Topoisomerase I expression in tumors as a biological marker for CPT-11 chemosensitivity in patients with colorectal cancer

Ikeguchi, Masahide; Arai, Yosuke; Maeta, Yoshihiko; Ashida, Keigo; Katano, Kuniyuki; Wakatsuki, Toshiro

doi:10.1007/s00595-011-4546-7

Cited by 37 publications

(25 citation statements)

References 32 publications

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“…These results are not supported by the earlier hypothesis that lower expression of Topo-1 is correlated with a worse response to Topo-1 inhibitors. 36,37 However, results of other studies from Dutch colorectal cancer group failed to replicate the findings and concluded that although absolute Topo-1 expression may play a role, it is likely that additional pathways contribute to irinotecan sensitivity of Topo-1. 38,39 Therefore, these results indicate that clinical significance of Topo-1 is still unknown and remains controversial as prognostic marker.…”

Section: Numerous Preclinical and Clinical Studies Have Demonstrated contrasting

confidence: 47%

Pharmacodynamic and pharmacogenomic study of the nanoparticle conjugate of camptothecin CRLX101 for the treatment of cancer

Gaur

Wang

Kretzner

et al. 2014

Nanomedicine: Nanotechnology, Biology and Medicine

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Section: Numerous Preclinical and Clinical Studies Have Demonstrated contrasting

confidence: 47%

Pharmacodynamic and pharmacogenomic study of the nanoparticle conjugate of camptothecin CRLX101 for the treatment of cancer

Gaur

Wang

Kretzner

et al. 2014

Nanomedicine: Nanotechnology, Biology and Medicine

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“…In current chemotherapeutic treatment for CRC, irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is one of the key cytotoxic drugs with a 30% single agent response rate and 50% response rate when combined with other agents such as 5-Fu/leucovorin (LV) (2). However, more than 40% of patients treated with this drug have severe toxicities, such as diarrhea and neutropenia that limit its efficacy (3), and there remain many patients treated with CPT-11 who become resistant and exhibit further tumor progression despite their initial response (4). Thus, it remains important to search for novel agents for new combination treatments to enhance efficiency, reduce toxicities and avoid the progression of colorectal tumors.…”

Section: Introductionmentioning

confidence: 99%

Enhanced anti-colorectal cancer effects of carfilzomib combined with CPT-11 via downregulation of nuclear factor-κB in vitro and in vivo

Tang

et al. 2014

International Journal of Oncology

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Upregulation of nuclear factor-κB (NF-κB) in colorectal carcinoma (CRC) accelerates tumor growth, whereas, irinotecan (CPT-11)-induced NF-κB activation reduces chemosensitivity and weakens the anti-colorectal cancer function itself, while proteasome inhibitors can inhibit NF-κB and improve the effect of chemotherapy. Carfilzomib (CFZ) is a novel proteasome inhibitor that has been recently approved by the FDA and is in clinical use for the treatment of multiple myeloma, but little is known about its activity against CRC. The aim of the present study was to explore whether CFZ alone or in combination with CPT-11 is effective in CRC treatment. We evaluated the novel therapeutic ability and mechanism of action of CFZ in CRC in vitro and in vivo. SW620 cells were incubated with CFZ alone or in combination with CPT-11. Cell proliferation was assessed by WST-1 and clonogenic assays, the cytotoxic interaction was assessed with a combination index (CI). Cell cycle progression was analysed with flow cytometry. Cell apoptosis was evaluated by detecting the Annexin V/propidium iodide (PI) ratio, caspase 3 and CD95 expression, and with TUNEL staining. Cell migration and invasion was determined with a wound-healing assay and a Transwell matrix penetration assay. A CRC xenograft model was established to monitor tumor growth. EMSA was used to analyse NF-κB activation and western blot analysis was used to detect the protein levels of related signaling factors. CFZ significantly inhibited the growth of SW620 cells, and had synergistic inhibitory effects with CPT-11 on survival and colony formation; possibly by inhibition of NF-κB activation, MEK/ERK and PI3K/AKT pathway factor dephosphorylation and survivin downregulation. Co-administration of CFZ and CPT-11 induced G2/M arrest, increased p21WAF1/CIP, and decreased mutant p53 and cdc25c expression. Induction of apoptosis was accompanied by marked increases in PARP cleavage, caspase 3 activation, an increase of CD95 and p-p38, and ATF3 activation. Combination treatment lowered the invasive and migration ability of SW620 cells, reduced MMP and increased TIMP protein expression. Finally, co-administration of CFZ and CPT-11 suppressed tumor growth and increased apoptosis compared with single-agent treatment in SW620 xenograft models correlated with NF-κB downregulation. Carfilzomib alone or in combination with CPT-11 is effective against colorectal cancer through inhibition of multiple mechanisms related to NF-κB, and could be a potential novel therapy for CRC.

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“…Epigenetic regulation of topo-1 promoter is crucial for determining transcription factor binding (TFB), gene expression, and CPT-11 sensitivity in CRC cells [8]. However, most mCRC patients did not achieve an objective response [9]. Moreover, CPT-11 efficacy is burdened by a potentially severe toxicity.…”

Section: Introductionmentioning

confidence: 99%

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

et al. 2016

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Objective:Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients. Methods: With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival). Results: No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1). Conclusion: Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens.

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Topoisomerase I expression in tumors as a biological marker for CPT-11 chemosensitivity in patients with colorectal cancer

Cited by 37 publications

References 32 publications

Pharmacodynamic and pharmacogenomic study of the nanoparticle conjugate of camptothecin CRLX101 for the treatment of cancer

Pharmacodynamic and pharmacogenomic study of the nanoparticle conjugate of camptothecin CRLX101 for the treatment of cancer

Enhanced anti-colorectal cancer effects of carfilzomib combined with CPT-11 via downregulation of nuclear factor-κB in vitro and in vivo

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

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