Tipifarnib

Using Tipifarnib 5 μM for 72 hours, the percentage of apoptotic cells is significantly higher in drug-treated compared to DMSO-treated LGL T-cells. Using T-cells from healthy donors, Tipifarnib reduces the percentage of IFNγ-positive cells in a time-dependent manner. Tipifarnib reduces the amount of activated Ras in precipitates compared to DMSO. ^[2] Tipifarnib exerts selective in vitro toxicity against clonal MDS hematopoiesis at concentrations less than 10 nM the effect being more prominent in white cell progenitors. This action is not due to apoptosis induction as both normal and MDS progenitors displays equivalent DiOC3 and annexin V expression up to 72 hours after exposure to Tipifarnib. ^[3] Combining Tipifarnib with 10 nM 4-OH-ICI 46474 in the presence of E2 reduces the IC50 8-fold from 400 to 50 nM. ^[4] Tipifarnib induces apoptosis in U937 cells. ^[5] In addition, Tipifarnib inhibits isolated human farnesyltransferase for a lamin B peptide and for the K-RasB peptide with IC50 of 0.86 nM and 7.9 nM, respectively. ^[6]

Ki-67 is lower in the tumors treated with E2 withdrawal plus R115777 compared with E2 withdrawal alone. The combination of ICI 46474 and R115777 results in significantly lower Ki-67 compared with either ICI 46474 or R115777 alone (mean of 5% versus 16.9% and 67.3%, respectively). ^[4] In contrast, no significant difference in apoptotic scores is seen between the treatment groups. R115777 alone also reduces the CTI compared with control. The combination of ICI 46474 and R115777 or R115777 coupled with E2 withdrawal is most effective at lowering the CTI (0.8 and 0.7, respectively), which may account for the decrease in tumor volume. ^[4]

• Cell lines

  MACS-selected CD34+ cells

• Concentrations

  2.5 nM, 10 nM, 25 nM and 50 nM

• Incubation Time

  48 hours

• Method

  MACS-selected CD34+ cells are seeded in Methocult 4435 'complete' 1% bovine serum albumin, 3 U/mL recombinant human (rh) erythropoietin, 0.1 mM 2-mercaptoethanol, 2 mM L-glutamine and the following cytokines: 50 ng/mL rh stem cell factor, 20 ng/mL rh GM-CSF, 20 ng/mL rh IL-3, 20 ng/mL rh IL-6 and 20 ng/mL h G-CSF. DMSO or Tipifarnib is added at the concentrations of 2.5, 10, 25 and 50 nM at day 1. All cultures are performed in duplicates and the numbers of colonies are scored after 14 days of incubation at 37 °C in a humidified incubator containing 5% CO₂

• Animal Models

  Female ovariectomized Ncr foxhead nude mice

• Dosages

  50 mg/kg

• Administration

  Oral gavage