Palifosfamide Tromethamine

This study aims to design and develop novel and efficient anti-hypoxic cell tumor drugs. Using the TH-302 as lead compound, structural modifications are conducted to synthesize a series of novel derivatives to investigate the structural activity relationship (SAR) against ovarian cancer cell line (SKOV3) and glioblastoma cell line (U87MG) in vitro. The structural modifications mainly include four aspects: changes in substituents on N; changes in isomers; changes in nitro group position; changes in substituting halogens in phosphoramide mustard. The results of CCK-8 assay indicate that the steric hindrance and electronic effects of substituents on N have significant impacts on the activity, while changes in nitro group positions have minimal effects on the activity, and Bromo-phosphoramide mustard exhibits better activity than Chloro-phosphoramide mustard. Compounds 15c and 16d exhibit significantly superior antitumor activity compared to TH-302, with IC₅₀ values of 42 μM and 32 μM for SKOV3 cells, and IC₅₀ values of 47 μM and 41 μM for U87MG cells, respectively.

MRP-1 is implicated in multidrug resistance and was described as prognostic in high-risk patients with soft-tissue sarcoma (STS) in a previous study. The current research aimed to validate MRP-1 prognostic/predictive value in localized sarcomas treated with anthracyclines plus ifosfamide within the ISG-1001 phase III study. In addition, the inhibitory activity on MRP-1 was investigated in preclinical studies to identify new combinations able to increase the efficacy of standard chemotherapy in STS. MRP-1 expression was assessed by IHC in tissue microarrays from patients with STS and tested for correlation with disease-free survival (DFS) and overall survival (OS). In vitro studies tested the efficacy of MRP-1 inhibitors (nilotinib, ripretinib, selumetinib, and avapritinib) in sarcoma cell lines. The effect of combinations of the most active MRP-1 inhibitors and chemotherapy was measured on the basis of apoptosis. MRP-1 was evaluable in 231 of 264 cases who entered the study. MRP-1 expression (strong intensity) was independently associated with worse DFS [HR, 1.78; 95% confidence interval (CI), 1.11–2.83; P = 0.016], in the multivariate analysis, with a trend for a worse OS (HR, 1.78; 95% CI, 0.97–3.25; P = 0.062). In vitro studies showed that the addition of MRP-1 inhibitors (nilotinib or avapritinib) to doxorubicin plus palifosfamide, significantly increased cell death in SK-UT-1 and CP0024 cell lines. MRP-1 is an adverse predictive factor in localized high-risk patients with STS treated with neoadjuvant anthracyclines plus ifosfamide followed by surgery. In vitro findings support the clinical assessment of the combination of chemotherapy and MRP-1 inhibitors as a promising strategy to overcome the drug ceiling effect for chemotherapy.