Corticosteroid alteration of carboplatin-induced hematopoietic toxicity in a murine model.
Corticosteroids exhibit extensive hematopoietic effects both in vitro and in vivo. Some of the previously studied effects suggested that corticosteroids may alter hematopoietic toxicity of chemotherapeutic agents. In this study, we examined (1) the optimum dose and schedule of cortisone acetate (CA) to reduce hematopoietic toxicity of carboplatin (CB) and (2) possible mechanisms involved in this protective effect. CA given subcutaneously at 0.5 mg/d per mouse for 7 days before CB reduced CB-induced mortality due to neutropenia from 88% in controls to 14% in CA-treated mice (P < .05). Lower CA doses were not effective. Three days of pretreatment (but not 1 day) was as effective as 7 days. CA given after CB had no effect on mortality. Pharmacokinetic studies of CA at 0.5 mg per mouse demonstrated blood levels of cortisol achievable in patients (peak level, 82 micrograms/dL). CA treatment markedly reduced spleen cell number and colony-forming units-granulocyte/macrophage (CFU-GM) as well as bone marrow CFU-GM. Bone marrow CFU-GM removed from CA-treated mice demonstrated increased resistance to platinum and increased resistance to high specific activity 3H-thymidine. These findings suggest that treatment of mice with CA induces cellular resistance of hematopoietic precursors to platinum and, thus, reduces CB hematotoxicity. CA or other corticosteroids may be useful in reducing clinical toxicity of CB.
Rinehart
J
J
Division of Hematology and Oncology, Scott & White Clinic and Memorial Hospital, TX 76508, USA.
Keville
L
L
Measel
J
J
Spiekerman
A M
AM
Burke
K
K
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D016190:Carboplatin / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003348:Cortisone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects*; D006854:Hydrocortisone / Q000097:blood; D007279:Injections, Subcutaneous; D051379:Mice; D008809:Mice, Inbred C3H; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control
D003520:Cyclophosphamide; D016190:Carboplatin; D002945:Cisplatin; D003348:Cortisone; D006854:Hydrocortisone