Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low Cmax and improved tolerability, in patients with solid tumors

Ajani, Jaffer A.; Javle, Milind; Eng, Cathy; Fogelman, David R.; Smith, J.Lacey; Anderson, Barry; Zhang, Chun; Iizuka, Kenzo

doi:10.1007/s10637-020-00939-w

Cited by 5 publications

(5 citation statements)

References 36 publications

(43 reference statements)

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“…The inhibitory activity of DFP-11207 toward DPD and orotate phosphoribosyl transferase (OPRT) was comparable to that of CDHP and CTA alone. The pharmacokinetic study suggested that DFP-11207 resulted in lower C max and AUC values but longer T max and T 1/2 values of 5-FU, respectively, than S-1, which suggested that DFP-11207 is superior to avoid the 5-FU-induced severe hematological toxicity including neutropenia, in particular, thrombocytopenia, on top of the protection of 5-FU-induced GI toxicities. , …”

Section: Strategies To Counter Dpd-mediated Resistance To 5-fumentioning

confidence: 99%

“…The pharmacokinetic study suggested that DFP-11207 resulted in lower C max and AUC values but longer T max and T 1/2 values of 5-FU, respectively, than S-1, which suggested that DFP-11207 is superior to avoid the 5-FU-induced severe hematological toxicity including neutropenia, in particular, thrombocytopenia, on top of the protection of 5-FU-induced GI toxicities. 26,27 DPD Downregulators. Because sphingosine-1-phosphate receptor 2 (S1PR2) is closely associated with the expression of DPD in various cancer cells, inhibiting it may downregulate the DPD levels and finally reverse the 5-FU resistance.…”

Section: In Cancermentioning

confidence: 99%

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Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

Verma

Narendra

Raju

et al. 2022

ACS Pharmacol. Transl. Sci.

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5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutics for the treatment of cancers associated with the aerodigestive tract, breast, and colorectal system. The efficacy of 5-FU is majorly affected by dihydropyrimidine dehydrogenase (DPD) as it degrades more than 80% of administered 5-FU into an inactive metabolite, dihydrofluorouracil. Herein we discuss the molecular mechanism of this inactivation by analyzing the interaction pattern and electrostatic complementarity of the DPD–5-FU complex. The basis of DPD overexpression in cancer cell lines due to significantly distinct levels of the miRNAs (miR-134, miR-27b, and miR-27a) compared to normal cells has also been outlined. Additionally, some kinases including sphingosine kinase 2 (SphK2) have been reported to correlate with DPD expression. Currently, to address this problem various strategies are reported in the literature, including 5-FU analogues (bypass the DPD-mediated inactivation), DPD downregulators (regulate the DPD expression levels in tumors), inhibitors (as promising adjuvants), and formulation development loaded with 5-FU (liposomes, nanoparticles, nanogels, etc.), which are briefly discussed in this Review.

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Section: Strategies To Counter Dpd-mediated Resistance To 5-fumentioning

confidence: 99%

Section: In Cancermentioning

confidence: 99%

Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

Verma

Narendra

Raju

et al. 2022

ACS Pharmacol. Transl. Sci.

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“…The DPD inhibitors had combined with orally bioavailable fluorinated pyrimidine such as capecitabine or tegafur to verify the similar effect to continuous intra-venous infusion of 5-FU and did not prove molecules advantageous to continuous intra-venous infusion ( Kobayakawa and Kojima, 2011 ; Aguado et al, 2014 ). Furthermore, more oral fluoropyrimidine such as S1 (tegafur/gimeracil/oteracil) are in progress phase I clinical trials for tumors, including EC ( Ajani et al, 2020 ; Hosoda et al, 2020 ). However, up to date, the 5-FU is still the widest used fluorinated pyrimidine for cancer treatment.…”

Section: Resistance In Fluorinated Pyrimidinesmentioning

confidence: 99%

Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

Mao

Zeng

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Pharmaceutical therapies are essential for esophageal cancer (EC). For the advanced EC, the neoadjuvant therapy regimen, including chemotherapy plus radiotherapy and/or immunotherapy, is effective to achieve clinical benefit, even pathological complete response. For the unresectable, recurrent, and metastatic EC, the pharmaceutical therapy is the limited effective regimen to alleviate the disease and prolong the progression-free survival and overall survival. In this review, we focus on the pharmaceutical applications in EC treatment including cytotoxic agents, molecular targeted antibodies, and immune checkpoint inhibitors (ICIs). The chemotherapy regimen is based on cytotoxic agents such as platinum-based complexes, fluorinated pyrimidines and taxenes. Although the cytotoxic agents have been developed in past decades, the standard chemotherapy regimen is still the cisplatin and 5-FU or paclitaxel because the derived drugs have no significant advantages of overcoming the shortcomings of side effects and drug resistance. The targeted molecular therapy is an essential supplement for chemotherapy; however, there are only a few targeted therapies available in clinical practice. Trastuzumab and ramucirumab are the only two molecular therapy drugs which are approved by the US Food and Drug Administration to treat advanced and/or metastatic EC. Although the targeted therapy usually achieves effective benefits in the early stage therapy of EC, the patients will always develop drug resistance during treatment. ICIs have had a significant impact on routine clinical practice in cancer treatment. The anti-programmed cell death-1 monoclonal antibodies pembrolizumab and nivolumab, as the ICIs, are recommended for advanced EC by several clinical trials. However, the significant issues of pharmaceutical treatment are still the dose-limiting side effects and primary or secondary drug resistance. These defects of pharmaceutical therapy restrain the clinical application and diminish the effectiveness of treatment.

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“…An in vitro study using colon adenocarcinoma cells showed that a lethal dose 50% of continuous infusion of 5-FU was approximately 100 times lower than that administered in a pulsatile manner ( 12 ). In addition, it was reported that a continuous infusion of FU demonstrated higher therapeutic efficacy and minimal side effects compared with the bolus injection ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Gastrointestinal tumor-related perihepatic fluorouracil encapsulated lesions and liver metastases: a diagnostic imaging study based on contrast-enhanced computed tomography and magnetic resonance imaging

Li,

He,

Hao

et al. 2023

Quant Imaging Med Surg

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Background Perihepatic fluorouracil encapsulated lesions (FELs) can result in potentially confusing computed tomography (CT) and magnetic resonance imaging (MRI) features in postoperative examinations of gastrointestinal tumors. This retrospective study aimed to summarize the typical imaging features of FELs and determine the best imaging modality to distinguish FELs from liver metastases for junior residents. Methods Patients with FELs who had undergone gastrointestinal tumor surgery in Tongji Hospital from January 2016 to June 2022 were evaluated. The imaging features of FELs were summarized by two senior radiologists. Contrast-enhanced CT (CECT) was used as the primary follow-up tool for postoperative gastrointestinal tumor patients. Patients with FELs and available CECT and MRI examinations were matched with patients with liver metastases based on gender and age and presented in chronological order in a 2:1 ratio. Different imaging modality combinations were used for further evaluation, including a CECT group (modality Ⅰ), CECT and nonenhanced MRI group (modality Ⅱ) and CECT with all MRI sequences group (modality Ⅲ). Subsequently, two junior residents blindly evaluated three groups following a 4-week interval based on a 5-point scale (1= definite benign lesion, 2= probable benign lesion, 3= indeterminate, 4= probable liver metastasis, 5= definite liver metastasis). Results Imaging features of 33 patients with 36 FELs were analyzed. CECT and dynamic contrast-enhanced MRI (DCE-MRI) showed no enhancement in most lesions. Additionally, 20 patients with FELs meeting the requirements were matched with 40 patients with liver metastases. The highest sensitivity, specificity, and consistency for identifying liver metastases were achieved using a combination of CECT and MRI encompassing all sequences yielded, including modality Ⅰ (reader 1: 72.0% and 17.4%; reader 2: 62.0% and 17.4%; kappa value 0.295), modality Ⅱ (reader 1: 88.0% and 8.7%; reader 2: 92.0% and 34.8%; kappa value 0.259), and modality Ⅲ (reader 1: 98.0% and 34.8%; reader 2: 92.0% and 39.1%; kappa value 0.680). Conclusions FELs are typically non-enhancing lesions. In our study, two junior residents could best distinguish FELs from liver metastases using CECT with all MRI sequences.

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Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low Cmax and improved tolerability, in patients with solid tumors

Cited by 5 publications

References 36 publications

Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

Gastrointestinal tumor-related perihepatic fluorouracil encapsulated lesions and liver metastases: a diagnostic imaging study based on contrast-enhanced computed tomography and magnetic resonance imaging

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