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Background: The prognosis of early and very early relapse in acute lymphoblastic leukemia of childhood is still very poor unless a hematopoietic stem cell transplant is performed if a second remission can be achieved by induction chemotherapy. Therefore an intensification of chemotherapy is required., Materials and Methods: In the present study the molecular mechanisms of cisplatin- and/or hyperthermia-mediated cytotoxicity in CEM cells, a human T leukemia cell line, were investigated., Results: Both hyperthermia and cisplatin induced the activation of the effector caspases-3 and -6. However, caspase activation followed different time kinetics. While hyperthermia exerted maximum caspase activation immediately after application, cisplatin activated caspase-3 and -6 after 24 hours. At both time-points significant caspase-3 and -6 activation was observed when the cells were stimulated by a combination of heat and cisplatin. The application of z-VAD-fmk, a general caspase inhibitor, showed that hyperthermia mediated cytotoxicity mainly via caspase-dependent mechanisms, while cisplatin induced both caspase-dependent and -independent cytotoxicity. Time kinetic experiments revealed that hyperthermia induced cell death immediately after the heating pulse. In contrast, cisplatin-induced cell death had its maximum between 6 hours and 12 hours after the heating pulse. The combined application of heat and cisplatin induced two peaks of cytotoxicity, one immediately after the heating pulse and the other between 6 hours and 12 hours., Conclusion: Hyperthermia and cisplatin induced cell death in T leukemic cells by different molecular mechanisms, which might explain the enhanced cisplatin-induced cytotoxicity by hyperthermia.

The prognosis of patients with early ALL (acute lymphoblastic leukaemia) relapse is poor with conventional chemotherapy alone. Thus, intensified chemotherapy strategies are required. The application of hyperthermia enhances the efficacy of certain antineoplastic drugs such as ifosfamide. In this study, the effects and molecular mechanisms of ifosfamide (4hydroperoxy-ifosfamide = 4OOH-IFA)- and/or hyperthermia-induced cell death are investigated in CEM cells. Hyperthermia enhanced the efficacy of 4OOH-IFA in a subaddictive manner. Analysis of caspase activation revealed an early hyperthermia-induced stimulation of caspase-3 and -6 directly after the heating pulse, while maximum activation following stimulation with 4OOH-IFA was obtained after 24 hours of culture. The combination of 4OOH-IFA and hyperthermia mediated an overaddictive caspase stimulation directly following the heating phase. At this time also an overaddictive cytotoxic effect was noticed, being mainly responsible for the enhancing effects of hyperthermia on 4OOH-IFA cytotoxicity. In conclusion, hyperthermia enhanced the cytotoxic effect of 4OOH-IFA on CEM cells by stimulation of an early 4OOH-IFA effect. Thus, thermochemotherapy might be considered as an intensifying treatment option in relapsed T cell leukemias.