Final results of Australasian Gastrointestinal Trials Group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines

Ransom, David; Wilson, Kate; Fournier, Marion; Simes, R. John; Gebski, Val; Yip, Desmond; Tebbutt, Niall C.; Karapetis, Christos S.; Ferry, David; Gordon, Susan J.; Price, Tim

doi:10.1093/annonc/mdt479

Cited by 59 publications

(62 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The OS and progression-free survival (PFS) were similar [5]. Raltitrexed was also associated with a potentially lower risk of cardiotoxicity in patients with cardiac disease or in those who experienced a cardiac event with 5-FU [6].…”

Section: Introductionmentioning

confidence: 91%

A systematic review of raltitrexed-based first-line chemotherapy in advanced colorectal cancer

et al. 2014

View full text Add to dashboard Cite

Raltitrexed is a thymidylate synthase inhibitor belonging to the antimetabolite class of cytotoxic drugs. It is also effective in colorectal cancer (CRC) both as a single agent and in combination with other drugs, in particular in those patients with cardiologic risk factors or previous cardiotoxicity. The efficacy of first-line raltitrexed-based chemotherapy containing oxaliplatin (TOMOX) and irinotecan (TOMIRI) was investigated in this systematic review. Studies that enrolled advanced CRC patients for first-line therapy with TOMOX/TOMIRI combinations were identified using electronic databases (Pubmed, SCOPUS, Web of Science, EMBASE, and the Cochrane Library). A systematic analysis was carried out using Comprehensive Meta Analysis (version 2.2.064) software to calculate the pooled response rate and 95% confidence limits. The median pooled overall survival and progression-free survival were also calculated. Results for TOMOX and TOMIRI studies were compared using the two-sided Student's t-test. We tested for significant heterogeneity using Cochran's χ-test and I index. Twelve studies published between 2001 and 2012 were eligible for this analysis and a total of 735 patients were enrolled in these studies. The overall response rate was 40% (95% confidence interval 34-46%): 43.9% for TOMOX and 34.1% for TOMIRI arms. The weighted median overall survival and progression-free survival times were 14.6 and 6.7 months, respectively. Neutropenia and liver toxicity were more frequent with TOMOX, whereas neutropenia and diarrhea were more frequent with TOMIRI. However, compared with historical FOLFOX and FOLFIRI trials, raltitrexed-based doublets are associated with less neutropenia and gastrointestinal toxicity and uncommon cardiotoxicity. TOMOX and TOMIRI doublets are active as first-line chemotherapy for advanced CRC and seem useful in particular when the use of 5-fluorouracil is contraindicated for cardiac comorbidity.

show abstract

Section: Introductionmentioning

confidence: 91%

A systematic review of raltitrexed-based first-line chemotherapy in advanced colorectal cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Raltitrexed has been approved in Europe and China for the treatment of advanced colorectal cancer. A previous study demonstrated that the efficacy of raltitrexed alone, or in combination with oxaliplatin or irinotecan is comparable with that of fluorouracil (5-FU) or capecitabine, however, it is safer with regard to cardiac toxicity (10). Raltitrexed is also administered for the treatment of other solid tumors, including malignant pleural mesothelioma, pancreatic cancer, and head and neck neoplasms and has demonstrated good tolerance (7,11,12).…”

Section: Introductionmentioning

confidence: 99%

“…Raltitrexed is another chemotherapeutic agent and a folate antimetabolite, which specifically inhibits TS activity. It has been approved for patients with advanced colorectal cancer in Europe and China (10,17,18) and unlike 5-FU it rarely induces fluoropyrimidine-associated cardiotoxicity (19,20). For cancer patients with f luoropyrimidine-induced cardiotoxicity or a history of cardiac disease, raltitrexed may be a suitable alternative to 5-FU (18).…”

mentioning

confidence: 99%

Raltitrexed induces mitochondrial-mediated apoptosis in SGC7901 human gastric cancer cells

Xue

Chen

Qin

et al. 2014

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Raltitrexed is a specific inhibitor of thymidylate synthase (TS), which has been considered as a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In the present study, the apoptosis mechanisms of raltitrexed in SGC7901 human gastric cancer cells were investigated. The cytotoxic activity of raltitrexed on SGC7901 cells was determined by cell counting kit-8 (CCK-8) assay. The CCK-8 assay indicated that raltitrexed inhibits SGC7901 cell growth in a dose-and time-dependent manner. The morphological changes were observed by fluorescent microscopy, and characteristic morphological changes, including nuclear shrinkage and apoptotic bodies, were observed following Hoechst 33258 staining. The effects on apoptosis, cell cycle, mitochondrial transmembrane potential and reactive oxygen species (ROS) were measured by flow cytometry. The analysis revealed that raltitrexed exerted a growth inhibitory effect by inducing time-dependent apoptosis and cell-cycle arrest at the G 0 /G 1 phase. In addition, a compromised mitochondrial membrane potential and overproduction of ROS demonstrated the involvement of the mitochondrial signaling pathway. Raltitrexed-induced caspase-3-dependent apoptosis was identified using a caspase-3 activity assay and pretreatment with the caspase-3 inhibitor, Ac-DEVD-CHO (sequence, Ac-Asp-Glu-Val-Asp-CHO). The activity of caspase-3 was analyzed with a spectrometer. The protein expression levels of Bax, Bcl-2, cytochrome c, cleaved caspase-3 and TS were examined by western blot and the mRNA expression level of TS was detected by quantitative polymerase chain reaction. The analysis revealed that the protein levels of Bax, cytochrome c and cleaved caspase-3 were significantly increased by raltitrexed, while Bcl-2 expression levels were reduced. Furthermore, raltitrexed increased the expression of the TS protein and mRNA in a time-dependent manner. These results indicate that raltitrexed induces the apoptosis of SGC7901 cells through the caspase-3-dependent mitochondrial signaling pathway and upregulates the expression of the TS protein and mRNA.

show abstract

“…Existing chemotherapeutic formulations containing fluoropyrimidine and cisplatin do not have ideal curative effects and have many undesirable side effects [13][14][15]. Therefore, most gastric cancer patients who diagnosed with inoperable advanced or metastatic cancer require palliative care.…”

Section: Introductionmentioning

confidence: 99%

“…) 13. C-NMR (600 MHz, DMSO-d6): δ (ppm) 188.512, 149.012×2, 148.685×2, 135.860×2, 134.237×2, 128.103×2, 123.823×2, 114.412×2, 112.629×2, 66.548×2, 55.629×2, 48.626×2, 46.418×4, 27.901×2, 26.613×2, 22.509, 11.768×4.…”

mentioning

confidence: 99%

Design, synthesis, and anticancer evaluation of long-chain alkoxylated mono-carbonyl analogues of curcumin

Weng

Chen

et al. 2015

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

Final results of Australasian Gastrointestinal Trials Group ARCTIC study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines

Cited by 59 publications

References 22 publications

A systematic review of raltitrexed-based first-line chemotherapy in advanced colorectal cancer

A systematic review of raltitrexed-based first-line chemotherapy in advanced colorectal cancer

Raltitrexed induces mitochondrial-mediated apoptosis in SGC7901 human gastric cancer cells

Design, synthesis, and anticancer evaluation of long-chain alkoxylated mono-carbonyl analogues of curcumin

Contact Info

Product

Resources

About