Anemia, although a common accompaniment of cancer, is not usually viewed as an acute complication of myelotoxic chemotherapy, although it is well recognized that chemotherapeutic agents and regimens are associated with anemia, particularly with multiple dosings or repeated courses. Recombinant EPO preparations were effectively the first HGF to be evaluated for their ability to stimulate hematopoietic recovery in murine models, e.g., after irradiation (136) or 5-FU (137). Relatively few animal studies have directly examined the effects of exogenous EPO administration along with chemotherapy, although the role of exogenous EPO in alleviating the anemia associated with cancer and its treatment is well established (138).

One particularly interesting study in mice combined 7 d of etoposide (VP-16) therapy with simultaneous exogenous EPO administration. At lower VP-16 doses with exogenous EPO, higher reticulocytes and hematocrits were observed, but overall a negative interaction between VP-16 and exogenous EPO was evident: VP-16 had a larger antierythropoietic effect in EPO-treated compared with non-EPO-treated animals (122). Although combining this relatively non-cell cycle-specific agent with a lineage-specific growth factor resulted in net advantageous outcome over part of the chemotherapeutic agent's dose range, in fact over all doses, growth factor stimulation of erythropoiesis was found to occur but was largely cancelled out by the abrogative effect of concomitant cytotoxic drug administration.

A number of recent animal studies have focused on the effect of EPO-stimulated anemia alleviation to improve the anticancer efficacy of chemotherapeutic agents including cyclophosphamide (139) and cisplatin (140), of radiotherapy (141,142), and of phototherapy (143). These beneficial effects are thought to result from improved oxygen delivery to tumors resulting in sensitization to the cytotoxic modality. In one instance, a murine myeloma model, exogenous EPO itself was observed to stimulate immunologically mediated tumor regression (143,144).

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