The interaction of gemcitabine and cytarabine on murine leukemias L1210 orP388 and on human normal and leukemic cell growth in vitro

Background and Objectives. Gemcitabine (dFdC) is a new nucleoside antimetab olite of deoxycytidine sat resembles cytarabine (Ara-C) in both its structu re and metabolism. Little is known about dFdC efficacy in hematologic malig nancies, either as a single drug or in combination with other drugs. In thi s study we have tried to determine whether the cytotoxic effect of Ara-C ca n 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 thera py against leukemia (defined as the ase in lifespan, ILS) was assessed as t he percentage of the median survival time (MST) of the ted group (T) in rel ationship to that of the control group (C): ILS=[(MSTc/MSTT) -1]x100. In th e 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 wi th adequate concentrations of a combination of these drugs. Results The in vivo experiment revealed that in both Is tested, combined th erapy 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 othe r 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 tr eatment with dFdC alone. The in vitro experiments showed that dFdC used tog ether with Ara-C acted additively on normal as well as CML CFU-GM cells. Fu rthermore, the drugs used jointly inhibited the growth of colonies formed b y CML CFU-GM cells to a significantly higher degree than normal CFU-GM and the differences were statistically significant in the case of the combinati on of highest concentrations. Interpretation and Conclusions. Gemcitabine increased the activity of Ara-e . As these agents incorporate into DNA blocking chain elongation, and moreo ver, dFdC influences the cytotoxicity of Ara-C, our results could be explai ned by the drugs acting at these levels. dFdC used Jointly with Ara-C may h ave an important clinical implication in the treatment of CML and other hem atologic malignancies in future. (C) 2000 Ferrata Storti Foundation.