Many studies focus primarily on hematopoietic parameters after chemotherapy. For example, HuG-CSF accelerated granulopoietic recovery after cyclophosphamide in mice (120) and rats (121), after etoposide in mice (122), and after mitoxantrone and cyclophosphamide combination therapy in dogs (123). Animal models can allow evaluation of novel approaches to scheduling and drug delivery. The effectiveness of rectal administration of G-CSF by suppositories has been shown in cyclophosphamide-treated rabbits (124).
Scheduling issues can be more readily evaluated in animal models than in patients, particularly when theoretical risks exist. The risks and benefits of different schedules of exogenous G-CSF administration before and after a cyclophosphamide dose have been studied in mice (125). Exogenous G-CSF administration immediately before chemotherapy and continued after chemotherapy accelerated neutrophil recovery, although neutrophil nadirs were lower than with other schedules. Exogenous G-CSF administration stopping several days before therapy and restarting after chemotherapy resulted in the greatest granulopoietic effect. The effect of exogenous G-CSF to minimize the interval between cyclophosphamide administrations has been studied (126). Another scheduling evaluation showed that with exogenous G-CSF administration through 7 d of etoposide therapy, protection from neutropenia could still be achieved (122). A comparison of the granulopoietic effects of pegfilgrastim and filgrastim after 5-FU effectively addressed a scheduling issue (103).
More sophisticated studies have modeled the infective complications of chemotherapy. To model culture-positive febrile neutropenic complications of chemotherapy, cyclophosphamide-treated mice were treated with intraperitoneal exogenous G-CSF for 4 d and challenged with bacterial and fungal pathogens (P. aeruginosa, Serratia marcescens, Staphylococcus aureus, C. albicans) (127). This short G-CSF treatment protected mice from otherwise lethal inoculums of these pathogens, and synergism with antibiotics was demonstrated for P. aeruginosa infections. Another study assessed the effects of exogenous G-CSF and antibiotics in vancomycin-resistant Enterococcus faecalis-infected mice (128). Cyclophosphamide was administered to induce neutropenia, E. faecalis was inoculated, and then exogenous G-CSF was administered either alone or with antibiotics in various doses. The combination of exogenous G-CSF and antibiotics was more effective at enhancing survival than either antibiotic or exogenous G-CSF alone. Beneficial effects of G-CSF on the course of Gram-positive infections have been documented after cyclophosphamide administration in mice (129); interestingly, this study did not find comparable effects after irradiation.
Animal models are useful for evaluating novel agents in combination with or compared with HGF. SCH 14988 is a small molecule that enhances endogenous G-CSF production; it accelerated neutrophil recovery after cyclophosphamide administration in association with increased G-CSF concentrations (130). In combination with exogenous G-CSF, dipyridamole and adenosine monophosphate enhanced post-5-FU granu-lopoietic recovery (131).
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