Tumor hypoxia is associated with poor clinical outcome in a variety of
tumors, including cervical, head/neck and
breast cancer. Administration of erythropoietic factors has been suggested as a means of improving
tumor oxygenation (pO2). This study randomized rats to treatment with low-dose or high-dose
darbepoetin alfa or a placebo to determine the effect of
darbepoetin alfa on the pO2, growth and response to
radiation therapy of R3230 mammary
adenocarcinoma. Rats received 3 microg/kg (high dose) or 0.2 microg/kg (low dose)
darbepoetin alfa or placebo for eight doses prior to either (1) pO2 measurement and
pimonidazole staining or (2) irradiation or
sham irradiation on post-transplant day 20. In the animals randomized to
radiation treatment, placebo or
darbepoetin alfa administration at a reduced dose was continued for 9 weeks or until the
tumor diameter exceeded 15 mm (defined as failure for survival analysis). Treatment with high-dose and low-dose
darbepoetin alfa produced hematocrits of 68 and 56% compared to 44 and 45% in their respective control groups (both P < 10(-5)). At 18 days post-transplant,
tumor volume was not different for either
darbepoetin alfa group compared to the placebo group.
Tumor oxygenation, as measured by the fraction of pO2 measurement <10 mmHg and the intensity of
pimonidazole staining, was significantly improved in the high-dose group (P = 0.046 and 0.03, respectively, compared with controls) but not in the low-dose group. Growth delay curves after irradiation did not differ significantly for high- or low-dose
darbepoetin alfa compared to placebo. In this nonanemic animal model of mammary
adenocarcinoma,
darbepoetin alfa does not significantly alter
tumor growth or radioresponsiveness, even though it improves oxygenation when administered at high doses.