Pharmacokinetics and pharmacogenomics in esophageal cancer chemoradiotherapy

Sakaeda, Toshiyuki; Yamamori, Motohiro; Kuwahara, Akiko; Nishiguchi, Kohshi

doi:10.1016/j.addr.2008.10.005

Cited by 29 publications

(21 citation statements)

References 267 publications

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“…Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two major subtypes of esophageal cancer with ESCC accounting for more than 90% of esophageal cancer cases and characterized by frequent relapses and metastatic capabilities [4]. Despite advance in early detection and treatment with concurrent chemoradiation therapy (CCRT) alone or as an adjunct to surgery [5], esophageal cancer remains a major challenge and requires more effective therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

The Synthetic β-Nitrostyrene Derivative CYT-Rx20 Inhibits Esophageal Tumor Growth and Metastasis via PI3K/AKT and STAT3 Pathways

Chiu

Lee

et al. 2016

PLoS ONE

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The β-nitrostyrene family have been implicated for anti-cancer property. However, the pharmacological role of β-nitrostyrene in esophageal cancer remain unclear. Here, a β-nitrostyrene derivative, CYT-Rx20, was synthesized and assessed for its anti-cancer activities and underlying mechanism in esophageal cancer. CYT-Rx20 induced cytotoxicity in esophageal cancer cells by promoting apoptosis through activation of caspase cascade and poly(ADP-ribose) polymerase (PARP) cleavage. Besides, CYT-Rx20 inhibited esophageal cancer cell migration and invasion by regulating the expression of epithelial to mesenchymal transition (EMT) markers. CYT-Rx20 decreased cell viability and migration through suppression of the PI3K/AKT and STAT3 pathways. Of note, the cytotoxicity and anti-migratory effect of CYT-Rx20 were enhanced by co-treatment with SC79 (AKT activator) or colivelin (STAT3 activator), suggesting the dependency of esophageal cancer cells on AKT and STAT3 for survival and migration, an oncogene addiction phenomenon. In xenograft tumor-bearing mice, CYT-Rx20 significantly reduced tumor growth of the implanted esophageal cancer cells accompanied by decreased Ki-67, phospho-AKT, and phospho-STAT3 expression. In orthotopic esophageal cancer mouse model, decreased tumor growth and lung metastasis with reduced Ki-67 and phospho-STAT3 expression were observed in mice treated with CYT-Rx20. Together, our results suggest that CYT-Rx20 is a potential β-nitrostyrene-based anticancer compound against the tumor growth and metastasis of esophageal cancer.

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Section: Introductionmentioning

confidence: 99%

The Synthetic β-Nitrostyrene Derivative CYT-Rx20 Inhibits Esophageal Tumor Growth and Metastasis via PI3K/AKT and STAT3 Pathways

Chiu

Lee

et al. 2016

PLoS ONE

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“…Esophageal cancer is the 8th most common cancer in the world and one of the most lethal 10. Symptoms include dysphagia, odynophagia, and progressive weight loss.…”

Section: Discussionmentioning

confidence: 99%

“…A long-term evaluation of efficacy and toxicity with 139 patients resulted in a complete response (CR) rate of 56%, along with a 5-year survival rate of 29% 7-9. Currently, a definitive 5-FU/CDDP-based chemoradiotherapy (CRT) is recognized as one of the most promising treatments for esophageal cancer 10.…”

Section: Introductionmentioning

confidence: 99%

Replacement of cisplatin with nedaplatin in a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma

Kuwahara¹,

Yamamori²,

Nishiguchi³

et al. 2009

Int. J. Med. Sci.

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Objective: The effects of replacing cisplatin (CDDP) with cis-diammineglycolatoplatinum (nedaplatin, NDP), a second-generation platinum complex, on the pharmacokinetics of 5-fluorouracil (5-FU) were investigated in Japanese patients with esophageal squamous cell carcinoma, who were treated with a definitive 5-FU/CDDP-based chemoradiotherapy.Methods: Fifty-six patients were enrolled, 49 treated with CDDP and 7 treated with NDP. A course consisted of continuous infusion of 5-FU at 400 mg/m2/day for days 1-5 and 8-12, infusion of CDDP or NDP at 40 mg/m2/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. Plasma concentrations of 5-FU were determined by high performance liquid chromatography at 5 PM on days 3, 10, 38 and45, and at 5 AM on days 4, 11, 39 and 46.Results and conclusions: The circadian rhythm in plasma concentrations of 5-FU observed in the case of CDDP was altered when NDP was used instead. The clinical response can be predicted by monitoring plasma concentrations of 5-FU in the CDDP group, but not in the NDP group.

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“…The incidence of esophageal squamous cell carcinoma (ESCC) is higher than that of esophageal adenocarcinoma in east Asian countries, including Japan, whereas the incidence of esophageal adenocarcinoma is high in north America, the United kingdom/Ireland, and Australia 2. The standard therapeutic approach for ESCC has traditionally been radical surgery with node dissection; however, recent advances in chemoradiotherapy (CRT) have been widely accepted as a promising modality in both neoadjuvant and definitive settings for patients with ESCC 3, 4. A definitive CRT with 5-fluorouracil (5-FU) and cisplatin (CDDP) has been proposed as an organ-preserving treatment 5, 6, and clinical evidence supporting its efficacy has been collected in T4 and/or M1 lymph node 5, 6, and later stage II/III 7.…”

Section: Introductionmentioning

confidence: 99%

“…Because of the narrow therapeutic index of chemotherapeutic agents, pharmacogenomics has drawn increasing attention in the field of tailored medicine, ranging from gene expression profiles in tumor tissues to genetic signatures, including single nucleotide polymorphisms (SNPs) 3, 8, 9. The application of SNP genotyping to anticancer therapy is an attractive approach, and serious toxicities have been explained by SNPs in well-known drug-metabolizing enzyme- or drug-transporter-related genes 3, 8, 9. However, severe toxicities may have complicated associations with a large variety of genetic mutations; therefore, identification of novel markers using a different concept will be needed.…”

Section: Introductionmentioning

confidence: 99%

THRB Genetic Polymorphisms Can Predict Severe Myelotoxicity after Definitive Chemoradiotherapy in Patients with Esophageal Squamous Cell Carcinoma

Miki¹,

Nakamura²,

Kuwahara³

et al. 2012

Int. J. Med. Sci.

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Objective: Chemotherapy-related toxicities are difficult to predict before treatment. In this study, we investigated whether thyroid hormone receptor beta (THRB) genetic polymorphisms can serve as a potential biomarker in patients with esophageal squamous cell carcinoma (ESCC).Methods: Forty-nine Japanese patients with ESCC who received a definitive chemoradiotherapy (CRT) with 5-fluorouracil and cisplatin in conjunction with concurrent irradiation were retrospectively analyzed. Severe acute toxicities, including leukopenia, stomatitis, and cheilitis, were evaluated according to 6 single nucleotide polymorphisms (SNPs) in the gene; the intronic SNPs of rs7635707 G/T, rs6787255 A/C, rs9812034 G/T, and rs9310738 C/T and the SNPs in the 3′-untranslated region (3′-UTR) of rs844107 C/T and rs1349265 G/A.Results: Distribution of the 4 intronic SNPs, but not the 2 SNPs in the 3′-UTR, showed a significant difference between patients with and without severe acute leukopenia. Stomatitis and cheilitis were not associated with any of the 6 analyzed SNPs. Frequency of haplotype of the 4 intronic SNPs reached approximately 97% with the 2 major haplotypes G-A-G-C (73.4%) and T-C-T-T (23.5%).Conclusions: THRB intronic SNPs can provide useful information on CRT-related severe myelotoxicity in patients with ESCC. Future studies will be needed to confirm these findings.

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Pharmacokinetics and pharmacogenomics in esophageal cancer chemoradiotherapy

Cited by 29 publications

References 267 publications

The Synthetic β-Nitrostyrene Derivative CYT-Rx20 Inhibits Esophageal Tumor Growth and Metastasis via PI3K/AKT and STAT3 Pathways

The Synthetic β-Nitrostyrene Derivative CYT-Rx20 Inhibits Esophageal Tumor Growth and Metastasis via PI3K/AKT and STAT3 Pathways

Replacement of cisplatin with nedaplatin in a definitive 5-fluorouracil/cisplatin-based chemoradiotherapy in Japanese patients with esophageal squamous cell carcinoma

THRB Genetic Polymorphisms Can Predict Severe Myelotoxicity after Definitive Chemoradiotherapy in Patients with Esophageal Squamous Cell Carcinoma

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