BACKGROUND We studied the relationship between ras transfection and the drug resistance phenotype in the MCF-10A cell line (a non-transformed immortalized human breast epithelial cell line). MATERIALS AND METHODS Parental (MCF-10A) and c-Ha-ras transfected (MCF-10A H) cell lines were tested for resistance to Doxorubicin, Maphosphamide and Cisplatinum, by evaluating the inhibition of [3H]-thymidine incorporation. Cells were also examined for the expression of different resistance mechanisms by immunocytochemical and RT-PCR methods. RESULTS ras-transfected cells were much more resistant to Cis-platinum than parental ones. GST-pi the GST isoenzyme frequently involved in human cancers) increased only in transfected cells. No expression of any other resistance mechanisms (MDR, MRP, LRP) was found by immunocytochemistry either in parental or in transfected cells; nevertheless, the more sensitive RT-PCR tests detected mrp products in parental and in transfected cells: gene expression levels were low and equivalent in both cell lines. CONCLUSIONS ras transfection can induce resistance to Cis-platinum by increasing GST-pi expression.

Bone marrow samples from 33 patients affected by MM and MGUS, and 8 patients not affected by lymphoproliferative diseases were studied for expression of c-Jun (a component of the transcription factor AP-1) and glutathione-S-transferase pi (GST-pi) using immunocytochemical methods. A high and frequent expression of these two proteins was found both in MM and MGUS patients (31/33 patients positive for c-Jun and 29/33 patients positive for GST-pi) and in controls not affected by monoclonal gammopathy (7/8 patients positive for both c-Jun and GST-pi). No statistically significant correlation was found between c-Jun- and GST-pi-positive plasma cells. The expression of these two proteins was not related to clinical or laboratory data. Our results seem to confirm a possible role of the transcriptional complex AP-1 in activating GST-pi promoter in human plasma cells.

Multidrug resistance is frequently detected in haematological malignancies and in acute leukaemias with a poor prognosis. In the last few years, several reports seem to suggest that the new anthracycline derivative idarubicin and the anthraquinone mitoxantrone have some advantages in the management of untreated or relapsed acute leukaemias compared with older anthracyclines. This could be due to a different interaction of these drugs with multidrug resistance. To evaluate this possibility, we compared the activity of doxorubicin (DOXO), epirubicin (EPI), idarubicin (IDA) and mitoxantrone (MITO) on a murine, multidrug resistant, leukaemic cell line (P-388/Dx) cultured in vitro. id50 of IDA and MITO was in the ng range whereas that of DOXO and EPI was in the μg range. Moreover, IDA has a resistance index of 50 whereas DOXO has one of 250. Verapamil is able to almost completely abolish the resistance to IDA. Efflux experiments confirm that verapamil increases IDA intracellular concentration. IDA and MITO appear to be less involved in multidrug resistance than older anthracyclines.

BACKGROUND Lymphocytes from patients affected by B-cell chronic lymphocytic leukemia (B-CLL) have frequently been shown to be positive for the multidrug resistance (MDR) phenotype. However, this phenotype does not seem to be responsible for the resistance to alkylating agents usually employed in the management of CLL. METHODS Lymphocytes from 42 patients were evaluated by flow cytometry for P-170 expression and by spectrophotometry for glutathione-S-transferase (GST) activity. RESULTS Our findings show that GST is not related to any clinical parameter but is increased in treated patients. Conversely, 85% of patients were positive for P-170 and this was related to the percentage of CD5/CD19-positive lymphocytes. CD5/CD19-negative patients were also negative for P-170. MDR was not related to any clinical parameter evaluated nor to GST activity in lymphocytes. CONCLUSIONS MDR is constitutively expressed in B-cell chronic lymphocytic leukemia and seems to be related to a CD5/CD19 B-CLL phenotype. The increase of GST activity in treated patients is statistically significant (p < 0.005).

Summary. Bone marrow samples from 40 patients affected by multiple myeloma either treated or untreated were examined for expression of glutathione‐S‐transferase n (GST‐TT), P‐glycoprotein and the protein product of ras oncogenes family, p‐21, on plasma cells, by immuno‐cytochemical detection. 72% of evaluated samples were positive for P‐170 and 82% for GST‐7T without any correlation with clinical or prognostic parameters. A significant relationship between GST‐7T expression and P‐l 70 positivity was found and co‐expression was observed in 91% of evaluated samples.Expression of P‐170 and GST‐TT was found both in treated and untreated patients. However, patients evaluated before and after therapy showed an increase in the percentage of plasma cells positive for GST‐7T or P‐170 or both. Expression of p‐21 was not associated with these mechanisms of drug resistance.These data suggest that different resistance mechanisms are present in multiple myeloma.