycle one and in 16 patients after cycle two, After the first cycle, all patients showed a cytogenetic response of their graft (MCR in eight patients: three complete, five partial), after cycle two, seven patients obtained an MCR (one complete, six partial), Seven patients became eligible for autoSCT, All patients proceeded with IFN alpha maintenance. Currently, 16 patients are alive, At the latest cytogenetic examination of bone marrow, four patients showed an MCR and four a minor response. In conclusion, although a second cycle of CT may contribute to elimination of leukemia residing in the patient, it appeared to be ineffective in improving the Ph-negativity of the PBSC graft

Mobilisation of haemopoietic progenitors in CML:a second course of intensive chemotherapy does not improve Ph-negativity in stem cell harvests

We collected peripheral blood stem cells (PBSC) in 19 early chronic phase CML patients following each of two consecutive cycles of intensive chemotherapy (CT) to evaluate whether an additional cycle of CT would increase Philadelphia (Ph)-negativity of the PBSC harvest. Autologous SCT (autoSCT) was performed if a major cytogenetic response (MCR) of the PBSC harvest was obtained, CT consisted of cytarabine 200 mg/m(2)/day (days 1-7)/idarubicin 12 mg/m(2)/day (days 1-2) (cycle one) and cytarabine 2000 mg/m(2)/day (days 1-6)/amsacrine 120 mg/m(2)/day (days 1-3) (cycle two), One patient died of fungal pneumonia after the first cycle. Stem cells were harvested in 18 patients after cycle one and in 16 patients after cycle two, After the first cycle, all patients showed a cytogenetic response of their graft (MCR in eight patients: three complete, five partial), after cycle two, seven patients obtained an MCR (one complete, six partial), Seven patients became eligible for autoSCT, All patients proceeded with IFN alpha maintenance. Currently, 16 patients are alive, At the latest cytogenetic examination of bone marrow, four patients showed an MCR and four a minor response. In conclusion, although a second cycle of CT may contribute to elimination of leukemia residing in the patient, it appeared to be ineffective in improving the Ph-negativity of the PBSC graft