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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.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.

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

Mechanism of 5FU leading to RNA and DNA damage. Thymidylate synthase inhibition is the main mechanism of action of 5FU through its active metabolite FdUMP. Synthesis of the pyrimidine thymidine, which is required for DNA synthesis, is the result of blocking thymidylate synthase. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to for thymidine monophosphate (dTMP). The use of 5FU in cancer causes there to be a reduction leading to a scarcity of dTMP so that rapidly dividing cancer cells die from a lack of thymine.
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Figure 2: Mechanism of 5FU leading to RNA and DNA damage. Thymidylate synthase inhibition is the main mechanism of action of 5FU through its active metabolite FdUMP. Synthesis of the pyrimidine thymidine, which is required for DNA synthesis, is the result of blocking thymidylate synthase. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to for thymidine monophosphate (dTMP). The use of 5FU in cancer causes there to be a reduction leading to a scarcity of dTMP so that rapidly dividing cancer cells die from a lack of thymine.

Mentions: Like uracil, 5FU is salvaged to form 5-fluorouridine and then phosphorylated by nucleoside and nucleotide kinases as well as reduced by ribonucleotide reductase forming three different active metabolites (Figure 2). After incorporation of 5-fluorouridine triphosphate (FUTP) into cellular RNA, RNA processing and post-transcriptional modification can be inhibited [15,16]. During DNA synthesis, 5-fluoro-2′-deoxyuridine monophosphate (FdUMP) inhibits thymidylate synthase resulting in an imbalanced pool of deoxynucleotide triphosphates, particularly decreased deoxythymidine triphosphate (dTTP) and increased deoxyuridine triphosphate (dUTP). Absent dTTP, stalled DNA polymerases can incorporate 5-fluorodeoxyuridine triphosphate (FdUTP) or dUTP which are subsequently recognized as damaged DNA setting up a futile cycle of misincorporation and repair [15,16]. When DNA damage exceeds a cells ability to repair misincorporated FdUTP or dUTP, single strand and double strand breaks accumulate favoring cell death. Given these cellular actions of 5FU, its toxicity is generally considered a function of transport into the cell and metabolism to active metabolites, particularly FdUMP, while resistance occurs when 5FU metabolism is decreased or DNA repair is efficient.


Antimetabolite Treatment for Pancreatic Cancer.

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

Mechanism of 5FU leading to RNA and DNA damage. Thymidylate synthase inhibition is the main mechanism of action of 5FU through its active metabolite FdUMP. Synthesis of the pyrimidine thymidine, which is required for DNA synthesis, is the result of blocking thymidylate synthase. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to for thymidine monophosphate (dTMP). The use of 5FU in cancer causes there to be a reduction leading to a scarcity of dTMP so that rapidly dividing cancer cells die from a lack of thymine.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Mechanism of 5FU leading to RNA and DNA damage. Thymidylate synthase inhibition is the main mechanism of action of 5FU through its active metabolite FdUMP. Synthesis of the pyrimidine thymidine, which is required for DNA synthesis, is the result of blocking thymidylate synthase. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to for thymidine monophosphate (dTMP). The use of 5FU in cancer causes there to be a reduction leading to a scarcity of dTMP so that rapidly dividing cancer cells die from a lack of thymine.
Mentions: Like uracil, 5FU is salvaged to form 5-fluorouridine and then phosphorylated by nucleoside and nucleotide kinases as well as reduced by ribonucleotide reductase forming three different active metabolites (Figure 2). After incorporation of 5-fluorouridine triphosphate (FUTP) into cellular RNA, RNA processing and post-transcriptional modification can be inhibited [15,16]. During DNA synthesis, 5-fluoro-2′-deoxyuridine monophosphate (FdUMP) inhibits thymidylate synthase resulting in an imbalanced pool of deoxynucleotide triphosphates, particularly decreased deoxythymidine triphosphate (dTTP) and increased deoxyuridine triphosphate (dUTP). Absent dTTP, stalled DNA polymerases can incorporate 5-fluorodeoxyuridine triphosphate (FdUTP) or dUTP which are subsequently recognized as damaged DNA setting up a futile cycle of misincorporation and repair [15,16]. When DNA damage exceeds a cells ability to repair misincorporated FdUTP or dUTP, single strand and double strand breaks accumulate favoring cell death. Given these cellular actions of 5FU, its toxicity is generally considered a function of transport into the cell and metabolism to active metabolites, particularly FdUMP, while resistance occurs when 5FU metabolism is decreased or DNA repair is efficient.

Bottom Line: Less than 1% of diagnosed patients survive 5 years with an average survival time of only 4-8 months.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.

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