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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 ceil kinetic studies.

Aims and background Dose intensification of chemotherapy is associated with increased response rates in advanced breast cancer. Achievement of dose incrementation is usually limited by drug-dependent bone marrow toxicity. The recent availability of recombinant human colony-stimulating factors (CSFs) have made it possibile to evaluate their potential in ameliorating chemoterapy-induced myelosuppression. The aim of this study was to evaluate tolerability and effectiveness of an intensified mitoxantrone, methotrexate and mitomycin-C (3M) regimen, given with G-CSF support in patients with advanced breast cancer (ABC).Study design Twenty-eight eligible patients with advanced breast cancer were treated with mitomycin -C (7 mg/sqm iv every 4 weeks), methotrexate (35 mg/sqm iv) and mitoxantrone (7 mg/sqm iv every 2 weeks) for 6 cycles. Recombinant human granulocyte colony-stimulating factor (r-HuG-CSF, Filgrastim) (5 μg/kg/day) was given subcutaneously from day 2 to day 12 after each chemotherapy administration to prevent leukopenia.Results Of the 27 evaluable patients, 4 had complete response and 14 achieved partial response; the overall response rate was 63% (95% Cl; 46.8%-82.2%). The median duration of response was 8 months (range, 4-13+). Chemotherapy-related toxicity was mild: only 3 out of 163 courses had to be postponed due to myelotoxicity.Conclusions The 3M regimen given at 2- week intervals is a feasible, active and well toleratel treatment in patients not previously treated for metastatic breast cancer.