Amifostine improves the antileukemic therapeutic index of mafosfamide: implications for bone marrow purging.
One of the principal challenges of cancer chemotherapy is the relative inability of most anticancer drugs to distinguish between normal and neoplastic tissues. Consequently, a broad range of toxicities are experienced by patients, especially myelosuppression. Amifostine, a phosphorylated aminothiol, increases the selectivity of specific anticancer drugs for neoplastic cells by protecting normal tissues. One potential application of this protector is during bone marrow purging to selectively remove contaminating cancer cells. This study took normal or leukemic marrow from human subjects and evaluated the ability of amifostine to selectively protect normal bone marrow progenitor cells versus leukemic progenitor cells from the cytotoxic effect of mafosfamide. The dose response of mafosfamide amifostine on leukemia colony-forming units or normal marrow progenitor cells was determined and the LD95 was calculated. Amifostine pretreatment resulted in a statistically significant protection of granulocyte-macrophage colony-forming units and erythroid blast-forming units from the toxicity of mafosfamide (P = .031). Thus, amifostine protection of normal marrow progenitor cells allows a higher LD95 concentration of mafosfamide to be used in ex vivo purging. In contrast, amifostine pretreatment increased the cytotoxicity of mafosfamide on the fresh human leukemia progenitor cells (P = .006). The dual effect of amifostine protection of normal marrow progenitor cells coupled with amifostine-induced sensitization of the leukemia cells increases the possible cell-kill of leukemic stem cells. With amifostine pretreatment, at the LD95 concentrations of mafosfamide for marrow progenitor cells, there was an estimated 6 log increase in cell-kill of the leukemia cells. This selective cell-kill offers the potential for lowering the incidence of leukemic relapse, while preserving more normal stem cells for autologous transplantation.
Douay
L
L
Laboratoire d'hématologie, Hôpital d'enfants Armand Trousseau, Paris, France.
Hu
C
C
Giarratana
M C
MC
Bouchet
S
S
Conlon
J
J
Capizzi
R L
RL
Gorin
N C
NC
D004999:Amifostine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001853:Bone Marrow / Q000473:pathology; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation; D016923:Cell Death; D003520:Cyclophosphamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000473:pathology* / Q000628:therapy; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D014182:Transplantation, Autologous
D000970:Antineoplastic Agents; C048341:mafosfamide; D003520:Cyclophosphamide; D004999:Amifostine