Increased sensitivity to gemcitabine of P-gP and MRP overexpressing human non-small cell lung cancer cell lines.

Abstract

Gemcitabine (2′,2′-difluorodeoxycytidine, dFdC) is a deoxycytidine analog with proven activity in ovarian and Non-Small Cell Lung Cancer (NSCLC) both in vivo and in vitro (1–3). Deoxycytidine (dCyd) and dFdC are phosphorylated by deoxycytitidine kinase (dCK) to their monophosphates, which are subsequently phosphorylated to dCTP and dFdCTP, respectively. DFdCTP can be incorporated into both DNA and RNA (4,5). Other enzymes involved in deoxynucleoside metabolism are the mitochondrial enzyme thymid-ine kinase 2 (TK2) which phosphorylates the natural nucleosides thymidine (TdR), dCyd and deoxyuridine. This in contrast to the cytosolic enzyme thymidine kinase 1, which only phosphorylates thymidine but not dCyd (6). Since dCTP is the major feedback inhibitor of dCK and competes with dFdCTP for DNA polymerase, an increase in dCTP pools will decrease dFdC sensitivity (7,8).