Influence of gemcitabine (2′,2′‐difluoro‐deoxycytidine) and 2‐chlorodeoxyadenosine on growth of normal and leukemic cellsin vitro

Abstract

The aim of the study was to investigate the influence of gemcitabine (2',2'-difluorodeoxycytidine, dFdC) used alone and in combination with 2-chlorodeoxyadenosine (2-CdA) on the colony growth of normal granulocyte-macrophage progenitor cells (CFU-GM) from 15 hematologically healthy donors as well as on CFU-GM from 15 chronic myelogenous leukemia (CML) patients in semisolid cultures in vitro. dFdC and 2-CdA were used either separately or in the following combinations of concentrations: (1) 0.25 nM of dFdC and 2.5 nM of 2-CdA; (2) 0.5 nM of dFdC and 5 nM of 2-CdA; (3) 1 nM of dFdC and 10 nM of 2-CdA; (4) 2 nM of dFdC and 20 nM of 2-CdA. We observed that both dFdC and 2-CdA used separately inhibited the growth of colonies formed by normal and CML CFU-GM cells in a dose-dependent manner. Moreover, the combined therapy with dFdC and 2-CdA caused statistically significant inhibition of the colony growth in both normal and CML CFU-GM cultures. In addition, the inhibition of CML CFU-GM colony formation was greater and statistically significant in the case of the combined therapy using higher concentrations of these drugs as compared with inhibition of the growth of normal CFU-GM colonies. These observations were the basis for the evaluation of the interaction type between dFdC and 2-CdA. We have shown that dFdC used in a combination with 2-CdA acts in an additive way on normal and CML CFU-GM cells.

Immunohistochemical evaluation of cell proliferation and apoptosis markers in ovarian surface epithelial cells of cladribine-treated rats

“…Individual publications concern the damage of skin cells and the mucous membrane that was brought about by cladribine (Chubar and Bennett 2003; Rossini et al 2004). Moreover, several publications also described the cytotoxic activity of cladribine on stem cells (Chow et al 2002; Lech-Marańda et al 2000; Petzer et al 1991). In a study on the impact of cytostatic drugs on cells at various stages of maturity, Chow et al showed that cladribine induces apoptosis in CD34 + /CD38 + progenitor cells (Chow et al 2002).…”

“…In a study on the impact of cytostatic drugs on cells at various stages of maturity, Chow et al showed that cladribine induces apoptosis in CD34 + /CD38 + progenitor cells (Chow et al 2002). Lech-Marańda et al observed the inhibition of granulocyte–macrophage progenitor cell growth, and Petzer et al observed the inhibition of T lymphocyte colony forming cells subject to cladribine (Lech-Marańda et al 2000; Petzer et al 1991). …”

Imatinib-Resistant CML Cells Have Low ENT Activity But Maintain Sensitivity to Gemcitabine

“…[6,7] These nucleoside analogs are transported into cells mainly through ENTs. To investigate whether imatinib-resistant cells showed reduced sensitivity to gemcitabine (structure shown in Figure 3a), we incubated 32Dp185 and 32Dp185 STI-R cells with 1 μM gemcitabine for 12 hours and performed MTT assays.…”

“…Current treatment approaches include the combination of treatments using imatinib and compounds such as interferon-α (IFN-α), hemoharringtonine (HHT) and nucleoside analogs such as cytarabine and gemcitabine. [5][6][7][8] Mammalian equilibrative nucleoside transporters (ENTs) are facilitative transporters broadly selective for pyrimidine and purine nucleosides and are essential for the modulation of nucleoside concentration and nucleoside analog availability. Uptake of clinically important nucleoside analogs (e.g., gemcitabine, capecitabine, cytarabine (ara-C)) is mediated primarily by Equilibrative Nucleoside Transporter 1 (hENT1) in human cells.…”

A new multidrug reinduction protocol with topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine for relapsed or refractory acute leukemia

“…[30][31] In vitro cytotoxicity data suggest that gemcitabine has significant activity in acute leukemias. [32][33][34] Furthermore, in clinical studies, either alone, [35][36][37][38] or in combination with other agents, 39,40 gemcitabine has activity against human leukemias.…”