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Antimetabolite Treatment for Pancreatic Cancer.

Valenzuela MM, Neidigh JW, Wall NR - Chemotherapy (Los Angel) (2014)

Bottom Line: Less than 1% of diagnosed patients survive 5 years with an average survival time of only 4-8 months.Unfortunately, efforts to improve chemotherapy regimens by combining, 5-fluorouracil or gemcitabine with other drugs, such as cisplatin or oxaliplatin, have not increased cell killing or improved patient survival.However, resistance to these antimetabolites remains a problem highlighting the need to discover and develop new antimetabolites that will improve a patient's overall survival.

View Article: PubMed Central - PubMed

Affiliation: Center for Health Disparities Research and Molecular Medicine, Loma Linda University, Loma Linda, California, USA ; Department of Basic Sciences, Division of Biochemistry, Loma Linda University, Loma Linda, California, USA.

ABSTRACT

Pancreatic cancer is a deadly and aggressive disease. Less than 1% of diagnosed patients survive 5 years with an average survival time of only 4-8 months. The only option for metastatic pancreatic cancer is chemotherapy where only the antimetabolites gemcitabine and 5-fluorouracil are used clinically. Unfortunately, efforts to improve chemotherapy regimens by combining, 5-fluorouracil or gemcitabine with other drugs, such as cisplatin or oxaliplatin, have not increased cell killing or improved patient survival. The novel antimetabolite zebularine shows promise, inducing apoptosis and arresting cellular growth in various pancreatic cancer cell lines. However, resistance to these antimetabolites remains a problem highlighting the need to discover and develop new antimetabolites that will improve a patient's overall survival.

No MeSH data available.


Related in: MedlinePlus

The broad spectrum mechanism of action of Gem, depending on its phosphorylation state, can inhibit Ribonucleotide Reductase, Polymerase and Deaminase activities. Once these enzymes are irreversibly inhibited, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair and the cell dies via apoptosis.
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Figure 4: The broad spectrum mechanism of action of Gem, depending on its phosphorylation state, can inhibit Ribonucleotide Reductase, Polymerase and Deaminase activities. Once these enzymes are irreversibly inhibited, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair and the cell dies via apoptosis.

Mentions: Gemcitabine is a 2′-deoxycytidine analogue with fluorine substituted for hydrogen at the 2′ position of the furanose ring (Figure 3). Gemcitabine is a broad-spectrum agent, which has different mechanisms of action, depending upon its phosphorylation state (Figure 4) [8,25]. Uptake of Gem into the cell uses both human equilibrative nucleoside transporters (hENTs) and human concentrative nucleoside transporters (hCNTs) [27,28]. Inside the cell, gemcitabine is phosphorylated by deoxycytidine kinase into gemcitabine monophosphate (dFdCMP), which is further converted into its active di- and triphosphate (dFdCDP and dFdCTP) states by nucleotide kinases [29]. Ribonucleotide reductase is inhibited by dFdCDP leading to a reduction in dCTP levels. Reduced dCTP lessens the negative feedback regulation of deoxycytidine kinase and favors the efficient phosphorylation of gemcitabine [30]. The cytotoxic activity of gemcitabine leading to apoptosis is mainly the result of its triphosphate form. DNA polymerase activity is inhibited when dFdCTP is incorporated into the DNA strand leading to a termination of the DNA chain synthesis and single strand breakage [31–33]. Consequently, a depletion of dCTP levels, due to inhibition of ribonucleotide reductase activity, results in the competition of dFdCTP with dCTP leading to an increased incorporation of dFdCTP into the DNA strand [30]. In addition, high intracellular levels of dFdCTP also strongly inhibited dCMP deaminase activity, by directly inhibiting the deaminase as well as indirectly because of the decreased Dctp:dTTP ratio [34].


Antimetabolite Treatment for Pancreatic Cancer.

Valenzuela MM, Neidigh JW, Wall NR - Chemotherapy (Los Angel) (2014)

The broad spectrum mechanism of action of Gem, depending on its phosphorylation state, can inhibit Ribonucleotide Reductase, Polymerase and Deaminase activities. Once these enzymes are irreversibly inhibited, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair and the cell dies via apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494102&req=5

Figure 4: The broad spectrum mechanism of action of Gem, depending on its phosphorylation state, can inhibit Ribonucleotide Reductase, Polymerase and Deaminase activities. Once these enzymes are irreversibly inhibited, the cell cannot produce the deoxyribonucleotides required for DNA replication and repair and the cell dies via apoptosis.
Mentions: Gemcitabine is a 2′-deoxycytidine analogue with fluorine substituted for hydrogen at the 2′ position of the furanose ring (Figure 3). Gemcitabine is a broad-spectrum agent, which has different mechanisms of action, depending upon its phosphorylation state (Figure 4) [8,25]. Uptake of Gem into the cell uses both human equilibrative nucleoside transporters (hENTs) and human concentrative nucleoside transporters (hCNTs) [27,28]. Inside the cell, gemcitabine is phosphorylated by deoxycytidine kinase into gemcitabine monophosphate (dFdCMP), which is further converted into its active di- and triphosphate (dFdCDP and dFdCTP) states by nucleotide kinases [29]. Ribonucleotide reductase is inhibited by dFdCDP leading to a reduction in dCTP levels. Reduced dCTP lessens the negative feedback regulation of deoxycytidine kinase and favors the efficient phosphorylation of gemcitabine [30]. The cytotoxic activity of gemcitabine leading to apoptosis is mainly the result of its triphosphate form. DNA polymerase activity is inhibited when dFdCTP is incorporated into the DNA strand leading to a termination of the DNA chain synthesis and single strand breakage [31–33]. Consequently, a depletion of dCTP levels, due to inhibition of ribonucleotide reductase activity, results in the competition of dFdCTP with dCTP leading to an increased incorporation of dFdCTP into the DNA strand [30]. In addition, high intracellular levels of dFdCTP also strongly inhibited dCMP deaminase activity, by directly inhibiting the deaminase as well as indirectly because of the decreased Dctp:dTTP ratio [34].

Bottom Line: Less than 1% of diagnosed patients survive 5 years with an average survival time of only 4-8 months.Unfortunately, efforts to improve chemotherapy regimens by combining, 5-fluorouracil or gemcitabine with other drugs, such as cisplatin or oxaliplatin, have not increased cell killing or improved patient survival.However, resistance to these antimetabolites remains a problem highlighting the need to discover and develop new antimetabolites that will improve a patient's overall survival.

View Article: PubMed Central - PubMed

Affiliation: Center for Health Disparities Research and Molecular Medicine, Loma Linda University, Loma Linda, California, USA ; Department of Basic Sciences, Division of Biochemistry, Loma Linda University, Loma Linda, California, USA.

ABSTRACT

Pancreatic cancer is a deadly and aggressive disease. Less than 1% of diagnosed patients survive 5 years with an average survival time of only 4-8 months. The only option for metastatic pancreatic cancer is chemotherapy where only the antimetabolites gemcitabine and 5-fluorouracil are used clinically. Unfortunately, efforts to improve chemotherapy regimens by combining, 5-fluorouracil or gemcitabine with other drugs, such as cisplatin or oxaliplatin, have not increased cell killing or improved patient survival. The novel antimetabolite zebularine shows promise, inducing apoptosis and arresting cellular growth in various pancreatic cancer cell lines. However, resistance to these antimetabolites remains a problem highlighting the need to discover and develop new antimetabolites that will improve a patient's overall survival.

No MeSH data available.


Related in: MedlinePlus