Table 2.

Reversal of drug resistance in topotecan-selected mouse MEF3.8/T6400 cells and human IGROV1/T8 cells by FTC analogue Ko143

Values shown were derived from quadruplicate repeats. Ko143 was applied at zero, one, or eight times the EC90 concentration of 25 nm. The IGROV1 and IGROV1/T8 lines were assayed in the presence of 0.1 μm PSC833 to suppress confounding P-gp activity. RFs are calculated relative to the parent cell line in the absence of Ko143.

Drug + InhibitorMean IC50 (nm) ± SD and (resistance factor)
MEF3.8 (parent)MEF3.8/T6400 (resistant)IGROV1 (parent)IGROV1/T8 (resistant)
Mitoxantrone0.52 ± 0.12100 ± 15 (190)4.5 ± 0.3125 ± 20 (28)a
 + 25 nm Ko1431.10 ± 0.20 (2.1)10.5 ± 1.9 (20)a4.9 ± 0.5 (1.1)11 ± 3 (2.4)b
 + 200 nm Ko1430.34 ± 0.05 (0.65)0.35 ± 0.04 (0.67)3.7 ± 0.6 (0.8)2.2 ± 0.4 (0.5)
Topotecan33 ± 312,000 ± 1700 (360)a7.7 ± 1.0370 ± 40 (48)a
 + 25 nm Ko14335 ± 4 (1.1)1,150 ± 200 (35)a7.0 ± 0.7 (0.9)45 ± 8 (5.8)a
 + 200 nm Ko14336 ± 5 (1.1)98 ± 11 (3.0)a6.7 ± 0.6 (0.9)20 ± 2 (2.6)a
Vincristine0.31 ± 0.070.37 ± 0.03 (1.2)3.4 ± 0.81.8 ± 0.2 (0.5)
 + 25 nm Ko1430.34 ± 0.02 (1.1)0.37 ± 0.03 (1.2)3.1 ± 0.6 (0.9)1.7 ± 0.2 (0.5)
 + 200 nm Ko1430.26 ± 0.06 (0.84)0.36 ± 0.02 (1.2)3.7 ± 0.7 (1.1)2.0 ± 0.3 (0.6)
  • a,bCases where the drug-selected lines retained residual resistance significantly greater than that of the parent cell line (i.e., RF >1.0):

  • a (P < 0.005), and

  • b (P < 0.05).