Mechanisms of hyperthermia- and 4-hydroperoxy-ifosfamide-induced cytotoxicity in T cell leukemia

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.