A murine high-dose therapylstem cell support model is described using female BALB/c mice bearing the EMT-6 mammary carcinoma. Peripheral blood cells were prepared in syngeneic donor animals mobilized by treatment with cyclophosphamide and rhG-CSF. The most effective support regimen includes administration of fluid by gavage, rhG-CSF twice per day for I 2 days and peripheral blood cells administered i.v. on the day after cytotoxic therapy. Dose escalations of 2.2-to 13-fold over the usual conventional dose were possible in mice treated with single doses of cyclophosphamide, carmustine, melphalan, thiotepa, carboplatin or total body radiation, which compare favorably with dose escalations achievable in humans. Depletion and recovery rates of white blood cells and granulocytes in the mice were similar to those seen in humans. Rapid weight loss is a major factor in limiting further dose escalation. Single high-dose therapy with cyclophosphamide, melphalan, thiotepa and carboplatin, but not 5-fluorouracil, produced longer tumor growth delays than standard regimens of the same drugs. For melphalan and thiotepa, there was a direct correlation between drug dose, tumor growth delay and tumor surviving fraction. With cyclophosphamide, the tumor growth delay with high-dose therapy was greater than expected from the dose increase and the tumor surviving fraction data.o 1996 Wiley-Liss, Inc.From quantitative studies of "log" tumor cell killing in murine L1210 and P388 leukemias, Schabel recognized that "undertreatment" was the most likely reason for variability in regression rates/cure in established disease (Schabel et al., 1983;Teicher, 1992). As the importance of dose has become established clinically, SO has the ability to support critical normal tissues advanced. Clinical response rates in breast cancer and small cell lung cancer have improved with high-dose/ marrow support regimens; however, remaining disease often prevents tumor cure.The earliest in vivo pre-clinical tumor models were leukemias grown as ascites tumors. The end-point of experiments with these tumors was most often increase in life-span. As solid tumor models were developed, the appropriate end-points devised were tumor regressionlgrowth delay or control of a primary implanted tumor. These assays require that drugs be administered at doses producing tolerable normal tissue toxicity so that the response of the tumor to the treatment could be observed for a relatively long period of time. These end-points cannot be applied to the high-dose setting in which normally lethal doses of anti-cancer therapies can be administered with normal tissue support, such as bone marrow transplantation. Response to high-dose therapies has been assessed by use of excision assays (Teicher, 1992).One important difference between excision assays and the in situ assays of increase in life-span, tumor regression/growth delay or local tumor control is that excision assays require removal of the tumor from the environment in which it was treated. This difference and the nature of ...
