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.


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.
PharmaMar, Madrid, Spain.
Susana G
SG
Gómez
Juan A
JA
Bueren
Glynn T
GT
Faircloth
José
J
Jimeno
Beatriz
B
Albella
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides; D004149:Dioxoles / Q000633:toxicity*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D007546:Isoquinolines / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010455:Peptides / Q000633:toxicity*; D010456:Peptides, Cyclic / Q000633:toxicity*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D000970:Antineoplastic Agents; D047630:Depsipeptides; D004149:Dioxoles; D007546:Isoquinolines; D010455:Peptides; D010456:Peptides, Cyclic; D044005:Tetrahydroisoquinolines; C097897:kahalalide F; D000077606:Trabectedin; C098980:plitidepsin