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Expert Review of Anticancer Therapy Oct 2011Raltitrexed is a cytotoxic agent, rationally designed to inhibit a specific molecular target, thymidylate synthase. In contrast to other agents, raltitrexed inhibits... (Review)
Review
Raltitrexed is a cytotoxic agent, rationally designed to inhibit a specific molecular target, thymidylate synthase. In contrast to other agents, raltitrexed inhibits thymidylate synthase directly and specifically in a mixed, noncompetitive manner, which may lead to an improved toxicity profile. After promising Phase II trials exploring the activity of raltitrexed either as a single agent or in combination with a platinum agent, a Phase III randomized study demonstrated that the combination of raltitrexed and cisplatin improves overall survival in malignant pleural mesothelioma (MPM) and is superior compared with cisplatin alone, without harmful effect on health-related quality of life. Moreover, the cost-effectiveness analysis found raltitrexed plus cisplatin to be cost effective compared with cisplatin and compared with active supportive care. Based on these results, raltitrexed is registered for the treatment of MPM in several European countries. MPM is hard to treat and has a poor prognosis. New treatment options, such as a combination of cisplatin and raltitrexed, which improve patient outcomes with no detrimental effect on quality of life, are a welcome addition to our therapeutic portfolio.
Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Humans; Mesothelioma; Pleural Neoplasms; Quinazolines; Randomized Controlled Trials as Topic; Thiophenes; Thymidylate Synthase; Treatment Outcome
PubMed: 21999120
DOI: 10.1586/era.11.136 -
Expert Opinion on Drug Metabolism &... Nov 2009Raltitrexed was developed as a direct and specific inhibitor of thymidylate synthase. Early clinical trials showed similar activity to 5-fluorouracil (5-FU), mainly in... (Review)
Review
BACKGROUND
Raltitrexed was developed as a direct and specific inhibitor of thymidylate synthase. Early clinical trials showed similar activity to 5-fluorouracil (5-FU), mainly in metastatic colorectal cancer (MCRC).
METHODS
Pharmacokinetics are summarized and Phase III adjuvant and MCRC trials of raltitrexed are reviewed.
RESULTS
Response rates and overall survival with raltitrexed in MCRC are equivalent to 5-FU. Pooled analysis showed relapse free survival was 1 month longer with 5-FU compared with raltitrexed. Grade 3+ toxicity rates with raltitrexed compare favorably with 5-FU. Unexpectedly, however, treatment-related mortality (TRM) was greater with raltitrexed, mainly due to protocol violations. TRM was also greater in the adjuvant trial, leading to its discontinuation. In spite of excess TRM, much of which could have been avoided, overall survival was the same as with 5-FU. Quality of life was variously reported as better or inferior to 5-FU.
CONCLUSION
The simple once every 3 week regimen of raltitrexed has not fulfilled its promise. Meanwhile, the field change in MCRC management has left little space for raltitrexed. Withdrawal of the sponsor's support has left raltitrexed without the level of continuing investigation afforded to 5-FU. The use of raltitrexed in Canada is limited to patients exhibiting intolerance - mucosal, hematological and cardiac - to 5-FU.
Topics: Animals; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Humans; Quinazolines; Thiophenes; Thymidylate Synthase; Tissue Distribution
PubMed: 19863453
DOI: 10.1517/17425250903307455 -
Clinics and Research in Hepatology and... Apr 2014To evaluate the efficiency and safety profile of raltitrexed-based chemotherapy in the treatment of advanced colorectal cancer. (Meta-Analysis)
Meta-Analysis Review
AIMS
To evaluate the efficiency and safety profile of raltitrexed-based chemotherapy in the treatment of advanced colorectal cancer.
METHODS
An electronic search was undertaken to identify randomized controlled trials comparing raltitrexed-based regimen to 5-fluorouracil-based regimen in patients with advanced colorectal cancer. The outcomes included overall survival, overall response rate and toxicities.
RESULTS
This meta-analysis included 11 studies with 4622 patients. Overall, there were no significant differences between the two regimens in terms of overall survival (HR=1.06, 95% CI: 0.96-1.17, P=0.23) or overall response rate (RR=1.09, 95% CI: 0.86-1.38, P=0.47). In subgroup analysis, patients in raltitrexed/oxaliplatin group had significantly higher partial response (RR=1.53, 95% CI: 1.17-2.00, P=0.002), overall response rate (RR=1.42, 95% CI: 1.10-1.82, P=0.006), disease control rate (RR=1.16, 95% CI: 1.04-1.29, P=0.009) and lower progressive disease (RR=0.61, 95% CI: 0.45-0.84, P=0.002) when compared to 5-fluorouracil/leucovorin/oxaliplatin group. Occurrence of severe anemia (RR=2.23, 95% CI: 1.38-3.59, P=0.0001), asthenia (RR=2.29, 95% CI: 1.36-3.84, P=0.002), hepatic disorders (RR=7.51, 95% CI: 1.30-43.56, P=0.02), and nausea/vomit (RR=1.70, 95% CI: 1.03-2.81, P=0.04) were significantly higher with the raltitrexed arm treatment, while frequencies of grade 3/4 alopecia (RR=0.36, 95% CI: 0.26-0.50, P<0.00001) and stomatitis/mucositis (RR=0.14, 95% CI: 0.07-0.31, P<0.00001) were increased in the 5-fluorouracil group.
CONCLUSIONS
Raltitrexed-based chemotherapy regimen leads to an equivalent overall survival and response rates with acceptable toxicities compared to traditional 5-fluorouracil-based regimen in patients with advanced colorectal cancer. Raltitrexed can be a treatment option for these patients when 5-fluorouracil-based regimens are not tolerated or inappropriate.
Topics: Alopecia; Anemia; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Mucositis; Nausea; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Randomized Controlled Trials as Topic; Stomatitis; Thiophenes; Vomiting
PubMed: 24388340
DOI: 10.1016/j.clinre.2013.11.006 -
Annals of Oncology : Official Journal... Apr 2002Raltitrexed ('Tomudex') monotherapy is a conveniently administered alternative to 5-fluorouracil (5-FU) in the first-line treatment of advanced colorectal cancer (CRC),... (Review)
Review
Raltitrexed ('Tomudex') monotherapy is a conveniently administered alternative to 5-fluorouracil (5-FU) in the first-line treatment of advanced colorectal cancer (CRC), and has single-agent activity in a variety of advanced solid tumours. Although both raltitrexed and 5-FU are thymidylate synthase inhibitors, raltitrexed has a specific mode of action and a toxicity profile distinct from 5-FU. The mechanism of action of raltitrexed is also completely different from that of oxaliplatin, irinotecan and other drugs with which it has been combined. These properties, together with preclinical data, suggested that combinations of raltitrexed with 5-FU, other chemotherapeutic agents, or radiotherapy could result in improved therapies for a variety of advanced solid tumours, including advanced CRC. This review outlines the appropriate management of patients treated with raltitrexed, whether as monotherapy or in combination, and discusses the preliminary results of combination studies with raltitrexed in a range of tumour types including advanced CRC, malignant mesothelioma, gastric, pancreatic, head and neck, and non-small-cell lung cancers. Of particular interest is the combination of raltitrexed and oxaliplatin, which has shown promising antitumour effects in first-line treatment of advanced CRC and malignant mesothelioma, a disease that is refractory to chemotherapy.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Mesothelioma; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Thiophenes
PubMed: 12056700
DOI: 10.1093/annonc/mdf054 -
Anti-cancer Drugs Jul 2001Preclinical evidence of a schedule-dependent synergism between raltitrexed and 5-fluorouracil (5-FU) has prompted clinical studies of this combination. We review the... (Review)
Review
Preclinical evidence of a schedule-dependent synergism between raltitrexed and 5-fluorouracil (5-FU) has prompted clinical studies of this combination. We review the main preclinical and clinical results of raltitrexed/5-FU-based combination chemotherapy regimens in anticancer therapy. Promising results include: response rates of 25 and 23% with combinations of raltitrexed/5-FU/levofolinic acid (LFA) as first-line treatment and oxaliplatin/raltitrexed/5-FU/LFA as second-line treatment of metastatic colorectal cancer, respectively; and a 67% response rate in a phase I study of cisplatin/raltitrexed/5-FU/LFA as first-line treatment of advanced head and neck cancer, including a 100% response rate at the recommended dose. These combinations were well tolerated, with neutropenia as the main dose-limiting toxicity, allowing the drugs to be combined at the doses used in monotherapy. These results suggest a role for raltitrexed within combination regimens in colorectal cancer therapy, as well as other tumors such as head and neck cancer. A further potential application of raltitrexed in combination therapies is within multidisciplinary chemo-radiotherapy strategies, mainly in rectal cancer. Phase II studies are planned/ongoing to investigate these interesting possibilities.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Neoplasm Metastasis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Rectal Neoplasms; Thiophenes
PubMed: 11459994
DOI: 10.1097/00001813-200107000-00001 -
BMC Pharmacology & Toxicology Aug 2022Raltitrexed is a specific inhibitor of thymidylate synthase and a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In this study, we...
BACKGROUND
Raltitrexed is a specific inhibitor of thymidylate synthase and a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In this study, we investigated the effect of raltitrexed on the proliferation of HGC-27 human gastric cancer cells and its potential underlying molecular mechanism(s).
METHODS
RT-qPCR and western blotting were used to quantify RSK4 levels. Colony formation and flow cytometry assays were used to assess HGC-27 cell proliferation, cell cycle progression, mitochondrial membrane potential, and apoptosis. The expression of cell cycle and apoptosis markers were determined by western blotting.
RESULTS
Our results demonstrate that raltitrexed upregulated RSK4 mRNA and protein levels in HGC-27 cells. Moreover, raltitrexed significantly inhibited tumor cell colony formation, arrested the cell cycle, decreased the mitochondrial membrane potential, and induced apoptosis. We observed that raltitrexed was capable of upregulating the expression of Bax, cyclin A1, and CDK3, and downregulating the expression of Bcl-2 and cleaved caspase-3. Importantly, siRNA-mediated RSK4 knockdown significantly reduced the inhibitory effect of raltitrexed on cell proliferation and its promotion of cell apoptosis. Moreover, silencing of RSK4 inhibited the raltitrexed-induced upregulation of cytochrome C. In addition, the changes in molecular markers related to the cell cycle and apoptosis induced by raltitrexed were reduced upon RSK4 depletion.
CONCLUSION
Our study shows that RSK4 is a key target of raltitrexed in the regulation of gastric cancer cell proliferation, cell cycle progression, and apoptosis.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Quinazolines; Stomach Neoplasms; Thiophenes
PubMed: 36031631
DOI: 10.1186/s40360-022-00605-2 -
Science (New York, N.Y.) Jul 2013The efficacy of therapeutics is dependent on a drug binding to its cognate target. Optimization of target engagement by drugs in cells is often challenging, because drug...
The efficacy of therapeutics is dependent on a drug binding to its cognate target. Optimization of target engagement by drugs in cells is often challenging, because drug binding cannot be monitored inside cells. We have developed a method for evaluating drug binding to target proteins in cells and tissue samples. This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins. Using this assay, we validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues. CETSA is likely to become a valuable tool for the validation and optimization of drug target engagement.
Topics: Antimetabolites, Antineoplastic; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Monitoring; Folic Acid Antagonists; Hot Temperature; Humans; Kidney; Ligands; Liver; Molecular Targeted Therapy; Pharmaceutical Preparations; Protein Binding; Protein Stability; Proteins; Quinazolines; Thiophenes; Tissue Distribution
PubMed: 23828940
DOI: 10.1126/science.1233606 -
Drug and Therapeutics Bulletin Oct 1996Each year about 26,000 people in Britain develop colorectal cancer. Roughly half of these patients die from locally advanced or metastatic disease. Systemic... (Review)
Review
Each year about 26,000 people in Britain develop colorectal cancer. Roughly half of these patients die from locally advanced or metastatic disease. Systemic chemotherapy, usually with regimens including fluorouracil, can prolong survival in patients with advanced or recurrent disease and may improve their quality of life. [symbol: see text] Raltitrexed (Tomudex-Zeneca), a new class of cytotoxic drug introduced last year, is claimed to simplify treatment and be as effective as one established fluorouracil regimen while causing less toxicity. We review raltitrexed and assess its place in the treatment of patients in whom colorectal cancer is advanced.
Topics: Antimetabolites, Antineoplastic; Colorectal Neoplasms; Humans; Quinazolines; Thiophenes
PubMed: 8936802
DOI: No ID Found -
Drugs Mar 1998Raltitrexed (ZD-1694) is a quinazoline-based folate analogue that exerts its cytotoxic activity by the specific inhibition of thymidylate synthase. In vitro studies show... (Review)
Review
Raltitrexed (ZD-1694) is a quinazoline-based folate analogue that exerts its cytotoxic activity by the specific inhibition of thymidylate synthase. In vitro studies show that raltitrexed is actively transported into cells and is then rapidly and extensively metabolised to a series of polyglutamates. These metabolites are significantly more potent inhibitors of thymidylate synthase than the parent drug and are retained intracellularly, producing prolonged cytotoxic effects without the need for continuous drug exposure. Phase III clinical trials in patients with advanced colorectal cancer evaluated raltitrexed 3 mg/m2 administered as a 15-minute intravenous infusion once every 3 weeks. This schedule produced objective response rates of 14.3 to 19.3%, which were similar to those in patients treated with fluorouracil plus leucovorin (15.2 to 18.1%). Median survival durations ranged from 9.7 to 10.9 months with raltitrexed treatment and from 10.2 to 12.7 months with fluorouracil plus leucovorin. The major toxicities associated with raltitrexed involve the haematological and gastrointestinal systems, although severe asthenia also occurred in 6 to 18% of patients receiving the drug. Grade 3 or 4 nausea or vomiting occurred in up to 13% of raltitrexed recipients and grade 3 or 4 diarrhoea in up to 14%. Similar incidences of grade 3 or 4 nausea or vomiting and diarrhoea were seen with fluorouracil plus leucovorin treatment. Raltitrexed generally showed significant advantages over fluorouracil plus leucovorin with respect to the incidence of leucopenia and mucositis. A greater proportion of raltitrexed than fluorouracil plus leucovorin recipients were able to receive the scheduled dosage. Thus, with its similar efficacy to fluorouracil-based regimens, convenient administration schedule and favourable tolerability profile, raltitrexed provides clinicians with a worthwhile alternative to fluorouracil-based treatment for patients with advanced colorectal cancer.
Topics: Antimetabolites, Antineoplastic; Clinical Trials as Topic; Colorectal Neoplasms; Enzyme Inhibitors; Folic Acid Antagonists; Humans; Quinazolines; Thiophenes; Thymidylate Synthase
PubMed: 9530547
DOI: 10.2165/00003495-199855030-00012 -
European Journal of Cancer (Oxford,... Mar 1999Agents for use in combination therapy should be effective as monotherapy in the tumour type of interest, have different mechanisms of action or pharmacology, and... (Review)
Review
Agents for use in combination therapy should be effective as monotherapy in the tumour type of interest, have different mechanisms of action or pharmacology, and preferably non-overlapping toxicity profiles. Raltitrexed is effective as monotherapy in a number of tumour types, but it is hoped that combining it with other cytotoxic agents will lead to enhanced efficacy. Raltitrexed and 5-fluorouracil (5-FU) are specific and non-specific inhibitors, respectively, of thymidylate synthase, a critical enzyme in the de novo synthesis of DNA. Preclinical studies have indicated that raltitrexed and 5-FU have an incompletely overlapping spectrum of antitumour activity and may have additive or synergistic effects on colon carcinoma cells. These interactions are schedule-dependent (raltitrexed should precede 5-FU). Pre-treatment of colon carcinoma cells with raltitrexed has also been shown to increase intracellular levels of phosphoribosyl pyrophosphate resulting in increased incorporation of 5-FU nucleotides into RNA. Raltitrexed has a different mechanism of action from two other new agents active in colorectal cancer, irinotecan and oxaliplatin, and tumours are therefore not necessarily cross-resistant. Short pre-exposure of colon carcinoma cells to the irinotecan active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), prior to exposure to raltitrexed has consistently resulted in synergistic cell kill, whereas the reverse sequence is antagonistic. Preliminary results indicate that equitoxic doses of raltitrexed and cisplatin, or oxaliplatin, are antagonistic in two colon carcinoma cell lines. However, because there are major difficulties in translating preclinical drug combination results to the clinical settings, these results should be interpreted with caution.
Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Quinazolines; Thiophenes; Tumor Cells, Cultured
PubMed: 10645207
DOI: 10.1016/s0959-8049(99)00041-6