Reversal of P-glycoprotein mediated vincristine resistance of L1210/VCR cells by analogues of pentoxifylline - A QSAR study


  • I. Kupsakova
  • A. Rybar
  • P. Docolomansky
  • Z. Drobna
  • U. Stein
  • W. Walther
  • M. Barancik
  • A. Breier


  • European Journal of Pharmaceutical Sciences


  • Eur J Pharm Sci 21 (2-3): 283-293


  • In our previous papers we described the ability of methylxanthine pentoxifylline (PTX) to depress the P-glycoprotein (P-gp) mediated multidrug resistance (MDR) of the mouse leukemic cell line L1210/VCR. Other methylxanthines like caffeine and theophylline were found to be ineffective in this respect. In the present paper we have analysed the capability of 25 methylxanthines to depress MDR of L1210/VCR cells. These methylxanthines structurally differ in substituents located in positions N1, N3, N7 and C8. The results indicate that for an effective reversal of P-gp mediated MDR of our cells the existence of a longer polar substituent in the position N1 plays a crucial role. The elongation of the substituent in the positions N3 and N7 (from methyl to propyl) increases and in the position C8 (from H to propyl) decreases the efficacy of xanthines to reverse the vincristine resistance of L1210/VCR cells. The multiple linear regression for effectiveness of methylxanthines in reversal of P-gp mediated MDR of L1210/VCR cells (expressed as respective IC50r values) has been computed, with molar weight: Mw, molar volume: VM, molar refractivity: RM, crystal density: d and partition coefficient n-octanol/water: log P as descriptors. A high intercorrelation of MW, VM and R M was found for the tested group of methylxanthines indicating that only one of these parameters is necessary for testing a potential correlation. The best fit in the multiple linear regression was obtained for RM applied together with d and log P and resulted in a QSAR model given by the following equation: IC50r = -[(32.3 ± 7.2) × 10 -3 × RM] + [(10.1 ± 2.3) × d] + [(0.74 ± 0.10) × log P] - [10.5 ± 3.2]. Model revealed that: (i) the molar refractivity influences the effectiveness of xanthine positively; (ii) the crystal density and partition coefficient influence the MDR reversal effectiveness of xanthine negatively.