Abstract
Abstract Gemcitabine (dFdC) is an anti-cancer agent that is affected by cell cycle modulation. Staurosporine and 7-hydroxystaurosporine (UCN-01) are potent protein kinase C (PKC) inhibitors as well as inhibitors of cyclin dependent
Highlights
Gemcitabine is widely used for treatment of solid tumors and almost always combined, either with cytototic drugs such as cisplatin, paclitaxel and 5-fluorouracil (5-FU) or targeted drugs such as erlotinib [1]. dFdC is a deoxynucleoside analogue, in which the 2’ hydrogens of the nucleoside deoxycytidine are replaced by fluoride. dFdC needs to be phosphorylated by deoxycytidine kinase to become active
We evaluated the combination of dFdC with staurosporine and UCN-01 focusing on growth inhibition, cell death induction, cell cycle and the role of the p53 protein
Effects as induced by the first drug, prevented cells to cycle further and cells were forced into apoptosis which was most pronounced for the dFdC and UCN-01 combination in the cells with mutant p53, in contrast to the other lines
Summary
Gemcitabine (dFdC) is widely used for treatment of solid tumors and almost always combined, either with cytototic drugs such as cisplatin, paclitaxel and 5-fluorouracil (5-FU) or targeted drugs such as erlotinib [1]. dFdC is a deoxynucleoside analogue, in which the 2’ hydrogens of the nucleoside deoxycytidine are replaced by fluoride. dFdC needs to be phosphorylated by deoxycytidine kinase (dCK) to become active. DFdC needs to be phosphorylated by deoxycytidine kinase (dCK) to become active. The main mechanism of action is incorporation of its active metabolite dFdC triphosphate (dFdCTP) into the DNA [2]. DFdC diphosphate (dFdCDP) inhibits ribonucleotide reductase (RNR), an essential enzyme that is involved in DNA synthesis [3]. RNR is responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides that will be further phosphorylated to deoxynucleoside triphosphates (dNTPs). Inhibition of RNR is one of the self-potentiating properties of dFdC since this will lead to depletion of dNTP pools, increasing the dFdC incorporation into the DNA [4]. E.g. the combination of cisplatin and gemcitabine is based on a decreased repair of DNA-platinum adducts as well as an increased dFdC incorporation into DNA. Following preclinical data on the synergism of dFdC with cisplatin [5,6], this combination is considered to be one of the most active schedules against NSCLC and bladder cancer [1,7]
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