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Glufosfamide (β-D-glucosyHfosfamide mustard) is a new agent for cancer chemo­therapy. Its pharmacology is similar to commonly used oxazaphosphorines, but it does not require activation by hepatic cytochrome P-450 and preclinically demon­strates lower nephrotoxicity and myelosuppression than ifosfamide. The aim of the study was a comparison of the drug resistance profiles of glufosfamide and other oxazaphosphorines in childhood acute leukemias. Leukemic cells, taken from chil­dren with ALL on diagnosis (n = 41), ALL on relapse (n = 12) and AML on diagnosis (n = 13) were analyzed by means of the MTT assay. The following drugs were tested: glufosfamide (GLU), 4-HOO-ifosfamide (IFO), 4-HOO-cyclophosphamide (CYC) and mafosfamide cyclohexylamine salt (MAF). In the group of initial ALL samples median cytotoxicity values for GLU, IFO, CYC and MAF were 15.5, 33.8, 15.7 and 7.8,«M, re­spectively. In comparison with initial ALL samples, the relative resistance for GLU and IFO in relapsed ALL samples was 1.9 (p = 0.049) and 1.3 (ns), and in initial AML samples 31 (p < 0.001) and 5 (p = 0.001), respectively. All oxazaphosphorines pre­sented highly significant cross-resistance. Glufosfamide presented high activity against lymphoblasts both on diagnosis and on relapse.
Uptake and efflux of two anthracyclines, idarubicin (IDA) and daunorubicin (DNR), was studied in childhood acute leukemia samples. A comparison of IDA and DNR transport phenomena in relation to drug cytotoxicity and expression of P-glycoprotein (PGP) was made. Intracellular content of IDA/DNR was determined by flow cytometry using the fluorescent properties of the drugs. In vitro drug cytotoxicity was measured by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. PGP expression was analysed by flow cytometry. The uptake and efflux rates were non-significantly higher for IDA than DNR. There were no differences between three types of leukemia with respect to drug content during accumulation and retention. After correction for the cell volume, intracellular concentration of both drugs in each moment of uptake and efflux was significantly lower in relapsed ALL and AML samples in comparison with initial ALL cells. Efflux, but not uptake, of both drugs was inversely correlated with PGP expression and IDA, but not DNR, cytotoxicity. The cytotoxicity was correlated with drug accumulation for both drugs and with drug retention for IDA. In conclusion, it seems that (1) intracellular content was related to the lipophilic properties of the drugs rather than to the type of leukemia, (2) decreased intracellular concentration of both drugs might have an impact on compromised therapy results in AML and relapsed ALL children, (3) IDA presents higher cytotoxicity, which possibly might be decreased by the presence of PGP. These results might have a practical impact on the rational design of new chemotherapy protocols.
In vitro antileukemic activity of five glucocorticoids and their cross-resistance pat­tern in childhood acute lymphoblastic and non-lymphoblastic leukemia were deter­mined by means of the MTT assay in 25 leukemia cell samples of childhood acute leukemias. The equivalent antileukemic concentrations of the drugs tested were: 34 uM hydrocortisone (HC), 8 uM prednisolone (PRE), 1.5 uM methylprednisolone (MPR), 0.44 uM dexamethasone (DX) and 0.22 Mbetamethasone (BET). In comparison with initial ALL cell samples, the relapsed ALL group was more resistant to PRE (38-fold, p = 0.044), DX (> 34-fold, p = 0.04), MPR (38-fold), BET (45-fold) and HC (33-fold). TheAMLcell samples were even more resistant to: PRE (>85-fold, p=0.001), DX (> 34-fold, p = 0.004),MPR(> 69-fold, p = 0.036), BET (> 69-fold, p = 0.038) and HC (54-fold, p = 0.059) when compared with ALL on initial diagnosis. A significant cross-resistance among all the glucocorticoids used was found. Only in some individual cases the cross-resistance was less pronounced.
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