Chemotherapeutic responses of marine myeloid leukemias
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The murine myeloid leukaemias employed in this study were induced in male CBA/H mice following irradiation with sublethal doses of X-ray. The responses of these leukaemic cell lines and normal (murine) bone marrow cells to cytosine arabinoside and mitoxantrone treatment in vitro were monitored. Both clonogenic, and nonclonogenic chemotherapeutic assays such as radioactive precursor uptake, dye-exclusion assay and autoradiography were employed to determine drug-induced cell lethality. In addition, the in vitro proliferative responses of the leukaemic cell lines and normal bone marrow cells to growth factors were determined using a [3H]thymidine uptake assay. Both cytarabine and mitoxantrone were as toxic to normal bone marrow cells as to leukaemic cells from most of the cell lines. Mitoxantrone appears to be more potent than cytarabine against leukaemic cells in vitro. However, it was also more toxic to normal bone marrow cells. Generally, combinations of cytarabine and mitoxantrone resulted in an additive cytotoxic effect. Mitoxantrone appears to have a narrow therapeutic margin when administered to leukaemia bearing mice in vivo. The response of the (SA7) myeloid leukaemic cell line to mitoxantrone was distinctly different from those reported for murine lymphoid leukaemias (P388 and L1210). Doubling the mitoxantrone dose within the therapeutic range was not accompanied by an increase in the number of long-term survivors (cures). Bone marrow cells of cured mice or normal(CBA/H) mice administered low doses of mitoxantrone became less sensitive to subsequent treatment with mitoxantrone in vitro . Doses of mitoxantrone that resulted in loss of protective effect by bone marrow cells of normal mice were toxic to leukaemia bearing mice. Primary and low cell dose transplant myeloid leukaemias were less responsive to growth factors as compared to the high cell dose passages. The SA2 leukaemic cell line grew in vitro without requirement for growth factors. However, no growth was observed in serum-free medium which suggests that serum was providing the stimulus for in vitro proliferation. Leukaemic bone marrow cells from the SA7 high cell dose passage cell line, were normally responsive to growth factors in vitro. However, at relapse following in vivo treatment with mitoxantrone, the leukaemic cells became significantly (P=0.04) growth factor insensitive. Bone marrow cells of normal mice retained growth factor sensitivity following in vivo treatment with mitoxantrone. Furthermore, bone marrow cells of mice cured of leukaemia by mitoxantrone treatment in vivo were responsive to growth factors. Recovery of growth factor responsiveness occurred when the recurrent leukaemic cells were passaged in normal mice. However, no recovery of growth factor sensitivity was observed when recurrent leukaemic cells were passaged in mice that received a single dose of mitoxantrone (0.75mg/Kg) two days previously. Even after passage in normal mice, the recurrent leukaemic cells were in some cases, significantly (P=0.012) resistant to mitoxantrone treatment in vitro. The degree of resistance appears to depend on the dose of mitoxantrone employed in the treatment of the leukaemia. However, passaging the recurrent leukaemia in mitoxantrone pretreated mice did not increase the level of resistance developed by the leukaemic cells. These results suggest that these myeloid leukaemic cell lines may be useful models for preclinical evaluation of chemotherapeutic agents.
Thesis, PhD Doctor of Philosophy
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