Maintenance therapy with 6-mercaptopurine (6-MP) as its major component has been one of the main reasons for the drastic increase in overall survival of paediatric patients with acute lymphoblastic leukaemia (ALL). In our cohort, consisting of patients receiving maintenance therapy for ALL and encompassing time period of three decades, we evaluated dosage, safety and efficiency of 6-MP in the treatment of childhood ALL according to treatment protocol, age and gender. Slovenian paediatric ALL patients diagnosed and treated from 1970 to 2004 were identified through the national oncology patients` registry. Of 414 registered paediatric ALL patients, 320 received maintenance therapy for ALL and were included in the final study cohort. Information about age, gender, treatment protocol, 6-MP related toxic events and ALL relapse was extracted from patients` files. Differences in 6-MP dose reduction, 6-MP side effects and relapse according togender, age and treatment protocol were statistically evaluated. After adjustment for gender and age, the incidence of 6-MP dose reduction (p (0.001) and bone marrow suppression (p = 0.019) was higher in recent treatment protocols, while relapse was more common in older protocols (p ( 0.001). Younger patients had greater risk for sepsis/infection (p = 0.002), while greater age was a risk factor for osteonecrosis (p = 0.001). No statistically significant associations were found according to gender. In the retrospective study, encompassing three decades of maintenance treatment of childhood ALL in Slovenia, recent protocols exhibited greater effectiveness and toxicity than older protocols.
COBISS.SI-ID: 3839089
Evaluating immunomodulatory effects of xenobiotics is an important component of the toxicity studies. Herein we report on the establishment of a novel in vitro test system for the immunotoxicity screening of xenobiotics based on human lymphoblastoid cell lines (LCLs). Four immunotoxic compounds; tributyltin chloride, cyclosporine A, benzo(a)pyrene and verapamil hydrochloride, as well as three immune-inert compounds; urethane, furosemide and mannitol were selected for characterization. The treatment of LCLs with immunosuppressive compounds resulted in reduced viability. The IC50 values determined in human LCLs were in agreement with the data obtained for human peripheral mononuclear cells. Since cytokine production reflects lymphocytes responses to external stimuli, we evaluated the functional responses of LCLs by monitoring their pro-inflammatory and immunoregulatory cytokine production.Our findings prove that LCLs allowed for reliable differentiation between immunomodulatory and immune-inert compounds. Hence, pre-treatment with immunomodulatory compounds led to a decrease in the production of pro-inflammatory TNF[alpha] IL-6 and immunoregulatory IL-2, IL-4, IL-10 and IFN[gamma] cytokines, when compared to untreated ionomycin/PMA stimulated cells. Moreover, testing a panel of ten LCLs derived from unrelated healthy individuals reflects inter-individual variability in response to immunomodulatory xenobiotics. In conclusion, LCLs provide a novel alternative method for the testing of the immunotoxic effects of xenobiotics.
COBISS.SI-ID: 3803505