5-FU arrestes cells in S phase, and is not specific for just cancer cells. So normal HSCs cycling at the same time as chemo is given will be hit along with the cancer - resulting in cytopenias. In general most of the older chemotherapeutic drugs are not very targeted or specific and generally kill the most actively cycling cells through a variety of mechanisms, which unfortunately includes HSC in the bone marrow. Although newer targeted therapies will hopefully reduce the incidence of side effects such as cytopenia, the older drugs are still the cornerstone of therapy in most chemotherapeutic regimes.

@ Emmet. Thanks for the response. I suppose that arrest is may not be "toxic" per se however it is continued arrest that triggers a "stress" response of some type? Possibly then triggering pyroptosis (caspase-1 dependent death). These thoughts all came about because of the Masters et al. paper in Immunity last Dec 2012 demonstrating that HSCs in 5-FU treated animals die by pyroptosis leading to cytopenia. It really has me thinking as we work with pyroptosis models. // Newer drugs as you say all hold promise but will be balanced by cost/predicted patient outcomes by health care providers. Private or public. Probably a different thread there. :-)

Dear Colleagues,

Hematopoietic cells have limited lives; they need to be replenished. If they don't you will get cytopenias. There could be a number of mechanisms that would cause the replenishment to be slower than the death rate. Bone marrow microenvironment may be damaged; progenitor cells of different maturation stages might be affected. There are numerous combinations of numerous factors that play a role. In a patient receiving chemotherapy, acute neutropenias that occur usually within about 2-3 weeks after chemotherapy cannot be attributed to damage of HSC. Because that would take much longer. For acute neutropenias to occur, you need to have damage at the level of their precursors such that they can 1. no longer differentiate or 2. die and can no longer proliferate. In other words, the dama ge would be at the level of myeloid precursors, including myeloblasts, promyelocytes, and myelocytes.

Please remember that high proliferative activity is not a stemness feature. Indeed, the fact that most patients receiving heavy chemotherapy eventually recover from their neutropenia or pancytopenia shows that their HSC escaped the chemotherapy. In large part that is because these cells are in the non-cycling G0/1 pool.

In summary, the key take home messages are:

1. Chemotherapy induced cytopenias occur relatively fast and they are not caused by HSC damage

2. HSC are relatively resistant to chemotherapy that attacks mitotic cells

3. Most HSC are non-cycling