Background: Methotrexate (MTX) followed by 6-mercaptopurine (6MP) is one
of the best known combinations for the treatment of childhood acute lymphoblastic
leukaemia. Tiazofurin (TF) and 6-thioguanine (TG) are also used as chemotherapy
agents in the treatment of malignancies. We have examined the induction of apoptosis
by combinations of these drugs to gain more insights into their efficacy in the
treatment of malignancies.
Methods: The induction of apoptosis was examined in Molt-4, a human
malignant acute lymphoblastic T-cell line. The cells were exposed to increasing drug
concentrations at various exposure times. Annexin V/FITC and propidium iodide (PI)
were used as markers for apoptosis and cell death. Annexin V/FITC positive and PI
positive cells were detected by flow-cytometric analysis.
Results: Sequential 24-h exposure with MTX (0·005-0·02
µmol) followed by 6MP (1-10 µmol) and 24-h
exposure with TF (5·20 µmol) followed by TG (0·5-2
µmol) showed a more than additive induction of apoptosis compared
with single-drug exposure. Simultaneous administration of the drugs does not show an
additive effect on apoptosis.
Conclusions: The results of this study indicate that sequential
administration of MTX before 6MP and of TF before TG may be essential for therapeutic
success in the treatment of leukaemia.
