Ways of minimising hematopoietic damage induced by radiation and cytostatic drugs--the possible role of inhibitors

Abstract

Acute and chronic bone marrow toxicities are the major limiting factors in the treatment of cancer. They are related to two factors. (i) The first is a decrease in the number of hematopoietic stem cells and progenitors caused by both a lethal effect of cytotoxic agents on these cells and by differentiation of stem cells provoked by a feed-back mechanism, itself induced by the depletion of more mature marrow compartments. (ii) The second factor is a reduction in self-renewal capacity of stem cells, which is also related to both direct (mutation) and indirect (ageing of stem cell population) effects. Stimulators and inhibitors of bone marrow kinetics play a prominent role in the induction of damage and recovery patterns. Acute effects can be circumvented by an increase in the number of cell divisions in the more mature compartments. This amplification is enlarged by the administration of hemopoietic growth factors which enhance regeneration and shorten the duration of blood aplasia. However, these stimulators may contribute to the exhaustion of the stem cell pool and they may increase the severity of late effects. Protection against chronic effects is difficult; however, the ability to 'switch on' and 'switch off' proliferation opens new avenues which are currently being explored. In particular, inhibitors may protect stem cells against early and late damage by maintaining them in a quiescent state during a course of radiotherapy or chemotherapy. Several inhibitors of hematopoietic stem cell proliferation have been identified during the past 5 years. AcSDKP (Seraspenide) was the first to be isolated and its protective effects against cytotoxic agents were described over a decade ago in mice. Its physiological role is now well established in mouse and man. Preliminary results of a Phase I-Phase II clinical trial strongly suggest that it may have a useful clinical role. Further research is necessary to assess the long-term protective effects of this new family of regulators.