In vitro toxicity of three new antitumoral drugs (trabectedin, aplidin, and kahalalide F) on hematopoietic progenitors and stem cells.

OBJECTIVE: In addition to neutropenias and/or thrombocytopenias as a short-term effect, antineoplastics also can produce long-term effects as a consequence of damage to the hematopoietic stem cells. The aim of the present study was to evaluate the toxicity of three marine-derived antineoplastics on murine hematopoietic stem cells. These antitumoral compounds currently are being evaluated in patients in phase II (aplidin and kahalalide F) and phase II/III (trabectedin) clinical trials.
MATERIALS AND METHODS: Long-term competitive repopulating assays were performed in mice to analyze toxic effects on the hematopoietic stem cells responsible for the multipotential long-term repopulation of hematopoiesis. Furthermore, granulocytic and T- and B-lymphoid lineages were studied, as well as myeloid (CFU-GM) and megakaryocytic (CFU-Meg) progenitors.
RESULTS: When cells were treated in vitro for 24 hours with CFU-GM IC(50) dose of trabectedin (9.59+/-4.96 nM), no significant effects were observed in the stem cells. The dose of trabectedin that produced 90% of inhibition in CFU-GM (IC(90): 23.71+/-1.27 nM) only inhibited 45% survival of stem cells. Doses of aplidin that produced reductions of 50% (56.9+/-13.32 nM) or 90% (195.88+/-21.39 nM) in myeloid progenitors did not show any effect on hematopoietic stem cells. Kahalalide F did not show any toxic effect in either short-term or long-term repopulating cells up to 10 microM.
CONCLUSIONS: Our data show that the hematopoietic stem cells effects of antitumoral drugs can be properly characterized by the murine competitive repopulating assays. Our results suggest that long-term myelosuppression as a consequence of trabectedin, aplidin, or kahalalide F treatment would not be expected.