Cell cycle arrest of human hematopoietic progenitors induced by medroxyprogesterone acetate.
Clinical studies have shown that continuous or intermittent scheduled administration of medroxyprogesterone acetate (MPA) reduces the bone marrow toxicity induced by antitumor drugs. This MPA myeloprotection has been attributed to an arrest of hematopoietic progenitors in a quiescent phase, although no in vitro studies have demonstrated such an effect of MPA. Human bone marrow cells were preincubated for 3 days with MPA (100 ng/mL) and then exposed to sublethal doses of adriamycin; LD50 was significantly increased in MPA-preincubated cells (896 +/- 172 ng/mL) vs. control cells (162 +/- 37 ng/mL); this protective effect of MPA was shown to be more efficient against S-phase-specific drugs such as 5-fluorouracil (5-FU) than against non-phase-specific drugs such as cisplatin. MPA did not protect several human leukemic cell lines from the cytotoxic action of adriamycin. "Suicide" assays showed that the percentage of myeloid progenitor cells (granulocyte-macrophage colony-forming units [CFU-GM]) in S-phase was significantly reduced from 67 +/- 2.5% (control cells) to 38 +/- 5.5% (24-hour MPA-preincubated cells). These results demonstrate in vitro that MPA exerts a cell cycle arrest of hematopoietic precursors, protecting them from the toxicity of chemotherapy.
Quesada
A R
AR
Antibióticos Farma, Research and Development, Madrid, Spain.
Jimeno
J M
JM
Márquez
G
G
Aracil
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004317:Doxorubicin / Q000493:pharmacokinetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000473:pathology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004317:Doxorubicin; D017258:Medroxyprogesterone Acetate