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Evaluation of the effect of medroxyprogesterone acetate on bone marrow progenitor cells
P Pedrazzoli1, G Bacciocchi, G A Da Prada
1Divisione di Oncologia, Fondazione Clinica del Lavoro, Pavia, Italy.
Abstract:
Various clinical studies have demonstrated that high-dose medroxyprogesterone acetate (HD-MPA) can reduce hematologic toxicity in patients receiving chemotherapy for advanced solid tumors. The underlying mechanism(s) of this action is still unknown. A direct effect of MPA on hemopoietic cells has been postulated, but in vitro studies have given contradictory results. To clarify the biologic activity of MPA on hemopoiesis we have evaluated in vitro growth of pluripotent and committed progenitor cells from bone marrow cells which were preincubated in vitro with various doses of MPA and subsequently treated with or without the S-phase-specific drug arabinoside-cytosine (Ara-C). Four healthy subjects and 8 patients with advanced stage solid tumors with no bone marrow involvement were studied. In our experimental model we did not observe any effect of MPA on Ara-C killing of progenitor cells from either bone marrow mononuclear cells or bone marrow mononuclear cells depleted of T-lymphocytes and adherent cells. These results suggest that MPA does not act directly (or indirectly through the production of cytokines by T-lymphocytes and/or monocytes and macrophages) on bone marrow progenitors. In addition, the supposed mechanism of rendering stem cells less susceptible to the insult of cytotoxic drugs by lowering the number of progenitors in the S-phase has been ruled out by cell kinetic studies.
Insights
High-dose medroxyprogesterone acetate (HD-MPA) does not directly protect bone marrow progenitor cells from chemotherapy. This study found no evidence that HD-MPA influences chemotherapy
Area of Science:
- Hematology
- Pharmacology
- Oncology
Background:
- High-dose medroxyprogesterone acetate (HD-MPA) is clinically observed to reduce chemotherapy-induced hematologic toxicity in advanced solid tumors.
- The precise mechanisms underlying HD-MPA's protective effects on hematopoiesis remain unclear.
- Previous in vitro studies investigating medroxyprogesterone acetate (MPA)'s direct impact on hemopoietic cells have yielded conflicting results.
Purpose of the Study:
- To investigate the in vitro biologic activity of MPA on hemopoiesis.
- To determine if MPA directly affects the growth of pluripotent and committed progenitor cells.
- To assess MPA's influence on the efficacy of the S-phase-specific chemotherapy drug, arabinoside-cytosine (Ara-C).
Main Methods:
- Bone marrow cells from healthy subjects and cancer patients were preincubated with various doses of MPA.
- Cells were subsequently treated with or without Ara-C.
- In vitro growth of pluripotent and committed progenitor cells was evaluated.
- Cell kinetic studies were performed to assess S-phase activity.
Main Results:
- MPA did not demonstrate any effect on the killing of progenitor cells by Ara-C.
- This lack of effect was observed in both whole bone marrow mononuclear cells and those depleted of T-lymphocytes and adherent cells.
- Cell kinetic studies ruled out MPA's proposed mechanism of reducing S-phase progenitors to enhance resistance to cytotoxic drugs.
Conclusions:
- MPA does not appear to directly impact bone marrow progenitor cells.
- MPA's protective effect against chemotherapy-induced hematologic toxicity likely does not involve direct action on progenitor cells or indirect modulation via T-lymphocytes or myeloid cells.
- The findings suggest alternative mechanisms, not involving direct progenitor cell interaction, are responsible for HD-MPA's observed clinical benefits.