-
The Oncologist Jul 2007The incidence of malignant pleural mesothelioma (MPM) is increasing worldwide, and is predicted to peak in the next 10-20 years. Difficulties in MPM diagnosis and... (Review)
Review
The incidence of malignant pleural mesothelioma (MPM) is increasing worldwide, and is predicted to peak in the next 10-20 years. Difficulties in MPM diagnosis and staging, especially of early disease, have thwarted the development of a universally accepted therapeutic approach. Single modality therapies (surgery, radiotherapy, chemotherapy) have generally failed to significantly prolong patient survival. As a result, multimodality treatment regimens have been developed. Radical surgery with extrapleural pneumonectomy and adjuvant treatments has become the preferred option in early disease, but the benefits of such an aggressive approach have been questioned because of significant treatment-related morbidity and mortality. In the past few years, there have been several major advances in the management of patients with MPM, including more accurate staging and patient selection, improvements in surgical techniques and postoperative care, novel chemotherapy regimens with definite activity such as antifolate (pemetrexed or raltitrexed)-platinum combinations, and new radiotherapy techniques such as intensity-modulated radiation therapy. Induction chemotherapy followed by surgery and adjuvant radiotherapy has shown promising results. A number of molecular alterations occurring in MPM have been reported, providing broader insights into its biology and leading to the identification of new targets for therapy. However, currently available treatments still appear to have modest results. Further studies are needed to provide evidence-based recommendations for the treatment of early and advanced stages of this disease.
Topics: Combined Modality Therapy; Humans; Mesothelioma; Neoplasm Staging; Pleural Neoplasms; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 17673616
DOI: 10.1634/theoncologist.12-7-850 -
British Journal of Cancer 1998Since the publication of the results of phase I dose-finding studies, an extensive phase II and III clinical study programme has been undertaken to study the clinical... (Review)
Review
Since the publication of the results of phase I dose-finding studies, an extensive phase II and III clinical study programme has been undertaken to study the clinical efficacy and tolerability of the quinazoline folate analogue raltitrexed ('Tomudex'), a novel direct and specific inhibitor of thymidylate synthase. Two international phase III trials, studies 3 and 12, have compared raltitrexed 3 mg m(-2) with 5-fluorouracil (5-FU) plus low-dose leucovorin (LV) (Mayo regimen) or high-dose LV (Machover regimen) respectively. A North American study (study 10) was originally set up to compare two raltitrexed dosage arms (3.0 and 4.0 mg m[-2]) with 5-FU and low-dose LV, but the 4.0 mg m(-2) arm was discontinued prematurely because of excessive toxicity. Minimum follow-up times for studies 3, 10 and 12 were 15.5, 12 and 9 months, respectively (for data other than survival), with corresponding survival follow-up times of 26, 12 and 17 months. Objective response rates were similar for raltitrexed and 5-FU + LV, and palliative improvements were seen to a similar extent with both treatments in all phase III studies. Survival was statistically similar for raltitrexed and 5-FU + LV in both studies 3 and 12. Raltitrexed was, however, associated with inferior survival to 5-FU + low-dose LV in study 10, but there appears to be evidence that this was linked to an unconscious effect on investigator behaviour of early toxicity problems in this trial, in that patients appeared to be withdrawn from raltitrexed treatment without progression or protocolled toxicity. Moreover, it appeared that 5-FU + LV patients were continued on treatment after disease progression. 5-FU-based therapy was associated with a higher incidence of mucositis than raltitrexed in all studies, with the attainment of statistical significance in studies 3 and 12. Elevations in hepatic transaminase levels were seen with raltitrexed, but these are thought to be of no clinical significance. Overall, much greater levels of toxicity were seen with 5-FU + LV than with raltitrexed in early treatment cycles. In addition, retrospective UK audit data have shown the monthly cost of raltitrexed therapy to be similar to that of Mayo and continuous infusion 5-FU regimens, and appreciably lower than that of the de Gramont regimen of 5-FU (bolus + 22-h infusion) + high-dose LV. Thus, raltitrexed is an effective alternative to 5-FU-based therapy in patients with advanced colorectal cancer, with an acceptable and, unlike 5-FU, predictable toxicity profile. In particular, patients receiving raltitrexed may benefit from the minimization or avoidance of mucositis, and both patients and healthcare providers may find the convenient administration schedule of the drug advantageous.
Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Enzyme Inhibitors; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Quinazolines; Thiophenes; Thymidylate Synthase
PubMed: 9579851
DOI: 10.1038/bjc.1998.421 -
Experimental Biology and Medicine... Mar 2020Peritoneum is one of the most common metastatic sites of colorectal cancer (CRC). It has been reported that cytoreductive surgery combined with hyperthermic...
UNLABELLED
Peritoneum is one of the most common metastatic sites of colorectal cancer (CRC). It has been reported that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) prolongs the lifespan of patients with peritoneal carcinomatosis of colorectal origin (CRC-PC), while the drugs used for HIPEC are limited. We investigated the application of recombinant mutant human tumor necrosis factor-α (rmhTNF) combined with raltitrexed in the HIPEC treatment in a mice model with CRC-PC. , we detected the cytotoxicity and apoptosis of human colorectal cancer cells by 3–(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, Western blot, and TdT-mediated dUTP Nick End Labeling (TUNEL) assay. , we established xenograft models of CRC-PC and assessed the antitumor effect by imaging, peritoneal cancer index scoring, and TUNEL assay. The results showed that the combination of rmhTNF and raltitrexed under hyperthermia with a temperature of 42°C inhibited the growth of colorectal cancer cells significantly , and after HIPEC treatments with rmhTNF and raltitrexed, peritoneal tumor growth was prohibited . Our findings about the efficacy of rmhTNF and raltitrexed used for HIPEC to treat CRC-PC will provide experimental data and basis for their potential clinical application.
IMPACT STATEMENT
Colorectal peritoneal carcinomatosis exhibits poor prognosis and presents a treatment challenge. At present, the main treatment is surgery, supplemented by hyperthermic intraperitoneal chemotherapy (HIPEC), but the drugs used for HIPEC are limited. Our study found that the combination of recombinant mutant human TNF-α (rmhTNF) and raltitrexed (RTX) under hyperthermia with a temperature of 42°C had antitumor effect both and . The findings will provide experimental data and basis for the potential clinical application of rmhTNF and RTX, which might offer patients a new choice of therapeutic drugs.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma; Colorectal Neoplasms; HCT116 Cells; Humans; Injections, Intraperitoneal; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Peritoneal Neoplasms; Quinazolines; Recombinant Proteins; Thiophenes; Tumor Necrosis Factor-alpha
PubMed: 32041417
DOI: 10.1177/1535370220905047 -
Frontiers in Cardiovascular Medicine 2022The cardiotoxicity of fluoropyrimidines (FP) [5-Fluorouracil and Capecitabine] is often reported as acute cardiac ischemia with rest typical angina, signs of ischemia at...
The cardiotoxicity of fluoropyrimidines (FP) [5-Fluorouracil and Capecitabine] is often reported as acute cardiac ischemia with rest typical angina, signs of ischemia at electrocardiogram (ECG), and ventricular kinetics abnormalities. However, silent ischemia, effort-related toxicity, and ventricular arrhythmias (VA) have been also described. The aim of this study is to report a consecutive series of 115 patients with FP cardiotoxicity observed in a single center both within clinical prospective studies and during the clinical routine. The clinical presentation widely varied as regards symptoms, ECG abnormalities, and clinical outcomes. We report also the strategies used to prevent cardiotoxicity in a subgroup of 35 patients who continued o rechallenged FP therapy after cardiotoxicity. In nearly half of the patients, the cardiotoxicity was triggered by physical effort. Typical angina was rare: the symptoms were absent in 51% of cases and were atypical in half of the other cases. ST-segment elevation and VA were the most frequent ECG abnormality; however, ST segment depression or negative T waves were the only abnormalities in 1/3 of the cases. Troponins essays were often within the normal limits, even in presence of extensive signs of ischemia. The most effective strategy to prevent cardiotoxicity at rechallenge was reducing FP dosage and avoiding physical effort. Anti-ischemic therapies were not always effective. Raltitrexed was a safe alternative to FP. Fluoropyrimidine cardiotoxicity shows a wide variety of clinical presentations in real life, from silent ischemia to atypical symptoms, acute coronary syndrome, left ventricular dysfunction (LVD), VA, or complete atrio-ventricular block. Physical effort is the trigger of cardiotoxicity in nearly half of the cases. The recognition of cardiotoxicity cannot rely on symptoms only but requires an active screening with ECG and stress test in selected cases.
PubMed: 36186986
DOI: 10.3389/fcvm.2022.960240 -
BMC Cancer Mar 2023Anlotinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) which has exhibited encouraging clinical activity in advanced non-small cell lung cancer (NSCLC)...
BACKGROUND
Anlotinib is a multi-targeted receptor tyrosine kinase inhibitor (TKI) which has exhibited encouraging clinical activity in advanced non-small cell lung cancer (NSCLC) and soft tissue sarcoma. Raltitrexed is well known to be effective in the treatment of colorectal cancer in China. The present study aims to investigate the combinatory antitumor effect of anlotinib and raltitrexed on human esophageal squamous carcinoma cells and further explore the molecular mechanisms in vitro.
METHODS
Human esophageal squamous cell lines KYSE-30 and TE-1 were treated with anlotinib or raltitrexed, or both, then cell proliferation was measured by MTS and colony formation assay; cell migration and invasion were detected by wound-healing and transwell assays; cell apoptosis rate was studied by flow cytometry and the transcription of apoptosis-associated proteins were monitored by quantitative polymerase chain reaction (qPCR) analysis. Finally, western blot was performed to check phosphorylation of apoptotic proteins after treatment.
RESULTS
Treatment with raltitrexed and anlotinib showed enhanced inhibitory effects on cell proliferation, migration and invasiveness compared with raltitrexed or anlotinib monotherapy. Meanwhile, raltitrexed combined with anlotinib strongly increased cell apoptosis percentage. Moreover, the combined treatment down-regulated mRNA level of the anti-apoptotic protein Bcl-2 and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9), while up-regulated pro-apoptotic Bax and caspase-3 transcription. Western blotting showed that the combination of raltitrexed and anlotinib could inhibit the expression of phosphorylated Akt (p-Akt), Erk (p-Erk) and MMP-9.
CONCLUSIONS
This study indicated that raltitrexed enhanced the antitumor effects of anlotinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, providing a novel treatment option for patients with esophageal squamous cell carcinoma (ESCC).
Topics: Humans; Esophageal Squamous Cell Carcinoma; Carcinoma, Non-Small-Cell Lung; Esophageal Neoplasms; Matrix Metalloproteinase 9; Proto-Oncogene Proteins c-akt; Lung Neoplasms; Apoptosis
PubMed: 36870981
DOI: 10.1186/s12885-023-10691-y -
OncoTargets and Therapy 2020Apatinib has been proved effective in the treatment of advanced gastric cancer and a variety of solid tumors. Raltitrexed is emerging as a promising alternative for...
OBJECTIVE
Apatinib has been proved effective in the treatment of advanced gastric cancer and a variety of solid tumors. Raltitrexed is emerging as a promising alternative for treating advanced colorectal cancer in China. This work aims to study the combinatory antitumor effect of apatinib and raltitrexed on human esophageal squamous carcinoma cells (ESCC).
MATERIALS AND METHODS
Two VEGFR-2-positive human ESCC lines, KYSE-30 and TE-1, were treated with apatinib or raltitrexed, or both, then the cell proliferation rate was measured by MTS assay; cell migration and invasion were studied by transwell assays; cell apoptosis rate was determined by flow cytometry; cellular autophagy level affected was analyzed by Western blot analysis; finally, quantitative polymerase chain reaction (qPCR) was used to monitor transcription and Western blot was performed to check phosphorylation of apoptotic proteins after treatment.
RESULTS
Both apatinib and raltitrexed significantly inhibited KYSE-30 and TE-1 cell proliferation in a dose-dependent manner. Treatment with both drugs showed enhanced inhibitory effects on cell proliferation, migration, and invasiveness compared with apatinib monotherapy. Apoptosis percentages in both cell lines were also remarkably increased by the combined treatment. Moreover, the combination of apatinib and raltitrexed down-regulated mRNA level of the anti-apoptotic protein Bcl-2, while up-regulated pro-apoptotic protein PARP, Bax, and caspase-3 transcription. Western blot analysis showed that phosphorylation levels of Erk, Akt, and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9) were decreased in the combination group.
CONCLUSION
Taken together, these results indicate that raltitrexed enhances the antitumor effects of apatinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, implying a combination of raltitrexed and apatinib might be an effective option for treating esophageal squamous cell carcinoma patients.
PubMed: 33293826
DOI: 10.2147/OTT.S276125 -
Frontiers in Oncology 2022We reported the long-term outcomes of transcatheter chemoembolization (TACE) for patients with late-stage or recurrent oral carcinoma.
OBJECTIVE
We reported the long-term outcomes of transcatheter chemoembolization (TACE) for patients with late-stage or recurrent oral carcinoma.
METHODS
This retrospective study enrolled 18 patients with late-stage or recurrent oral carcinoma between December 2015 and April 2021. The tumor-feeding artery was catheterized, and cisplatin/oxaliplatin and 5-FU/raltitrexed were infused with embolization using polyvinyl alcohol or gelatin sponge. Computed tomography was performed at about 1, 3, and 6 months after the procedure, and every 6 months after that. During the procedure and follow-up, procedure outcomes, complications, treatment efficacy, and overall survival were analyzed.
RESULTS
A total of 31 sessions of TACE were performed, with a technical success rate of 100%. Of 12 patients combined with oral hemorrhage, two patients showed rebleeding 35 and 37 days later, with a clinical efficiency of hemostasis of 88.9%. Mild complications were observed in 11 patients (61.1%). Severe complications or procedure-related deaths were not observed during or after the procedure. The objective response rate and disease control rate were 20.0% and 86.7%, 38.5% and 61.5%, and 25.0% and 50.0% at 1, 3, and 6 months later, respectively. Seventeen patients (94.4%) were followed up, with a median duration of 37.8 months (IQR 22.3-56.8). Nine patients died of tumor progression, one died of massive rebleeding, and one died of severe lung infection. The median overall survival was 23.8 months.
CONCLUSION
TACE is a safe and effective procedure with minimal invasiveness for treating late-stage or recurrent oral carcinoma. TACE can be recommended as a palliative treatment, particularly for patients with oral hemorrhage.
PubMed: 35936680
DOI: 10.3389/fonc.2022.831583 -
Biochimica Et Biophysica Acta Jul 2002ZD9331 is an antifolate drug that potently and specifically inhibits thymidylate synthase (TS). In contrast with TS inhibitors such as raltitrexed, it cannot be... (Review)
Review
ZD9331 is an antifolate drug that potently and specifically inhibits thymidylate synthase (TS). In contrast with TS inhibitors such as raltitrexed, it cannot be polyglutamated, leading to antitumour activity independent of folylpolyglutamyl synthetase (FPGS) activity. The growth inhibition IC50 values for ZD9331 and raltitrexed were determined for a panel of 18 human tumour cell lines, that included six colon and six ovarian. The colon lines largely displayed overlapping sensitivities to both drugs with only one of the six lines being drug resistant. In contrast, the ovarian cell lines displayed non-overlapping sensitivities with four being highly resistant to raltitrexed and only one was cross-resistant to ZD9331. Studies were undertaken to explain these results. The colon and ovarian cell lines were characterised for TS activity, and TS and FPGS mRNA expression. TS activity correlated with sensitivity to ZD9331 (r=0.50; p=0.097) and raltitrexed (r=0.74; p=0.0063). Provided the data from the highly drug-resistant cell lines (BE and 41 M) were omitted, TS mRNA expression levels also correlated with ZD9331 (r=0.77; p=0.013) and raltitrexed IC50 (r=0.84; p=0.0031). FPGS mRNA expression correlated with higher sensitivity to raltitrexed relative to ZD9331 (higher ZD9331/raltitrexed IC50 ratios) (r=0.62; p=0.048). Similarly, cell lines with IC50 ratios>median expressed a 1.8-fold higher median level of FPGS mRNA (p=0.0087) compared with those with ratios
raltitrexed in ovarian tumour cell lines expressing low levels of FPGS. These data, and others demonstrating a lack of cross-resistance between cisplatin and ZD9331, support the clinical evaluation of ZD9331 in platinum-refractory ovarian cancer. Topics: Antineoplastic Agents; Colonic Neoplasms; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Folic Acid Antagonists; Gene Expression; Humans; Ovarian Neoplasms; Peptide Synthases; Quinazolines; RNA, Messenger; RNA, Neoplasm; Thiophenes; Thymidylate Synthase; Tumor Cells, Cultured
PubMed: 12084463
DOI: 10.1016/s0925-4439(02)00084-4 -
Annals of Translational Medicine Dec 20225-Fluorouracil and its oral prodrug, capecitabine, are frequently used in the treatment of gastrointestinal cancers-including gastric cancer-but carry a cardiotoxicity...
BACKGROUND
5-Fluorouracil and its oral prodrug, capecitabine, are frequently used in the treatment of gastrointestinal cancers-including gastric cancer-but carry a cardiotoxicity risk. Raltitrexed (brand name Tomudex), a direct inhibitor of thymidylate synthase, has been successfully used as an alternative to fluoropyrimidines in patients with 5-fluorouracil-induced cardiac events. We report the first case, to our knowledge, of raltitrexed used with trastuzumab and platinum-based chemotherapy as a substitute for fluoropyrimidines following cardiotoxicity in a 78-year-old male patient with metastatic gastric cancer.
CASE DESCRIPTION
The patient experienced a myocardial infarction 3 days after beginning treatment with capecitabine, carboplatin, and trastuzumab for metastatic HER2 gastric adenocarcinoma. Capecitabine was replaced with raltitrexed, and the patient ultimately received seven cycles of chemotherapy, five of which included raltitrexed. There were no cardiotoxic events attributable to raltitrexed, although the patient did experience hypotensive episodes, premature ventricular contractions, myelosuppression, and anemia. Progression-free survival was 4.5 months, within the expected range achieved with the ToGA regimen (trastuzumab, cisplatin, 5-fluorouracil chemotherapy). At time of writing, the patient has been alive for 48 weeks since diagnosis.
CONCLUSIONS
In summary, raltitrexed appears to be a safe alternative to fluoropyrimidines when combined with trastuzumab and platinum, although more data is needed to determine its relative effectiveness.
PubMed: 36618781
DOI: 10.21037/atm-2022-69 -
British Journal of Clinical Pharmacology Mar 2021Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5-fluorouracil (5FU) intolerance... (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5-fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m every 3 weeks. However, every 2 weeks administration at 2 mg/m demonstrated a favourable toxicity profile.
METHOD
We performed a randomized crossover comparative population PK study between every 2 weeks TOMOX (RTX 2 mg/m ) and every 3 weeks TOMOX (RTX 3 mg/m ).
RESULTS
A three-compartment model and a proportional error model best describe the data. Creatinine clearance and sex, but not body surface area (BSA), were covariates of RTX clearance leading to decrease of its interindividual variability of 28%. Weight and body surface area were covariates of central and peripheral volumes of distribution, respectively, leading to decreases of interindividual variability of 34.6% and 100%, respectively. In contrast to the dose, AUC was a good predictor of liver toxicity (P = 0.006, OR = 3.91, 95%CI = [1.48-10.34]). Using covariates to compute individual clearance and a threshold AUC (1.639, determined in this study), a covariates-based dose was calculated, leading to less variability in AUC than observed with the actual BSA-based or fixed doses.
CONCLUSION
These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA.
Topics: Cross-Over Studies; Fluorouracil; Humans; Liver; Quinazolines; Thiophenes
PubMed: 32789966
DOI: 10.1111/bcp.14519