Cardiotoxicity induced by fluoropyrimidine drugs in the treatment of gastrointestinal tumors

In this editorial,we review the article published in World J Gastrointest Oncol 2019,11:1031-1042.We specifically focus on the occurrence,clinical characteristics,and risk factors of fluoropyrimidine drug-related cardiotoxicity in patients with gastrointestinal tumors.Despite significant advancements in diagnostic and therapeutic techniques that have reduced mortality rates associated with digestive system tumors,the incidence and mortality rates of treatment-related car-diotoxicity have been increasing,severely impacting the survival and prognosis of cancer patients.Fluoropyrimidine drugs are widely used as antimetabolites in the treatment of malignant tumors,including gastrointestinal tumors,and they represent the second largest class of drugs associated with cardiotoxicity.However,there is often a lack of awareness or understanding regarding their cardiotoxic effects and associated risks.

The efficacy of fluoropyrimidine.based adjuvant chemotherapy on biliary tract cancer after R0 resection

Background: The optimal treatment strategy for biliary tract cancer(BTC) after curative?intent resection remains con?troversial. The purpose of this study was to evaluate the efficacy of fluoropyrimidine?based adjuvant chemotherapy for BTC patients undergoing microscopically margin?negative(R0) resection.Methods: We retrospectively analyzed the clinical data of BTC patients who underwent curative?intent R0 resection. Patients were eligible if they received either fluoropyrimidine?based adjuvant chemotherapy or observation after R0 resection.Results: A total of 153 patients were included. In the entire patient cohort, no significant differences were observed in 5?year overall survival(OS) rates(48.4% vs. 39.6%, P = 0.439) or 3?year recurrence?free survival(RFS) rates(49.1% vs. 39.5%, P = 0.299) between patients who received fluoropyrimidine?based adjuvant chemotherapy or observation. However, for patients with stages Ⅱ and Ⅲ BTC, chemotherapy significantly improved 5?year OS rate(52.4% vs. 35.6%, P = 0.002) and 3?year RFS rate(55.5% vs. 39.1%, P = 0.021) compared with observation.Conclusion: Fluoropyrimidine?based adjuvant chemotherapy may prolong the survival of patients with stages Ⅱ and Ⅲ BTC after R0 resection.

Fluoropyrimidine-induced cardiotoxicity

Cardio-oncology is a discipline based on early screening,monitoring,and treating chemotherapy-induced cardiotoxicity.There are many chemotherapeutics known for their cardiac toxic effects,including fluoropyrimidines.Fluoropyrimidine represents the cornerstone of many types of cancer and each year almost two million cancer patients undergo this treatment.Fluoropyrimidine-induced cardiotoxicity can be manifested in several forms,from angina pectoris to sudden death.This paper is a review of how the cardiotoxicity of fluoropyrimidines is presented,the mechanisms of its occurrence,its diagnosis,and management.

The use of pharmacogenetics to increase the safety of colorectal cancer patients treated with fluoropyrimidines

Fluoropyrimidines(FP)are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast,head and neck and gastric cancer.FP present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening toxicity.With the high number of patients receiving FP-based therapies,and the significant effects of toxicities on their quality of life,the prevention of FP-related adverse events is of major clinical interest.Host genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase(DPYD)gene are related to the occurrence of extremely severe,early onset toxicity in FP treated patients.The pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic guidelines.Several prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical practice.Multiple pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways,TYMS and MTHFR,but no additional clinically validated genetic markers of toxicity are available to date.The development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic markers.Moreover,the investigation of the genetic variation in the patients immunological system,a pivotal target in cancer treatment,could bring notable advances in the field.This review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.

CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild-type metastatic colorectal cancer patients:promising findings from a prospective,open-label,randomized,phase III trial

Background:The 5-fluorouracil/leucovorin plus oxaliplatin(FOLFOX)regimen is the standard first-line treatment for metastatic colorectal cancer(mCRC),however,the optimal second-line regimen for KRAS wild-type mCRC patients is still investigational.In this study,we aimed to determine the clinical efficacy and safety of CMAB009 plus irinotecan compared to irinotecan-only as a second-line regimen for treating KRAS wild-type mCRC patients.Methods:Patients with KRAS wild-type mCRC who had previously failed to respond to FOLFOX treatment were ran-domly assigned in a 2:1 ratio,to receive CMAB009 plus irinotecan or irinotecan-only.Patients receiving irinotecan-only were permitted to switch to CMAB009 therapy on disease progression and were grouped as the sequential-CMAB009 arm.The primary endpoints were overall response rate(ORR)and median progression-free survival(PFS).The second-ary endpoints were median overall survival(OS),disease control rate(DCR),clinical benefit rate(CBR),and duration of response(DOR).Results:The CMAB009 plus irinotecan arm demonstrated significantly improved ORR(33.2%vs.12.8%;P<0.001)and longer median PFS(169 days vs.95 days;P<0.001)as compared to the irinotecan-only arm.Patients receiv-ing CMAB009 plus irinotecan also demonstrated improved DCR(80.1%vs.65.2%,P<0.001),CBR(30.0%vs.14.6%,P<0.001),and DOR(210 days vs.109 days;P<0.001)as compared to irinotecan-only.However,patients treated with CMAB009 had an increased risk of skin rash(66.9%vs.5.5%,P<0.001)and paronychia(9.8%vs.0.0%,P<0.001).Anti-drug antibodies(ADA)were detected in 3.6%of patients,and only 0.9%of patients who received CMAB009 experienced hypersensitivity reactions.In patients receiving sequential-CMAB009 therapy after failure with irinotecan,their median PFS was 84 days (95% CI 65 to 113 days). The median OS was 425 days for patients receiving CMAB009 plus irinotecan and 401 days for those with sequential-CMAB009 (P = 0.940). Conclusions: Treatment with CMAB009 plus irinotecan was found to be a superior second-line regimen in com-parison to irinotecan-only in KRAS wild-type mCRC patients. Further, switching to CMAB009 can be considered as an efficient third-line of treatment after treatment failure with second-line irinotecan-only. Trial registration ClinicalTrials.gov: NCT01550055, retrospectively registered on March 9, 2012.

Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase

Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.

Improvement of prognosis for unresectable biliary tract cancer

AIM:To evaluate the chemotherapeutic outcomes and confirm the recent improvement of prognosis for unresectable biliary tract cancer.METHODS:A total of 186 consecutive patients with unresectable biliary tract cancer,who had been treated with chemotherapy between 2000 and 2009 at five institutions in Japan,were retrospectively analyzed.These patients were divided into three groups based on the year beginning chemotherapy:Group A(2000-2003),Group B(2004-2006),and Group C(2007-2009).The data were fixed at the end of December 2011.Overall survival and time-to-progression were analyzed and compared chronologically.RESULTS:No patient characteristics were significantly different among the three groups.The gallbladder was involved in about half of the patients in each group,and metastatic biliary tract cancer was present in three quarters of the enrollees.In Group A,5-fluorouracilbased chemotherapies were primarily selected as firstline chemotherapy,and only 24% were treated with second-line chemotherapy.In Group B,gemcitabine or S-1 monotherapy was mainly introduced as firstline chemotherapy,and 51% of the patients who were refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with monotherapy.In Group C,the combination therapy with gemcitabine and S-1 was mainly chosen as first-line chemotherapy,and 53% of the patients refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with combination therapy.The median timeto-progressions were 4.4 mo,3.5 mo and 5.9 mo in Groups A,B and C,respectively(4.4 mo vs 3.5 mo vs 5.9 mo,P < 0.01).The median overall survivals were 7.1,7.3,and 11.7 mo in Groups A,B and C(7.1 mo vs 7.3 mo vs 11.7 mo,P = 0.03).Induction rates of all three drugs(gemcitabine,platinum analogs,and fluoropyrimidine) in Groups A,B and C were 4%,2% and 27%(4% vs 2% vs 27%,P < 0.01).CONCLUSION:The prognosis of unresectable biliary tract cancer has improved recently.Using three effective drugs(gemcitabine,platinum analogs,and fluoropyrimidine) may improve the prognosis of this cancer.

Designing and Synthesis of New Fluorine Substituted Pyrimidine-Thion-5-Carbonitriles and the Related Derivatives as Photochemical Probe Agents for Inhibition of Vitiligo Disease

A new biocidal agents fluorine substituted-3-thioxopyrimidine-5-carbonitriles (2-9) and/or the related fluorine substi- tuted pyrimido (4,5-d) pyrimidines (10-14) were synthesized by the cycloaddition of fluorinated β- arylidine malo- nonitriles (1a-c) followed by a nucleophilic attack against α,β-bifunctional reagents in different conditions. Structures of the fluorine targets were characterized by their elemental analysis and spectral data (UV, IR, 1H NMR, 13C NMR and mass measurements) and further evaluated as photochemical probe for inhibition of Vitiligo, it was found that compounds 5, 9, 11 and 12 exhibited high potency over the investigated compounds.

Rationale and Study Protocol of the J-SAVER Study: A Phase II Study of S-1 on Alternate Days Combined with Bevacizumab in Patients Aged ≥75 Years with Metastatic Colorectal Cancer

Fluoropyrimidine combined with bevacizumab is commonly used in elderly patients with metastatic colorectal cancer worldwide. However, the proportion of elderly patients who discontinued treatment due to toxicities was higher than that of younger patients. The aim of this study is to develop a less toxic schedule of S-1, while maintaining the anti-tumor effect. This phase II study is aimed to evaluate an alternate-day administration of S-1 combined with bevacizumab in untreated elderly patients (aged ≥75 years) with metastatic colorectal cancer. The primary endpoint is progression-free survival, and the secondary endpoints are safety, response rate, and overall survival. The expected median progression-free survival is 8.5 months, and the minimum efficacy threshold is 5.0 months. The total required sample size is calculated as 50 patients, with a 2-sided type I error of 0.10 and a power of more than 80%. This study is ongoing, and fifty-four patients were enrolled until October 2016. We hope that S-1 on alternate days combined with bevacizumab for elderly patients with colorectal cancer is well tolerated and can maintain effectiveness. Trial registration: UMIN clinical trials UMIN000010402.

Review of 5-FU resistance mechanisms in colorectal cancer:clinical significance of attenuated on-target effects

The emergence of chemoresistant disease during chemotherapy with 5-Fluorouracil-based(5-FU-based)regimens is an important factor in the mortality of metastatic CRC(mCRC).The causes of 5-FU resistance are multifactorial,and besides DNA mismatch repair deficiency(MMR-D),there are no widely accepted criteria for determining which CRC patients are not likely to be responsive to 5-FU-based therapy.Thus,there is a need to systematically understand the mechanistic basis for 5-FU treatment failure and an urgent need to develop new approaches for circumventing the major causes of 5-FU resistance.In this manuscript,we review mechanisms of 5-FU resistance with an emphasis on:(1)altered anabolic metabolism limiting the formation of the primary active metabolite Fluorodeoxyuridylate(5-Fluoro-2'-deoxyuridine-5'-O-monophosphate;FdUMP);(2)elevated expression or activity of the primary enzymatic target thymidylate synthase(TS);and(3)dysregulated programmed cell death as important causes of 5-FU resistance.Importantly,these causes of 5-FU resistance can potentially be overcome through the use of next-generation fluoropyrimidine(FP)polymers(e.g.,CF10)that display reduced dependence on anabolic metabolism and more potent TS inhibitory activity.

DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug

Hand-foot syndrome(HFS)is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes.Even though the cause and pathophysiology of HFS are relatively widely reported,how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied.Additionally,prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce.In our study,we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS.Mechanistically,DNA damage,as the primary cytotoxic cause,in keratinocytes induces cell cycle arrest,activates the cGAS-STING signaling pathway,and subsequently mediates cellular senescence,ultimately fueling a robust secondary inflammatory response that results in HFS.More importantly,the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence.These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.

Improved potency of F10 relative to 5-fluorouracil in colorectal cancer cells with p53 mutations

Aim:Resistance to fluoropyrimidine drugs(FPs)is a major cause of mortality in colorectal cancer(CRC).We assessed the potency advantage of the polymeric FP F10 relative to 5-fluorouracil(5-FU)in four human CRC cell lines that differ only in TP53 mutational status to determine how p53 mutations affect drug response and whether F10 is likely to improve outcomes.Methods:HCT-116 human CRC cells(p53^(+/+))and three isogenic variants(p53^(-/-),R248W/+,R248W/-)were assessed for drug response.Resistance factors were derived from cell viability data and used to establish the relative potency advantage for F10.Rescue studies with exogenous uridine/thymidine determined if cytotoxicity resulted from DNA-directed processes.Results:Significant resistance to 5-FU resulted from p53-loss or from gain-of-function(GOF)mutation(R248W)and was greatest when GOF mutation was coupled with loss of wild-type p53.F10 is much more potent than 5-FU(137-314-fold depending on TP53 mutational status).F10 and 5-FU induce apoptosis by DNA-and RNA-directed mechanisms,respectively,and only F10 shows a modest enhancement in cytotoxicity upon co-treatment with leucovorin.Conclusion:TP53 mutational status affects inherent sensitivity to FPs,with p53 GOF mutations most deleterious.F10 is much more effective than 5-FU regardless of TP53 mutations and has potential to be effective to CRC that is resistant to 5-FU due,in part,to TP53 mutations.

Entrapment of DNA topoisomerase-DNA complexes by nucleotide/nucleoside analogs

Topoisomerases are well-validated targets for cancer chemotherapy and DNA topoisomerase 1(Top1)is the sole target of the camptothecin(CPT)class of anticancer drugs.Over the last 20 years,multiple studies have shown Top1 activity is modulated by non-native DNA structures and this can lead to trapping of Top1 cleavage complexes(Top1cc)and conversion to DNA double strand breaks.Among the perturbations to DNA structure that generate Top1cc are nucleoside analogs that are incorporated into genomic DNA during replication including cytarabine,gemcitabine,and 5-fluoro-2’-deoxyuridine(FdU).We review the literature summarizing the role of Top1cc in mediating the DNA damaging and cytotoxic activities of nucleoside analogs.We also summarize studies demonstrating distinct differences between Top1cc induced by nucleoside analogs and CPTs,particularly with regard to DNA repair.Collectively,these studies demonstrate that,while Top1 is a common target for both Top1 poisons such as CPT and nucleoside analogs such as FdU,these agents are not redundant.In recent years,studies have shown that Top1 poisons and nucleoside analogs together with other anti-cancer drugs such as cisplatin cause replication stress and the DNA repair pathways that modulate the cytotoxic activities of these compounds are being elucidated.We present an overview of this evolving literature,which has implications for how targeting of Top1 with nucleoside analogs can be used more effectively for cancer treatment.