Enhanced Induction of Apoptosis in Lung Adenocarcinoma After Preoperative Chemotherapy with Tegafur and Uracil (UFT)

Morio, Atsushi; Miyamoto, Hideaki; Izumi, Hiroshi; Futagawa, Toshiro; Oh, Tsumin; Yamazaki, Akio; Konno, Hidehiro

doi:10.1007/s00595-004-2814-5

Cited by 4 publications

(1 citation statement)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although under normal conditions uracil is excluded from DNA by maintaining a low cellular dUTP pool through the action of deoxyuridine triphosphate nucleotidohydrolase (dUTPase), upon TS inhibition large amounts of dUTP and FdUTP accumulate which overwhelms the dUTPase activity. Thus, dUMP and FdUMP are incorporated into genomic DNA, which may directly lead to cytotoxicity either by causing mutations and resulting protein miscoding ( 10 ), or by triggering apoptosis ( 11 ). Alternatively, the presence of uracil and 5-FU in DNA may result in ‘futile cycling’ of uracil base excision repair (BER) because of the depleted dTTP pool ( Figure 1B ).…”

Section: Introductionmentioning

confidence: 99%

Linking uracil base excision repair and 5-fluorouracil toxicity in yeast

Seiple

Jaruga

Dizdaroğlu

et al. 2006

Nucleic Acids Research

141

122

View full text Add to dashboard Cite

5-fluorouracil (5-FU) is a widely used anticancer drug that disrupts pyrimidine nucleotide pool balances and leads to uracil incorporation in DNA, which is then recognized and removed by the uracil base excision repair (BER) pathway. Using complementary biochemical and genetic approaches we have examined the role of uracil BER in the cell killing mechanism of 5-FU. A yeast strain lacking the enzyme uracil DNA glycosylase (Ung1), which excises uracil from the DNA backbone leaving an abasic site, showed significant protection against the toxic effects of 5-FU, a G1/S cell cycle arrest phenotype, and accumulated massive amounts of U/A base pairs in its genome (∼4% of T/A pairs were now U/A). A strain lacking the major abasic site endonuclease of Saccharomyces cerevisiae (Apn1) showed significantly increased sensitivity to 5-FU with G2/M arrest. Thus, efficient processing of abasic sites by this enzyme is protective against the toxic effects of 5-FU. However, contrary to expectations, the Apn1 deficient strain did not accumulate intact abasic sites, indicating that another repair pathway attempts to process these sites in the absence Apn1, but that this process has catastrophic effects on genome integrity. These findings suggest that new strategies for chemical intervention targeting BER could enhance the effectiveness of this widely used anticancer drug.

show abstract

Section: Introductionmentioning

confidence: 99%

Linking uracil base excision repair and 5-fluorouracil toxicity in yeast

Seiple

Jaruga

Dizdaroğlu

et al. 2006

Nucleic Acids Research

141

122

View full text Add to dashboard Cite

show abstract

Risk of recurrence after surgical resection of small-sized invasive lung adenocarcinoma

Morio

Miyamoto

Izumi

2005

Jpn J Thorac Cardiovasc Surg

Self Cite

View full text Add to dashboard Cite

show abstract

Drug-induced apoptosis in yeast

Almeida

Silva

Mesquita

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

In order to alter the impact of diseases on human society, drug development has been one of the most invested research fields. Nowadays, cancer and infectious diseases are leading targets for the design of effective drugs, in which the primary mechanism of action relies on the modulation of programmed cell death (PCD). Due to the high degree of conservation of basic cellular processes between yeast and higher eukaryotes, and to the existence of an ancestral PCD machinery in yeast, yeasts are an attractive tool for the study of affected pathways that give insights into the mode of action of both antitumour and antifungal drugs. Therefore, we covered some of the leading reports on drug-induced apoptosis in yeast, revealing that in common with mammalian cells, antitumour drugs induce apoptosis through reactive oxygen species (ROS) generation and altered mitochondrial functions. The evidence presented suggests that yeasts may be a powerful model for the screening/development of PCD-directed drugs, overcoming the problem of cellular specificity in the design of antitumour drugs, but also enabling the design of efficient antifungal drugs, targeted to fungal-specific apoptotic regulators that do not have major consequences for human cells.

show abstract

Enhanced Induction of Apoptosis in Lung Adenocarcinoma After Preoperative Chemotherapy with Tegafur and Uracil (UFT)

Cited by 4 publications

References 13 publications

Linking uracil base excision repair and 5-fluorouracil toxicity in yeast

Linking uracil base excision repair and 5-fluorouracil toxicity in yeast

Risk of recurrence after surgical resection of small-sized invasive lung adenocarcinoma

Drug-induced apoptosis in yeast

Contact Info

Product

Resources

About