Gene Expression Profiling of the Irinotecan Pathway in Colorectal Cancer

Yu, Jinsheng; Shannon, William D.; Watson, Mark A.; McLeod, Howard L.

doi:10.1158/1078-0432.ccr-04-1254

Cited by 52 publications

(42 citation statements)

References 35 publications

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“…26), was used to control variation in RNA concentration across individual samples. Finally, the value of sample RNA level normalized to the internal reference gene was scaled to a 1Â sample so that the minimal level was 1 in the entire data set.…”

Section: Methodsmentioning

confidence: 99%

DNA Repair Pathway Profiling and Microsatellite Instability in Colorectal Cancer

Mallon²,

Zhang

et al. 2006

Clinical Cancer Research

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Background: The ability to maintain DNA integrity is a critical cellular function. DNA repair is conducted by distinct pathways of genes, many of which are thought to be altered in colorectal cancer. However, there has been little characterization of these pathways in colorectal cancer. Method: By using theTaqMan real-time quantitative PCR, RNA expression profiling of 20 DNA repair pathway genes was done in matched tumor and normal tissues from 52 patients with Dukes' C colorectal cancer. Results: The relative mRNA expression level across the 20 DNA repair pathway genes varied considerably, and the individual variability was also quite large, with an 85.4 median fold change in the tumor tissue genes and a 127.2 median fold change in the normal tissue genes. Tumornormal differential expression was found in 13 of 20 DNA repair pathway genes (only XPA had a lower RNA level in the tumor samples; the other 12 genes had significantly higher tumor levels, all P < 0.01). Coordinated expression of ERCC6, HMG1, MSH2, and POLB (R S z 0.60) was observed in the tumor tissues (all P < 0.001). Apoptosis index was not correlated with expression of the 20 DNA repair pathway genes. MLH1 and XRCC1 RNA expression was correlated with microsatellite instability status (P = 0.045 and 0.020, respectively). An inverse correlation was found between tumor MLH1 RNA expression and MLH1 DNA methylation (P = 0.003). Conclusion: Our study provides an initial characterization of the DNA repair pathways for understanding the cellular DNA damage/repair system in human colorectal cancer.

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Section: Methodsmentioning

confidence: 99%

DNA Repair Pathway Profiling and Microsatellite Instability in Colorectal Cancer

Mallon²,

Zhang

et al. 2006

Clinical Cancer Research

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“…Quantitative Real-time PCR The primers and probes for each of the 21 drug pathway genes have been described previously (34). The reaction system consisted of cDNA 10 ng, TaqMan Universal PCR Master Mix (2Â) 5.0 AL, forward primer (10 Amol/L) 0.6 AL, reverse primer (10 Amol/L) 0.6 AL, TaqMan probe (5 Amol/L) 0.4 AL, and DNase-free water f10 AL.…”

Section: Methodsmentioning

confidence: 99%

Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors

Azrak¹,

Pendyala

et al. 2005

Molecular Cancer Therapeutics

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The combination of methylselenocysteine and irinotecan (CPT-11) is synergistic against FaDu and A253 xenografts. Methylselenocysteine/CPT-11 increased tumor cure rate to 100% in FaDu and to 60% in A253. In this study, the effect of methylselenocysteine on pharmacokinetic and pharmacogenetic profiles of genes relevant to CPT-11 metabolic pathway was evaluated to identify possible mechanisms associated with the observed combinational synergy. Nude mice bearing tumors (FaDu and A253) were treated with methylselenocysteine, CPT-11, and a combination of methylselenocysteine/CPT-11. Samples were collected and analyzed for plasma and intratumor concentration of CPT-11 and 7-ethyl-10-hydroxyl-camptothecin (SN-38) by high-performance liquid chromatography. The intratumor relative expression of genes related to the CPT-11 metabolic pathway was measured by real-time PCR. After methylselenocysteine treatment, the intratumor area under the concentration-time curve of SN-38 increased to a significantly higher level in A253 than in FaDu and was associated with increased expression of CES1 in both tumors. Methylselenocysteine/CPT-11 treatment, compared with CPT-11 alone, resulted in a significant decrease in levels of ABCC1 and DRG1 in FaDu tumors and an increase in levels of CYP3A5 and TNFSF6 in A253 tumors. No statistically significant changes induced by methylselenocysteine/CPT-11 were observed in the levels of other investigated variables. In conclusion, the significant increase in the cure rate after methylselenocysteine/CPT-11 could be related to increased drug delivery into both tumors (CES1), reduced resistance to SN-38 (ABCC1 and DRG1) in FaDu, and induced Fas ligand apoptosis (TNFSF6) in A253. No correlation was observed between cure rate and other investigated variables (transporters, degradation enzymes, DNA repair, and cell survival/death genes) in either tumor. [Mol Cancer Ther 2005;4(5):843 -54]

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“…Human Taf12 (hTaf12) is an RNA polymerase II TATA box-binding factor involved in transcription and was recently identified as an oncogene in brain tumors (55). Elevated hTdp1 levels are seen in certain rhabdomyosarcomas (RMSs) (56), Dukes C colorectal cancer (57), and nonsmall cell lung cancer (58). Neither of these genes has been previously linked to CIN in human cells.…”

Section: Analysis Of the Dcin Gene Catalog Uncovers Multiple Mechanismsmentioning

confidence: 99%

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

Duffy

Fam

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Somatic copy number amplification and gene overexpression are common features of many cancers. To determine the role of gene overexpression on chromosome instability (CIN), we performed genome-wide screens in the budding yeast for yeast genes that cause CIN when overexpressed, a phenotype we refer to as dosage CIN (dCIN), and identified 245 dCIN genes. This catalog of genes reveals human orthologs known to be recurrently overexpressed and/or amplified in tumors. We show that two genes, TDP1, a tyrosyl-DNA-phosphdiesterase, and TAF12, an RNA polymerase II TATA-box binding factor, cause CIN when overexpressed in human cells. Rhabdomyosarcoma lines with elevated human Tdp1 levels also exhibit CIN that can be partially rescued by siRNA-mediated knockdown of TDP1. Overexpression of dCIN genes represents a genetic vulnerability that could be leveraged for selective killing of cancer cells through targeting of an unlinked synthetic dosage lethal (SDL) partner. Using SDL screens in yeast, we identified a set of genes that when deleted specifically kill cells with high levels of Tdp1. One gene was the histone deacetylase RPD3, for which there are known inhibitors. Both HT1080 cells overexpressing hTDP1 and rhabdomyosarcoma cells with elevated levels of hTdp1 were more sensitive to histone deacetylase inhibitors valproic acid (VPA) and trichostatin A (TSA), recapitulating the SDL interaction in human cells and suggesting VPA and TSA as potential therapeutic agents for tumors with elevated levels of hTdp1. The catalog of dCIN genes presented here provides a candidate list to identify genes that cause CIN when overexpressed in cancer, which can then be leveraged through SDL to selectively target tumors.dosage chromosome instability | overexpression | synthetic dosage lethality | TDP1 | rhabdomyosarcoma

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Gene Expression Profiling of the Irinotecan Pathway in Colorectal Cancer

Cited by 52 publications

References 35 publications

DNA Repair Pathway Profiling and Microsatellite Instability in Colorectal Cancer

DNA Repair Pathway Profiling and Microsatellite Instability in Colorectal Cancer

Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors

Overexpression screens identify conserved dosage chromosome instability genes in yeast and human cancer

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