Experimental study on effect of the timing of rhG-CSF administration on neutropenia induced by cyclophosphamide

We evaluated effect of the timing of recombinant human granulocyte colony stimulating factor (rhG-CSF) administration on neutropenia in mice induced by cyclophosphamide (CPA). The schedule of rhG-CSF injection in relation to CPA administration was designed as follows: Treatment with rhG-CSF after CPA administration (post-treatment group), treatment with rhG-CSF both before and after CPA administration (pre- and post-treatment group, this group was divided into another 3 groups depending on pre-treatment schedule). As a control, only CPA injection without rhG-CSF. Comparative study was performed according to neutrophil counts in peripheral blood and expansion of granulocyte colony-forming progenitor cells (granulocyte progenitor cells). 1. In post-treatment group as well as in pre- and post-treatment group, recovery of neutrophil counts were promoted and duration of neutropenia was shortened compared with control. 2. By administration of CPA, all of the S-phase granulocyte progenitor cells were injured and only a part of granulocyte progenitor cells outside the S-phase survived in all groups. 3. By administration of rhG-CSF for 2 days, suicide rate rose as rhG-CSF administration continued and began to decline 2 days after discontinuation of rhG-CSF. Subsequently, there was the lowest fall in number of granulocyte progenitor cells outside the S-phase 1 day after discontinuation of rhG-CSF and highest peak 3 days after discontinuation of rhG-CSF. 4. Among pre- and post-treatment groups, nadirs of granulocyte progenitor cells and neutrophil counts were decreased more than those of control, when CPA was administered 1 day after pretreatment. In contrast, when CPA was administered 3 days after pretreatment, nadirs of granulocyte progenitor cells and neutrophil counts were apparently increased, severity of neutropenia seemed to be reduced of all groups. These results suggested as follows: (1) Neutrophil counts after CPA were influenced by number of granulocyte progenitor cells outside the S-phase when CPA was administered; (2) Suitable pretreatment schedule might be more effective than post-treatment with rhG-CSF. Expansion of granulocyte progenitor cells seems to be related to neutropenia induced by chemotherapeutic agents and should be taken into consideration when evaluating the timing of rhG-CSF administration on neutropenia.