Tomudex (raltitrexed)

CAP targets TYMS to induce ferroptosis by activating NOX, thereby inhibiting HCC progression.

Compared with 5-fluorouracil, raltitrexed offers distinct pharmacokinetic and practical advantages, including prolonged intracellular retention and a short infusion schedule...Accumulating evidence from retrospective studies, prospective single-arm trials, and limited comparative analyses suggests that raltitrexed-based regimens demonstrate meaningful antitumor activity in conventional and drug-eluting bead TACE, as well as in oxaliplatin-based HAIC, with objective response rates, disease control, and survival outcomes comparable to established chemotherapy protocols...Overall, raltitrexed represents a rational and increasingly utilized component of arterial-based therapies for unresectable HCC. However, current evidence is predominantly derived from retrospective and single-arm studies, and well-designed randomized trials and biomarker-driven approaches are required to define its optimal role in clinical practice.

In conclusion, raltitrexed peritoneal infusion chemotherapy is effective and safe for the treatment of patients with intermediate and advanced CC; it can effectively reduce serum tumour marker levels and adverse reaction incidence and improve the survival quality of patients. Raltitrexed peritoneal infusion chemotherapy thus exhibits high clinical application value.

P=N/A, N=42, Chongqing Medical University First Affiliated Hospital; Chongqing Medical University First Affiliated Hospital

For patients with advanced CRC (T3/T4), laparoscopic radical resection combined with intraoperative raltitrexed IPC is feasible and exhibits an acceptable short-term safety profile. Observed short-term changes in tumor markers are considered exploratory findings and require validation in subsequent, large-scale prospective studies with extended follow-up periods.

In this phase II trial, raltitrexed did not show significant response rates in patients with advanced CRC. Due to limited ORR of raltitrexed, value of TS expression as a biomarker was inconclusive. No new safety signals for raltitrexed were demonstrated.

Previously, we established that treating HCT116 colon cancer cell lines with either raltitrexed (RTX) or 5-fluoro-2'-deoxyuridine (5FdUR), two potent inhibitors of thymidylate synthase, results in characteristic genomic uracil patterns...The mutational spectra and the clustered nature of these transitions suggested the involvement of APOBEC3 DNA cytidine deaminases, several of which were induced under these conditions. Notably, this mutagenic response coincides with decreased cytotoxicity compared with the low-dose 5FdUR or any efficient doses of RTX, providing insights that may be relevant for personalized cancer therapy.

In vitro validation narrowed compounds of interest to raltitrexed, alisertib, GTX-007, LY315920, and PD0325901. Treatment with alisertib leads to decrease in H2AK119ub and shift in the immune tumor microenvironment. Alisertib efficacy in HGSC is dependent on functional CBX2 and cell target engagement confirms selectivity for CBX2, supporting that alisertib activity involves CBX2 inhibition.

P1, N=42, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

Compounds 1c and 2i exhibited potent TS inhibition with IC50 values of 11.50 ± 1.08 nM and 17.12 ± 0.91 nM, respectively, comparable to the standard drug raltitrexed (IC50 = 12.51 ± 0.91 nM)...Additionally, compounds 1c and 2i exhibited good stability in 300 ns molecular dynamics simulations along with acceptable drug-like properties and oral bioavailability. These findings suggest that compounds 1c and 2i are promising lead candidates for the development of TS inhibitors.

The TOMOX-Bev combination is a feasible second-line mCRC treatment with an acceptable toxicity profile. Recruitment failure prevents efficacy conclusions, but TOMOX-Bev may be an alternative if fluropyrimidines are contraindicated.

P2, N=38, Recruiting, Nanfang Hospital, Southern Medical University