Long survival of leukemic mice by repeated combination treatment of cyclophosphamide and recombinant human granulocyte colony-stimulating factor.
The therapeutic and hematological effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in combination with cyclophosphamide (CY) were investigated in a murine myeloid leukemia model. Ten daily administrations of rhG-CSF following CY prolonged the survival time of leukemic mice more than either agent alone. Hematological examination indicated that this effect was attributable to suppression with rhG-CSF of the leukemic repopulation after CY injection. In addition, rhG-CSF accelerated recovery from CY-induced neutropenia. Based on these hematological changes, a treatment regimen was established consisting of a single injection of CY on day 1 and daily injections of rhG-CSF on days 2-6; this combination treatment was given to the leukemic mice for up to four cycles, with a pause of one day between each cycle. The leukemic mice completed each cycle of treatment with few failures, and it resulted in a long survival time for the leukemic mice. The mean survival time of the mice receiving four cycles of treatment was 47 days, 30 days longer than that of the untreated mice. Hematological examination performed at the end of each cycle showed that the leukemic cell population was controlled at a level equal to or below the pre-treatment level, and peripheral blood neutrophils were maintained at a level equal to or above the normal level. These results indicate the possible effectiveness of combining rhG-CSF with chemotherapeutic drugs in controlling leukemic cell growth, and the effectiveness of rhG-CSF in enhancing neutrophil recovery after chemotherapy. However, it was found that the leukemic cells became resistant to treatment with rhG-CSF after four cycles of combination treatment, suggesting that great care should be taken in the clinical application of rhG-CSF, even when the growth of acute myelogenous leukemia cells is not apparently stimulated by it.
Tamura
M
M
Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical Co. Ltd, Shizuoka, Japan.
Nomura
H
H
Ono
M
M
Bessho
M
M
Hirashima
K
K
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000166:cytology; D011994:Recombinant Proteins / Q000008:administration & dosage; D016019:Survival Analysis
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide