Staurosporine increases toxicity of gemcitabine in non-small cell lung cancer cells: role of protein kinase C, deoxycytidine kinase and ribonucleotide reductase.

Gemcitabine, a deoxycytidine analog, active against non-small cell lung cancer, is phosphorylated by deoxycytidine kinase (dCK) to active nucleotides. Earlier, we found increased sensitivity to gemcitabine in P-glycoprotein (SW-2R160) and multidrug resistance-associated protein (SW-2R120), overexpressing variants of the human SW1573 non-small cell lung cancer cells. This was related to increased dCK activity.

Pharmacological aspects of the enzastaurin-pemetrexed combination in non-small cell lung cancer (NSCLC).

Conventional regimens have limited impact against NSCLC. Current research is focusing on multiple pathways as potential targets, and this review describes pharmacological aspects underlying the combination of the PKCbeta-inhibitor enzastaurin with the multitargeted antifolate pemetrexed. Pemetrexed is commonly used, alone or combined with platinum compounds, in NSCLC treatment, and ongoing studies are evaluating its target, thymidylate synthase (TS), as predictor of drug activity.

Synthesis and biological activity of a gemcitabine phosphoramidate prodrug.

A gemcitabine (2',2'-difluorodeoxycytidine, dFdC) phosphoramidate prodrug designed for the intracellular delivery of gemcitabine 5'-monophosphate was synthesized. The prodrug was about an order of magnitude less active than gemcitabine against wild-type cells, and the nucleoside transport inhibitor dipyridamole reduced prodrug activity. The prodrug was more active than gemcitabine against two deoxycytidine kinase-deficient cell lines.

Pyrimidine and purine analogues, effects on cell cycle regulation and the role of cell cycle inhibitors to enhance their cytotoxicity.

In anti-cancer treatment, deoxynucleoside analogues are widely used in combination chemotherapy. Improvement can be achieved by rational design of novel combinations with cell cycle inhibitors. These compounds inhibit protein kinases, preventing the cell cycle from continuing when affected by deoxynucleoside analogs.

Quantitative real time PCR of deoxycytidine kinase mRNA by Light Cycler PCR in relation to enzyme activity and gemcitabine sensitivity.

Deoxycytidine kinase (dCK) is essential for the phosphorylation of gemcitabine and can predict response to gemcitabine in vivo. Conventional Competitive Template-Reverse Transcriptase-Polymerase Chain Reaction (CT-RT-PCR) was correlated with real time PCR using a Light Cycler (LC) with SYBR-Green detection to enable rapid and sensitive detection of dCK mRNA expression. We used cDNA from human xenografts to establish a relation between dCK activity and gemcitabine sensitivity.

Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression.

Pemetrexed (ALIMTA, MTA) is a novel thymidylate synthase (TS) inhibitor and has shown activity against colon cancer, mesothelioma and nonsmall-cell lung cancer. We induced resistance to Pemetrexed in the human colon cancer cell line WiDr by using a continuous exposure to stepwise increasing Pemetrexed concentrations (up to 20 microM) as well as a more clinically relevant schedule with intermittent exposure (up to 50 microM) for 4 hr every 7 days, resulting in WiDr variants WiDr-cPEM and WiDr-4PEM, respectively. However, using the same conditions, it was not possible to induce resistance in the WiDr/F cell line, a variant adapted to growth under low folate conditions.