The effect of darbepoetin alfa on growth, oxygenation and radioresponsiveness of a breast adenocarcinoma.
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.
Kirkpatrick
John P
JP
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA. jkirk@radonc.duke.edu
Hardee
Matthew E
ME
Snyder
Stacey A
SA
Peltz
Catherine M
CM
Zhao
Yulin
Y
Brizel
David M
DM
Dewhirst
Mark W
MW
Blackwell
Kimberly L
KL
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D017024:Chemotherapy, Adjuvant; D000068256:Darbepoetin alfa; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000528:radiation effects; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate; D016896:Treatment Outcome
D011838:Radiation-Sensitizing Agents; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D010100:Oxygen