Background and Objectives. Gemcitabine (dFdC) is a new nucleoside antimetabolite of deoxycytidine sat resembles cytarabine (Ara-C) in both its structure and metabolism. Little is known about dFdC efficacy in hematologic malignancies, either as a single drug or in combination with other drugs. In this study we have tried to determine whether the cytotoxic effect of Ara-C can be increased by using In combined therapy with dFdC. Design and Methods. in the in vivo part of our study, mice bearing L1210 or P388 leukemia were treated dFdC and Ara-C. The drugs were administered and in combination according to the following schedules: Ara-C and dFdC at the same time, dFdC before Ara-C, and Ara-C before dFdC. The efficacy of therapy against leukemia (defined as the ase in lifespan, ILS) was assessed as the percentage of the median survival time (MST) of the ted group (T) in relationship to that of the control group (C): ILS=[(MSTc/MSTT) -1]x100. In the in vitro part of our study, normal granulocyte-macrophage colony-forming unit (CFU-GM) cells as as CFU-GM cells obtained from patients with chronic myeloid leukemia (CML) were incubated either with dFdC or Ara-C alone or with adequate concentrations of a combination of these drugs. Results The in vivo experiment revealed that in both Is tested, combined therapy with dFdC given before Ara-C and dFdC given at the same time with Ara-C were more effective than monotherapy with either dFdC or Ara-C, The other treatment rule (Ara-C before dFdC) did not significantly,ng the survival time of the treated mice bearing L1210 or P388 leukemia as compared with treatment with dFdC alone. The in vitro experiments showed that dFdC used together with Ara-C acted additively on normal as well as CML CFU-GM cells. Furthermore, the drugs used jointly inhibited the growth of colonies formed by CML CFU-GM cells to a significantly higher degree than normal CFU-GM and the differences were statistically significant in the case of the combination of highest concentrations. Interpretation and Conclusions. Gemcitabine increased the activity of Ara-e. As these agents incorporate into DNA blocking chain elongation, and moreover, dFdC influences the cytotoxicity of Ara-C, our results could be explained by the drugs acting at these levels. dFdC used Jointly with Ara-C may have an important clinical implication in the treatment of CML and other hematologic malignancies in future. (C) 2000 Ferrata Storti Foundation.
