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 m arrow toxicity induced by antitumor drugs. This MPA myeloprotection ha s been attributed to an arrest of hematopoietic progenitors in a quies cent phase, although no in vitro studies have demonstrated such an eff ect of MPA. Human bone marrow cells were preincubated for 3 days with MPA (100 ng/mL) and then exposed to sublethal doses of adriamycin; LD( 50) was significantly increased in MPA-preincubated cells (896 +/- 172 ng/mL) vs. control cells (162 +/- 37 ng/mL); this protective effect o f MPA was shown to be more efficient against S-phase-specific drugs su ch as 5-fluorouracil (5-FU) than against non-phase-specific drugs such as cisplatin. MPA did not protect several human leukemic cell lines f rom the cytotoxic action of adriamycin. ''Suicide'' assays showed that the percentage of myeloid progenitor cells (granulocyte-macrophage co lony-forming units [CFV-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 cycl e arrest of hematopoietic precursors, protecting them from the toxicit y of chemotherapy.