Apatinib and gamabufotalin co-loaded lipid/Prussian blue nanoparticles for synergistic therapy to gastric cancer with metastasis

Due to the non-targeted release and low solubility of anti-gastric cancer agent,apatinib(Apa),a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects.In order to avoid these drawbacks,lipid-film-coated Prussian blue nanoparticles(PB NPs)with hyaluronan(HA)modification was used for Apa loading to improve its solubility and targeting ability.Furthermore,anti-tumor compound of gamabufotalin(CS-6)was selected as a partner of Apawith reducing dosage for combinational gastric therapy.Thus,HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor tissue.In vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating vascular endothelial growth factor receptor(VEGFR)and matrix metalloproteinase-9(MMP-9).In vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic effects.In summary,we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer(GC)therapy.

Apatinib reduces liver cancer cell multidrug resistance by modulating NF-κB signaling pathway

Objectives:This investigation aimed to elucidate the inhibitory impact of apatinib on the multidrug resistance of liver cancer both in vivo and in vitro.Methods:To establish a Hep3B/5-Fu resistant cell line,5-Fu concentrations were gradually increased in the culture media.Hep3B/5-Fu cells drug resistance and its alleviation by apatinib were confirmed via flow cytometry and Cell Counting Kit 8(CCK8)test.Further,Nuclear factor kappa B(NF-κB)siRNA was transfected into Hep3B/5-Fu cells to assess alterations in the expression of multidrug resistance(MDR)-related genes and proteins.Nude mice were injected with Hep3B/5-Fu cells to establish subcutaneous xenograft tumors and then categorized into 8 treatment groups.The treatments included oxaliplatin,5-Fu,and apatinib.In the tumor tissues,the expression of MDRrelated genes was elucidated via qRT-PCR,immunohistochemistry,and Western blot analyses.Results:The apatinibtreated mice indicated slower tumor growth with smaller size compared to the control group.Both the in vivo and in vitro investigations revealed that the apatinib-treated groups had reduced expression of MDR genes GST-pi,LRP,MDR1,and p-p65.Conclusions:Apatinib effectively suppresses MDR in human hepatic cancer cells by modulating the expression of genes related to MDR,potentially by suppressing the NF-κB signaling pathway.

Disitamab vedotin combined with apatinib in gastric cancer: A case report and review of literature

BACKGROUND In patients with human epidermal growth factor receptor 2(HER2)-overex-pressing gastric cancer(GC),the combination of HER2 targeting and a standard first-line chemotherapy regimen has been demonstrated to significantly improve their prognosis.However,in a proportion of patients,cancer progresses within a short period of time,and there is currently no standard treatment after disease progression.CASE SUMMARY This study presents a case of a 51-year-old male with advanced GC who un-derwent radical resection(Billroth type II subtotal gastrectomy and gastrojejun-ostomy)and resection of liver metastases.Immunohistochemical staining revealed a HER2 score of 2+,a dMMR status,and a Ki67 proliferation index of 30%to 40%.The gene test results indicated the presence of ERBB2 amplification and a PD-L1 expression level of less than 5%.Since December 2021,the patient has experienced disease progression during both first-line(two cycles of KN026 combined with KN046)and second-line(five cycles of nivolumab combined with trastuzumab and SOX chemotherapy)treatment regimens.The patient's prognosis following the first and second lines of treatment was unfavorable,with pro-gression occurring in a relatively short time.For third-line therapy,disitamab vedotin(RC48)plus apatinib was used.At the time of this report,the patient had achieved a progression-free survival(PFS)of 25.8 months,which exceeded the median survival time for patients with advanced GC.CONCLUSION Despite the unfavorable prognosis associated with advanced GC,the imple-mentation of personalized treatment approaches may still prove beneficial for select patients.In patients with HER2-positive GC with extensive metastatic involvement,the use of the HER2-targeted combination with apatinib has demonstrated the potential to prolong both PFS and overall survival.

Apatinib对卵巢癌细胞A2780增殖及紫杉醇敏感性的影响

目的:研究阿帕替尼(apatinib)对卵巢癌细胞A2780增殖及紫杉醇敏感性的影响,并探讨其相关机制。方法:CCK-8法检测apatinib对A2780细胞增殖的影响,克隆形成实验检测apatinib对A2780细胞增殖能力的作用,流式细胞术检测apatinib对A2780细胞凋亡和细胞周期分布的影响,Western blot法检测apatinib靶蛋白。结果:与对照组比较,apatinib明显抑制卵巢癌A2780细胞的增殖及克隆形成(P<0.01)。Apatinib作用24h后,A2780细胞凋亡率明显增加(P<0.01),呈浓度依赖性的细胞周期阻滞。Apatinib诱导A2780细胞中CDK2表达下降和p21表达上升。小剂量apatinib显著提高A2780细胞对紫杉醇的敏感性。结论:Apatinib可显著抑制卵巢癌细胞的增殖并增强其对紫杉醇的敏感性。

小分子酪氨酸激酶抑制剂Apatinib对白血病HL-60细胞株抑制增殖作用及机制

目的探讨新型小分子酪氨酸激酶抑制剂apatinib体外对白血病HL-60细胞增殖的影响及机制。方法分别采用MTT法、流式细胞仪检测apatinib对白血病HL-60细胞株的细胞毒IC50值、细胞周期、凋亡的影响,Western Blot法观察apatinib对白血病细胞Erk1/2和Akt磷酸化的影响。结果 Apatinib对白血病细胞株HL-60增殖有明显抑制作用,IC50值为4.96±0.32μmol/L;apatinib能增加HL-60细胞凋亡率,并呈浓度依赖性;与对照组相比,经不同浓度apatinib处理的HL-60细胞,其细胞周期分布无明显改变(P>0.05);Western Blot结果显示,经apatinib处理48h后的HL-60细胞,其P-Erk1/2及P-Akt蛋白表达降低。结论 apatinib可通过下调P-Erk1/2及P-Akt蛋白表达诱导HL-60细胞凋亡,抑制其增殖。

Extraordinary response of metastatic pancreatic cancer to apatinib after failed chemotherapy: A case report and literature review

Chemotherapy has limited efficacy in the treatment of advanced and metastatic pancreatic cancer(PC), and has serious side effects. The development of novel effective agents, especially targeted therapy, is essential for patients with PC. We present a 58-year-old Chinese woman initially diagnosed with locally advanced PC. As the disease progressed to Stage Ⅳ, the patient was unable to tolerate chemotherapy after the fourth-line treatment. She was then treated with apatinib, a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 and achieved a progression-free-survival of 7 mo. All drug-related side effects were well controlled with medication. To the best of our knowledge, this is the first case of PC which responded to apatinib. Considering this remarkable response, apatinib may be a promising agent in the treatment of PC. We also reviewed the literature on chemotherapy and targeted therapy, especially the anti-angiogenesis therapy for patients with PC, and investigated the effect of apatinib in other solid tumors as well.

Apatinib联合5-Fu协同抑制乳腺癌MCF-7细胞的体外研究

目的探讨阿帕替尼(Apatinib)联合5-氟尿嘧啶(5-Fu)对乳腺癌MCF-7细胞的抑制作用。方法采用人乳腺癌细胞株MCF-7,首先采用MTT法及应用流式细胞仪测定不同浓度apatinib作用后对其细胞增殖和周期的影响,其次将MCF-7细胞分为4组,即对照组、Apatinib单药组、5-Fu单药组、Apanitib+5-Fu联合组。对各组细胞给予相应药物处理,48 h后分别应用流式细胞仪检测各组药物对MCF-7细胞株凋亡的作用。结果 Apatinib单药对MCF-7细胞有增殖抑制作用,且存在时间剂量依赖关系,而对其细胞周期影响不大。与对照组相比,Apatinib联合5-Fu作用后有协同诱导凋亡作用,经流式细胞仪检测,Apatinib组诱导的细胞凋亡率为12.05%,5-Fu组为25.76%。与单药组比,Apatinib+5-Fu联合组凋亡率升高更为明显,达34.90%(P<0.05)。结论 Apatinib和5-Fu的联合应用在体外协同抑制乳腺癌MCF-7细胞并诱导凋亡,使抗肿瘤活性显著增强。

Phase Ⅱ study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA

Objective:Apatinib is an oral TKI targeting VEGFR-2.Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated m BC.Oral vinorelbine also holds promise as a treatment of choice in patients with m BC.This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated m BC.In addition,we detected gene variants in ct DNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative m BC who were pretreated with anthracycline/taxanes.Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1,8,and 15 of every cycle(3 weeks).The primary endpoint was PFS.The secondary endpoints were ORR,CBR,OS,and safety.Patients eligible for ct DNA detection were evaluated before and during treatment.Results:Forty patients were enrolled.The median PFS was 5.2 months(95%CI,3.4–7.0 months),and the median OS was 17.4 months(95%CI,8.0–27.0 months).The ORR was 17.1%(6/35),and the CBR was 45.7%(16/35).The most common AEs included gastrointestinal reaction,myelosuppression,and hypertension.In 20 patients,ct DNA was detected at baseline and during treatment.A significant difference was found in PFS for undetected vs.detected baseline ct DNA(13.9 months vs.3.6 months,P=0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative m BC,with acceptable and manageable toxicity profiles.Patients with no gene variant detected and lower variant allele frequencies in ct DNA at baseline showed longer PFS.

Multicenter phaseⅡstudy of apatinib single or combination therapy in HER2-negative breast cancer involving chest wall metastasis

Objective:Breast cancer(BC)with chest wall metastasis(CWM)usually shows rich neovascularization.This trial explored the clinical effect of apatinib on human epidermal growth factor receptor 2(HER2)-negative advanced BC involving CWM.Methods:This trial involved four centers in China and was conducted from September 2016 to March 2020.Patients received apatinib 500 mg/d[either alone or with endocrine therapy if hormone receptor-positive(HR+)]until disease progression or unacceptable toxicity.Progression-free survival(PFS)was the primary endpoint.Results:We evaluated 26 patients for efficacy.The median PFS(mPFS)and median overall survival(mOS)were4.9[range:2.0-28.5;95%confidence interval(95%CI):2.1-8.3]months and 18(range:3-55;95%CI:12.9-23.1)months,respectively.The objective response rate(ORR)was 42.3%(11/26),and the disease-control rate was76.9%(20/26).In the subgroup analysis,HR+patients compared with HR-negative patients had significantly improved mPFS of 7.0(95%CI:2.2-11.8)months vs.2.3(95%CI:1.2-3.4)months,respectively(P=0.001);and mPFS in patients without or with chest wall radiotherapy was 6.4(95%CI:1.6-19.5)months vs.3.0(95%CI:1.3-4.6)months,respectively(P=0.041).In the multivariate analysis,HR+status was the only independent predictive factor for favorable PFS(P=0.014).Conclusions:Apatinib was highly effective for BC patients with CWM,especially when combined with endocrine therapy.PFS improved significantly in patients with HR+status who did not receive chest wall radiotherapy.However,adverse events were serious and should be carefully monitored from the beginning of apatinib treatment.

A retrospective analysis of the safety and efficacy of apatinib in treating advanced metastatic colorectal cancer

Objective Colorectal cancer(CRC) is a heterogeneous disease in which both epigenetic alterations and gene mutations transform normal cells into cancer cells. Apart from a variety of standard treatments, there are few options available to improve a CRC patient's overall survival(OS) and quality of a life. The objective of the present retrospective study was to analyze the response and toxicity associated with apatinib in patients with metastatic CRC(m CRC).Method Data on the use of apatinib as salvage therapy were collected from patients diagnosed with m CRC, Eastern Cooperative Oncology Group(ECOG) performance status ≤ 3, from the Luhe Hospital. A total of 17 patients with stage IV unresectable m CRC, who received at least one cycle of apatinib, between October 2015 and February 2017, were involved in this study. Our primary endpoints were the overall response rate(ORR) and disease control rate(DCR), and the secondary objectives were progression-free survival(PFS), OS and safety.Result Seventeen patients with a median age of 62 years(34–83 years) were enrolled. Twelve patients were male, and the location of the primary tumor was in the colon and the rectum in 9 and 8 patients, respectively. Liver metastasis was observed in 9 patients and lung metastasis in 5. The ECOG performance status was 0 to 2 in 13 patients. The ORR at the first evaluation was 17.6 %(3/17). The DCR was 82.4%(14/17). The median PFS was 3.0 months(95% confidence interval(CI): 1.924–4.076 months) and the median OS was 5.4 months(95% CI: 3.383–7.417 months). Grade 1–2 adverse events included hypertension(52.9%), fatigue(64.7%), anorexia(29.4%), hoarseness(23.5%), proteinuria(23.5%), and development of rashes(17.6%). Grade 3 adverse events included thrombocytopenia(5.9%) and proteinuria(5.9%). There were no Grade 4 adverse events in our analysis.Conclusions Apatinib was found to be both safe and effective in the treatment of advanced m CRC, and its associated toxicities were acceptable and manageable. However, further studies are required to validate these findings.

Apatinib as an alternative therapy for advanced hepatocellular carcinoma

Angiogenesis plays an important role in the occurrence and development of tumors.Registered tyrosine kinase inhibitors targeting vascular endothelial growth factor reduce angiogenesis.Apatinib,a tyrosine kinase inhibitor,can specifically inhibit vascular endothelial growth factor receptor 2,showing encouraging anti-tumor effects in a variety of tumors including advanced hepatocellular carcinoma(HCC).This article intends to review the clinical research and application prospects of apatinib in the field of HCC.

Apatinib radiosensitizes hepatocellular carcinoma in vitro and in vivo

Objective:Limited effective interventions for advanced hepatocellular carcinoma(HCC)are available.This study aimed to investigate the potential clinical utility of apatinib,a highly selective inhibitor of the vascular endothelial growth factor receptor-2(VEGFR2)tyrosine kinase,as a radiosensitizer in the treatment of HCC.

Clinical study of apatinib in the treatment of stage IV osteogenic sarcoma after failure of chemotherapy

Objective:To analyze the efficacy and safety o f apatinib in the treatment of stage IV osteogenic sarcoma after chemotherapy failure through a single-arm,prospective,and open clinical phase II study.Methods:Information on 34 patients with stage IV osteogenic sarcoma treated with apatinib after failure o f chemotherapy in Tianjin Medical University Cancer Institute and Hospital between September 2015 and December 2019 was collected and analyzed.The participants included 23 males and 11 females,with an average age of 35.24 years(11-73 years).The objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),PFS rate(PFR),and overall survival(OS)were evaluated.The treatmentrelated adverse events(AEs)and safety of apatinib were also evaluated.Results:O f the 34 patients,33 were able to be evaluated for efficacy.One patient received apatinib treatment for less than one cycle;therefore,only safety analysis was performed.The 12-week clinical evaluation showed that 2 patients had a partial response(PR),24 patients had stable disease(SD),and 7 patients had progressive disease(PD).The ORR,DCR,and PFR at 12 weeks were 6.06%(2/33),78.79%(26/33),and 82%,respectively.By the end of the follow-up,6 patients had SD(18.18%,6/33),27 patients had PD(81.82%,27/33),and 15 patients died because of disease progression(45.45%,15/33).The ORR was 0(0/33),the DCR was 18.18%(6/33),and the median PFS(mPFS)was 7.89 months(95%Cl:4.56-11.21).The median OS(mOS)was 17.61 months(95%Cl:10.85-24.37).The most common treatment-related AEs were hand-foot syndrome(35.29%,12/34),proteinuria(32.35%,11/34),and hypertension(32.35%,11/34).

Transarterial Chemoembolization Combined with Apatinib for Treatment of Advanced Hepatocellular Carcinoma:Analysis of Survival and Prognostic Factors

Objective Apatinib is a novel inhibitor of vascular endothelial growth factor receptor-2.The goal of this study was to evaluate overall survival(OS)after a combination of transarterial chemoembolization(TACE)and apatinib in patients with advanced hepatocellular carcinoma(HCC)and to identify the factors affecting patient survival.Methods Fifty-one patients with advanced HCC who received TACE in combination with apatinib in our hospital from June 2015 to May 2017 were enrolled.The OS and progression-free survival(PFS)were calculated using the Kaplan-Meier method.The log-rank test and Cox regression model were used to determine the factors affecting OS.Results The median OS and PFS of the patients were 15 months and 10 months,respectively.The 1-,2-,and 3-year survival rates were 64.7%,23.5%,and 1.8%,respectively.Univariate survival analysis showed that patients with Child-Pugh A(P=0.006),reduction rate of proper hepatic artery(P=0.016),hand-foot syndrome(P=0.005),secondary hypertension(P=0.050),and without ascites(P=0.010)had a better OS.Multivariate analysis showed that hand-foot syndrome(P=0.014),secondary hypertension(P=0.017),and reduction rate of proper hepatic artery(P=0.025)were independent predictors of better OS.Conclusion TACE combined with apatinib is a promising treatment for advanced HCC.Hand-foot syndrome,secondary hypertension,and the reduction rate of proper hepatic artery were associated with a better OS.

Antitumor and vascular effects of apatinib combined with chemotherapy in mice with non-small-cell lung cancer

Objective The aim of this study was to investigate the antitumor and vascular effects of apatinib use combined with chemotherapy on mice with non-small-cell lung cancer(NSCLC).Methods First,60 tumor-bearing nude mice were randomly divided into control,low-dose,and high-dose groups.Four nude mice per group were sacrificed before administration and on days 1,3,7,and 10 after administration.HIF-1αexpression in tumor tissues was detected.Second,32 nude mice were randomly divided into control,premetrexed,synchronous,and sequential groups.The weights and tumor volumes of mice were recorded.Results(1)HIF-1αexpression decreased significantly on days 3 and 7 after low-dose apatinib treatment.There was no significant difference in HIF-1αexpression in the high-dose apatinib group(P>0.05).MMP-2 and MMP-9 expression levels in the low-dose apatinib group were significantly lower than those in the control group(P<0.05).(2)In the low-dose apatinib group,the microvessel density increased gradually from days 3 to 7 post-treatment,while that in the high-dose apatinib group decreased significantly.(3)The inhibitory effect of sequential therapy using low-dose apatinib and pemetrexed was optimal,while that of synchronous treatment was not better than that of pemetrexed usage alone.Sequential treatment using low-dose apatinib and pemetrexed exerted the best antitumor effect.(4)The expression levels of p-AKT,p-mTOR,p-MEK,and p-ERK in the sequential group were significantly lower than those in the other three groups(P<0.05).Conclusion Apatinib usage involves certain considerations,such as dose requirements and time window for vascular normalization during lung cancer treatment in nude mice,suggesting that dynamic contrast-enhanced magnetic resonance imaging and other tests can be conducted to determine the vascular normalization window in patients with lung cancer and to achieve the optimal anti-vascular effect.

Traditional Chinese Medicine for Treatment of Apatinib-induced Hand and Foot Skin Reaction:A case report

Squamous cell carcinoma arising at maxillary sinus is a rare neoplasm, characterized by aggressive growth pattern and glooming prognosis. A 78-year-old woman presented with left maxillary sinus carcinoma. The patient received four courses of chemotherapy after surgery in our center. Eight months after treatment, the patient experienced local progress, severe gastrointestinal reactions and asthenia. Then apatinib was used as third-line treatment. Good curative effect was achieved with 250 mg apatinib per day, while adverse reaction such as hand and foot skin reaction affected the quality of her life. Traditional Chinese medicine exhibits good results and no obvious side effects in relieving hand and foot skin reaction. Traditional Chinese medicine is Chinese treasure, it remains challenging, and further investigations are needed.

Apatinib,S-1 Combined with Paclitaxel Perfusion in the Treatment of Malignant Seroperitoneum of Gastric Cancer

Objective:To analyze the effect of apatinib,S-1 combined with paclitaxel perfusion on malignant seroperitoneum of gastric cancer.Methods:From December 2019 to May 2020,172 patients with gastric cancer treated in our hospital were randomly divided into two groups:observation group and control group,86 cases each.The control group adopted the method of S-1 combined with paclitaxel perfusion therapy in the treatment of malignant seroperitoneum of gastric cancer.The observation group was given oral apatinib on the basis of S-1 combined with paclitaxel perfusion therapy,and the dosage was 500 mg/d.Results:The total effective treatment in the control group was 43.02%,while the total effective rate in the observation group was 69.77%;the drug resistance of the two groups of patients increased and the adverse reactions were low.Conclusion:Apatinib and S-1 combined with paclitaxel perfusion therapy can effectively improve the treatment effect,stabilize the patient's condition,increase the patient's drug resistance to adverse reactions,and have a good prognosis.

Hepatocellular carcinoma successfully treated with ALPPS and apatinib: A case report

BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has becoming ever more recognized in the treatment of hepatocellular carcinoma (HCC).Nevertheless,long-term survival rate and postoperative complications are far from ideal,mainly since the majority of patients treated with ALPPS surgery have large or multiple lesions and microvascular tumor thrombus.CASE SUMMARY We present the case of a 47-year-old male patient with a huge right hepatic mass and an estimated insufficient residual liver,who was successfully treated with ALPPS surgery and apatinib.Postoperative pathology revealed HCC with several significant microvascular embolisms.Twenty months after operation,no tumor reoccurrence was observed.CONCLUSION Our case indicated that combined targeted drug therapy with ALPPS can lead to long-term survival for patients with large HCC.

Successful apatinib treatment for advanced clear cell renal carcinoma as a first-line palliative treatment: A case report

BACKGROUND Apatinib is an orally bioavailable small-molecule receptor tyrosine kinase inhibitor.In December 2014,the China Food and Drug Administration made it the first anti-angiogenic therapy to be approved for treating metastatic gastric cancer.It was specifically designated as a third-line or later treatment for metastatic gastric cancer.CASE SUMMARY Here,we present a case of advanced renal cell carcinoma(RCC)with multiple metastases(Stage IV)in a 48-year-old male with an extremely poor general status(Karnofsky 30%).He was initially given pazopanib as a targeted therapeutic.However,he experienced severe adverse reactions within two weeks,including grade IV oral mucositis.We,thus,tried switching his targeted treatment to an apatinib dose of 250 mg once daily since April 2018.The patient demonstrated striking benefits from this switch to the apatinib palliative treatment.Nearly one month later,his pain and other associated symptoms were alleviated.The patient was able to move freely and had an excellent general status(Karnofsky 90%).His progress has been followed up with regularly,allowing for a documented progression-free survival interval of approximately 32 mo.CONCLUSION This case suggests that,like other multi-target drugs,apatinib may be a useful first-line therapeutic drug for advanced RCC.It may be a particularly helpful curative option when patients are found to be intolerant of other targeted drugs.

Treatment of aggressive pancreatic solid pseudo-papillary neoplasms with apatinib plus S-1 chemotherapy:A case report and literature review

Solid pseudopapillary neoplasm(SPN) is a rare indolent pancreatic neoplasm that occurs mostly in females. Although the malignancy potential is quite limited for SPN, these tumors can sometimes be aggressive and lead to inferior prognosis for male patients. In this case report, we present a special case of a male patient with SPN who experienced an aggressive tumor expansion after two surgical resections. For further treatment, we decided to administer chemotherapy with apatinib and S-1, and subsequent CT/MRI tumor monitoring indicated satisfactory control of tumor expansion. The effectiveness of apatinib plus the S-1 regimen should be tested for more patients with SPN in the future.