Tipifarnib  (Synonyms: IND 58359; R115777)

Steroid-depleted cells are seeded into 12-well plates at a density of appr 1×10⁴ cells per well or into 96-well plates at a density of 4,000 cells per well, in dextran-coated charcoal medium. After 24 h, monolayers are treated with E2 plus inhibitors either alone or in combination. The 12-well plates are treated for 6 days with daily changes. Cell number is then determined using a Z1 Coulter counter. The 96-well plates are treated with a single dose and left for 96 h at which time cell viability is measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay as described previously. The interaction between Tipifarnib and 4-OH-ICI 47699 is analyzed by the median effect plot method described by Chou and Talalay. Calculation of the combination index took into account a nonfixed drug ratio and is based on the assumption that the action of the two drugs is mutually nonexclusive for the strict detection of synergism. A combination index < 1 indicates synergism, combination index=1 indicates additivity, and a combination index > 1 indicates antagonism. Experiments are repeated thrice.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Female ovariectomized Ncr foxhead nude mice are kept under sterile conditions with free access to food and water. MCF-7 xenografts are initiated by implantation of 2-mm diameter tumor fragments from established tumors. Once tumors reach a diameter of appr 7 mm, mice are randomized to receive vehicle [20% w/v β-cyclodextrin (pH 2.5) for Tipifarnib, 50% PEG 300, 50% H₂O + 1 drop 1N HCl per 3 mL for ICI 47699], Tipifarnib (50 mg/kg twice daily), ICI 47699 (20 mg/kg), or a combination of both Tipifarnib and ICI 47699. Two further treatment arms are used to assess the effect of E2 withdrawal (removal of the E2 pellet) or E2 withdrawal combined with Tipifarnib (50 mg/kg twice daily). All drugs are given by oral gavage daily for 5 consecutive days followed by a 2-day rest period, for a total of 19 days. The experiment is done twice giving similar results; therefore, the growth data are combined for statistical analysis. There are six tumor-bearing animals in each group and all tumors are harvested on day 19. Tumor volumes are calculated using the formula a × b² × π/6, where a and b are orthogonal tumor diameters and expressed as a percentage of the volume at the start of treatment (relative tumor volume). Overall statistical difference is calculated using the Kruskal-Wallace test and statistical differences between individual treatment arms are calculated using the Mann-Whitney test.

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

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