Use of marine toxins in combination with cytotoxic drugs for induction of apoptosis in acute myelogenous leukaemia cells.

Intensive chemotherapy for acute myelogenous leukaemia (AML) results in an overall long-term disease-free survival of < 50%. This percentage reflects an improved survival for certain subsets of patients with low-risk cytogenetic abnormalities after treatment with high-dose cytarabine, whereas lower long-term survival is seen for other patients and especially for the large group of elderly patients. New treatment strategies are therefore considered in AML and one approach is to target the regulation of apoptosis in AML cells with new pharmacological agents. Regulation of apoptosis seems to be clinically important in AML as intracellular levels of apoptosis-regulating mediators can be used as predictors of prognosis in AML. It is also well documented that cytotoxic drugs exert important antileukaemic effects through induction of apoptosis. Marine toxins represent new pharmacological agents with proapoptotic effects and should be considered for combination therapy with cytotoxic drugs. These agents are already useful laboratory tools for in vitro studies of AML cells but it is still too early to conclude whether they will become useful in clinical therapy. One of the major problems to be investigated is the toxicity of combination therapy, although this may be solved by the coupling of toxins to antibodies or growth factors with a preferential binding to AML cells. Other problems that have to be addressed are the possible effect of the toxins' tumour promoting effects on chemosensitivity in relapsed AML and the possibility of cross-resistance between cytotoxic drugs and toxins.