Tomudex (raltitrexed)

P2, N=30, Not yet recruiting, Clinical Oncology School of Fujian Medical University,Fujian Cancer Hospital; Fujian Cancer Hospital

P2, N=110, Not yet recruiting, Fudan University

P2, N=124, Not yet recruiting, Fudan University

Using proliferation assays, we investigated their potential to protect cancer cells from cytotoxicity of the antifolates methotrexate, pemetrexed (Alimta), raltitrexed (Tomudex) and pralatrexate (Folotyn). However, protection from inhibition by various antifolates was solely achieved by l-LV and dl-LV. In general l-LV acts similar to the dl-LV formulations, however disparate effects were observed when d-LV and l-LV were used in combination, conceivably by d-LV affecting (anti)folate transport and intracellular metabolism.

All the synthesized compounds exhibited good anticancer activity, but among them, compounds 1n and 2j showed excellent anticancer activity, having IC50 values of 1.98 ± 0.69, 2.18 ± 0.93, 4.04 ± 1.06, and 4.18 ± 1.87 µM; and 1.48 ± 0.86, 3.18 ± 0.79, 3.44 ± 1.51, and 5.18 ± 1.85 µM, against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines respectively with control raltitrexed (IC50 1.07 ± 1.08, 1.98 ± 0.72, 1.34 ± 1.0, and 3.09 ± 0.96 µM, respectively) and hTS inhibitory activity with IC50 values of 20.47 ± 1.09 and 13.48 ± 0.96 nM with control raltitrexed (IC50 14.95 ± 1.01 nM)...Additionally, the assessment of physicochemical, biochemical, structural, and toxicological characteristics were also in the acceptable range for these compounds. Based on the anticancer activity of compounds, SAR was also performed for lead optimization.

CAP undergoes metabolism conversion to interfere pyrimidine metabolism, which targets TYMS-mediated differentiation of Th1, thereby playing a significant role in mitigating acute cardiac allograft rejection in murine models.

P=N/A, N=1115, Recruiting, RenJi Hospital

Irinotecan and 5-fluorouracil (FOLFIRI) was administered to another 50 patients, who served as the control group...Neutropenia (12.2%), thrombocytopenia (10.2%), anemia (27.3%), proteinuria (38.1%) and hematuria (21.0%) were also common grade 1-2 adverse events. In conclusion, TOMIRI may be recommended as an effective and safe second-line treatment for metastatic CRC in the clinic.

P2, N=42, Not yet recruiting, Fudan University

P2, N=42, Not yet recruiting, Fudan University

P2, N=66, Recruiting, West China Hospital

P=N/A, N=25, Recruiting, Anhui Provincial Hospital | N=59 --> 25

P=N/A, N=59, Recruiting, Anhui Provincial Hospital

Raltitrexed can inhibit the growth of esophageal cancer ECA109 cells and has a radiosensitization effect.

Second, minor changes in the raltitrexed molecule changed its target in Mtb from PptT to dihydrofolate reductase (DHFR). Third, the structure-activity relationship for over 800 raltitrexed analogs only became interpretable when we quantified and characterized the compounds' intrabacterial accumulation and transformation.

The positive rate of carcinoembryonic antigen mRNA in the raltitrexed intraperitoneal perfusion group (8.47%) was significantly lower than that in the saline intraperitoneal perfusion group (22.81%) after surgery. Raltitrexed perfusion during radical surgery is safe and feasible for elderly patients with CRC and can reduce the positive rate of carcinoembryonic antigen mRNA in peritoneal lavage fluid, so it can be explored as a treatment option.

Our study is the first to reveal that RTX induces prostate cancer cells apoptosis through inhibiting the expression of HSPA8 and further inducing ROS-mediated ER stress pathway action. This study suggests that RTX may be a novel promising candidate drug for prostate cancer therapy.

P2, N=39, Active, not recruiting, Fudan University | Recruiting --> Active, not recruiting | Trial completion date: Jun 2024 --> Feb 2024

P4, N=30, Recruiting, The First Affiliated Hospital of Nanchang University

Visual inspection and binding energy analysis revealed that the compounds OSU-03012, Raltitrexed, Ostarine (MK-2866), Dovitinib (TKI-258), and Varespladib (LY315920) had strong binding affinity for the MCL-1 protein. These findings suggest that these compounds may be useful as MCL-1 inhibitors in the treatment of breast cancer. However, additional experimental validation is required to confirm these findings.

The PFS and OS of irinotecan plus raltitrexed may be better than that of irinotecan monotherapy, especially in second line treatment, which should be confirmed with a phase III study including much more patients.

When we treated high and low PNP expressing CLL B-cells from untreated patients with drugs known to be active in CLL, interestingly we found high PNP expressing CLL B-cells are sensitive to Bcl2 inhibitor venetoclax and AXL kinase inhibitor TP-0903 versus low PNP expressing CLL B-cells...However treatment of CLL B-cells from untreated patients cultured alone or co-cultured with BMSCs with TYMS inhibitor raltitrexed did not show any killing indicating an alternate role of TYMS in BMSC cultured CLL B-cells...In conclusion, these results indicate that active purine and pyrimidine metabolism in CLL B-cells augmented by the BM environment can support CLL B-cell survival and drug resistance and possible induction of EMT components. Future studies are underway to understand the role and regulation of PNP and TYMS in CLL disease progression and drug resistance for both untreated and treated CLL patients.

No abstract available

Patients previously radically treated (surgery or CCRT), histologically confirmed, local or regional recurrence esophageal squamous carcinoma, qualified for the study design, were treated with 25-28 times radiotherapy plus raltitrexed once every 3 weeks for up to two cycles. Sintilimab has shown promising clinical efficacy and a manageable safety profile as maintenance therapy after CCRT for local/regional recurrent esophageal squamous carcinoma. In addition, further confirmation from a large-scale real-world study is still needed.

Based on the molecular docking studies, four ligands (T36, T39, T40, and T13) were identified to have better interactions and docking scores with the catalytic sites [dUMP (pyrimidine) and folate binding sites] of hTS protein than standard drug, raltitrexed...The designed molecules stabilized the inactive conformation of hTS, resulting in the inhibition of hTS. The designed compounds will undergo synthesis and biological evaluation, which may yield selective, less toxic, and highly potent hTS inhibitors.Communicated by Ramaswamy H. Sarma.

The incidence of any grade of treatment-related AEs was 88.6%, most of which were mild to moderate, and no treatment-related deaths occurred. Raltitrexed combined with S-1 and bevacizumab shows promising antitumor activity and safety and could be an alternative for patients with metastatic CRC who are refractory or intolerant to standard therapy.

Fruquintinib, regorafenib, trifluridine/tipiracil (TAS-102), panitumumab and cetuximab combined with single-agent chemotherapy regimens are currently recommended as third-line therapies for patients exhibiting disease progression...The mFOLFOX6 regimen was administered...Liver metastases (intestinal-type adenocarcinoma) were detected in November 2018, and second-line therapy with the FOLFIRI regimen was initiated in January 2019...Third-line therapy with fruquintinib, raltitrexed, and S-1 achieved a PR that permitted surgical resection and enabled a relatively long progression-free survival. The findings suggest that the three agents regimen might be clinically effective as late-line therapy for mCRC.

The efficacies of DEB-TACE loaded with pirarubicin, raltitrexed, or arsenic trioxide in treating HCC were generally comparable, and the survival benefit of patients was similar. The short-term efficacy of the pirarubicin group and arsenic trioxide group was slightly better than that of the raltitrexed group.

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).

Our study shows that RSK4 is a key target of raltitrexed in the regulation of gastric cancer cell proliferation, cell cycle progression, and apoptosis.

P1/2, N=50, Not yet recruiting, China Medical University, China

We tested the effect of UNG2 KO on the efficacy of multiple TS inhibitors (5-fluorouracil, fluorodeoxyuridine, pemetrexed, and raltitrexed), and we determined that only fluorodeoxyuridine and raltitrexed were significantly more potent in UNG2 KO cells compared to wild-type HT29 cells (fluorodeoxyuridine IC50: 2 mM (wt) vs. 3 nM (KO); raltitrexed IC50: 14 nM (wt) vs. 2 nM (KO)). Interestingly, UNG2 protein levels can also be depleted by the HDAC inhibitors SAHA and MS275, providing a pharmacologic strategy to reduce UNG2 activity in cells...Our combined genetic and pharmacologic strategies targeting UNG2 activity in cells are defining cell death mechanisms for combination therapies of TS inhibitors and HDAC inhibitors. Future work will examine these drug combinations in additional cell lines to understand optimal therapeutic combinations and to further refine mechanisms of cell death.

The combination of irinotecan with raltitrexed is an efficient, convenient, and acceptable toxic regimen for second-line treatment for mCRC patients.

DEB-TACE loaded with epirubicin and raltitrexed improves the short-term outcomes, reduces the tumor load, decreases the incidence of adverse events, and improves the survival rate in patients with intermediate and advanced PHC.

To show that crystallographic and inhibition kinetic information can provide indicators of cancer cell growth inhibition by combinations of two anti-human thymidylate synthase (hTS) drugs, we obtained the X-ray crystal structure of the hTS:raltitrexed:5-fluorodeoxyuridine monophosphate (FdUMP) complex...When administered in combination to A2780 and A2780/CP ovarian cancer cells, the two drugs inhibited ovarian cancer cell growth additively/synergistically. Together, these results support the idea that X-ray crystallography can provide structural indicators for designing combinations of hTS (or any other target)-directed drugs to accelerate preclinical research for therapeutic application.

P2, The RS regimen demonstrated favorable effects in patients with mCRC following failure of standard chemotherapy, and could be a new choice for third-line treatment, and must be verified in future randomized clinical trials (Clinical trial: NCT02618356).

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. 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.

Here, we investigated the efficacies of approved antifolates, methotrexate, pemetrexed, and raltitrexed (RTX), on MYCN-amplified and nonamplified neuroblastoma cell lines. Interestingly, RTX treatments induced single-stranded DNA damage response in MYCN-amplified cells to a greater extent than in the non-amplified cells. We propose that the high DNA replication stress and elevated levels of DNA damage, which are a result of deregulated expression of MYCN target genes, could be the cause of increased sensitivity to RTX.

Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and/or 5-FU and/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs.