Differential effects of gemcitabine on ribonucleotide pools of twenty-one solid tumour and leukaemia cell lines

To gain a more detailed insight into the metabolism of 2',2'-difluoro-2'-de oxycytidine (dFdC, gemcitabine, Gemzar) and its effect on normal ribonucleo tide (NTP) metabolism in relation to sensitivity, we studied the accumulati on of dFdCTP and the changes in NTP pools after dFdC exposure in a panel of 21 solid tumour and leukaemia cell lines. Both sensitivity to dFdC and acc umulation of dFdCTP were clearly cell line-dependent: in this panel of cell lines, the head and neck cancer (HNSCC) cell line 22B appeared to be the m ost sensitive, whereas the small cell lung cancer (SCLC) cell lines were th e least sensitive to dFdC. The human leukaemia cell line CCRF-CEM accumulat ed the highest concentration of dFdCTP, whereas the non-SCLC cell lines acc umulated the least. Not only the amount of dFdCTP accumulation was clearly related to the sensitivity for dFdC (R = -0.61), but also the intrinsic CTP /UTP ratio (R = 0.97). NTP pools were affected considerably by dFdC treatme nt: in seven cell lines dFdC resulted in a 1.7-fold depletion of CTP pools, in two cell lines CTP pools were unaffected, but in 12 cell lines CTP pool s increased about 2-fold. Furthermore, a 1.6-1.9-fold rise in ATP, UTP and GTP pools was shown in 20, 19 and 20 out of 21 cell lines, respectively. On ly the UTP levels after treatment with dFdC were clearly related to the amo unt of dFdCTP accumulating in the cell (R = 0.64 (P < 0.01)), but not to th e sensitivity to dFdC treatment. In conclusion, we demonstrate that besides the accumulation of dFdCTP, the CTP/UTP ratio was clearly related to the s ensitivity to dFdC. Furthermore, the UTP levels and the CTP/UTP ratio after treatment were related to dFdCTP accumulation. Therefore; both the CTP and UTP pools appear to play an important role in the sensitivity to dFdC. (C) 2000 Elsevier Science B.V. All rights reserved.