Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androg...Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.展开更多
Cabazitaxel is a second-generation taxane with promising anti-tumor activity and is approved for treating hormone-refractory metastatic prostate cancer previously treated with docetaxel. Although first-generation taxa...Cabazitaxel is a second-generation taxane with promising anti-tumor activity and is approved for treating hormone-refractory metastatic prostate cancer previously treated with docetaxel. Although first-generation taxanes （i.e. paclitaxel and docetaxel） have sparked broad interest in a variety of drug delivery vehicles, fewer have yet been developed for cabazitaxel. This review summarizes several clinical-stage approaches for taxane formulation and recent efforts to develop novel cabazitaxel delivery systems.展开更多
The potential side effects of cabazitaxel(CBZ)in the field of cancer treatment have become a great limitation to its further clinical application.Liposomal delivery is a well-established approach to increase the thera...The potential side effects of cabazitaxel(CBZ)in the field of cancer treatment have become a great limitation to its further clinical application.Liposomal delivery is a well-established approach to increase the therapeutic index of hydrophobic drugs.In this study,a PEGmodified liposome was developed for efficiently encapsulating CBZ,thus enhancing its specific tumor inhibition effect and reducing the systemic toxicity.It was found that the loading efficiency of CBZ into the liposome could be improved with the increase of lipophilic materials,as it could be over 80%under the weight ratio of 20:1(total lipid:CBZ).The diameter of CBZ loaded liposome(CBZ@Lipo)was^100 nm.And the liposome suspending in aqueous medium was stable at 4°C for at least one month,according to the change of its size distribution.The killing ability of CBZ@Lipo to cancer cells was significantly lower comparing to that of CBZ solution,which could be attributed to the slow release of CBZ from the liposomes.However,CBZ@Lipo could induce an obvious apoptosis of the cancer cells at low concentration.Furthermore,CBZ@Lipo exhibited an expressively enhanced tumor growth inhibition effect comparing to CBZ solution.More importantly,CBZ@Lipo showed an obviously higher biosafety proved by lower hemolysis probability,stable body weight of mice during the whole experiment and no obvious lesion in histology analysis.Our work provided a useful reference of the formulation of CBZ,which had potential for greater clinical application.展开更多
Objective:In this study,we aim to enhance the anti-prostate cancer efficacy of cabazitaxel(CTX)and reduce its immunosuppression and systemic toxicity by developing CTX-loaded liposomes modified with ginsenoside Rk1(Rk...Objective:In this study,we aim to enhance the anti-prostate cancer efficacy of cabazitaxel(CTX)and reduce its immunosuppression and systemic toxicity by developing CTX-loaded liposomes modified with ginsenoside Rk1(Rk1/CTX-Lip).Methods:Physical and chemical properties of Rk1/CTX-Lip were investigated.We evaluated the biological functions of Rk1/CTXLip,both in vitro and in vivo.A subcutaneous prostate cancer(RM-1)-bearing mouse model was established to study the efficacy of Rk1/CTX-Lip inhibition in tumors.Simultaneously,a Candida albicans infection model was established in tumor-bearing mice to study the infection-relieving efficacy of Rk1/CTX-Lip.Finally,biocompatibility and in vivo safety of Rk1/CTX-Lip were evaluated.Results:We successfully prepared Rk1/CTX-Lip,achieving high CTX encapsulation efficiency(97.24±0.75)%and physical stability.Rk1/CTX-Lip demonstrated evasion of macrophage phagocytosis,effective tumor tissue targeting,and a significant reduction(>50%)in average tumor volume compared with Chol/CTX-Lip.Moreover,it relieved the concurrent infection burden and effectively regulated immune organs and cells,demonstrating superior biocompatibility.Conclusion:Rk1/CTX-Lip presents a promising new therapy for prostate cancer and holds potential for relieving concurrent fungal infections in cancer patients with low immunity.展开更多
The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of ...The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.展开更多
目的:探究榄香烯(ELE)增强卡巴他赛(CTX)抗胶质瘤疗效,制备一种共载ELE/CTX的双靶向阳离子脂质体(LIP)用于胶质瘤的治疗研究,并达到增加药效、减少不良反应的作用,经体外药效学试验揭露其优势及作用机制。方法:采用高速剪切法联合探头...目的:探究榄香烯(ELE)增强卡巴他赛(CTX)抗胶质瘤疗效,制备一种共载ELE/CTX的双靶向阳离子脂质体(LIP)用于胶质瘤的治疗研究,并达到增加药效、减少不良反应的作用,经体外药效学试验揭露其优势及作用机制。方法:采用高速剪切法联合探头超声法制备脂质体ELE/CTX@LIP,并采用纳米粒径电位仪对其粒径及电位进行表征,采用高效液相色谱法(HPLC)测定ELE/CTX包封率及载药量;采用细胞增殖与活性检测法(CCK-8)检测ELE/CTX体外细胞增殖抑制活性;通过JMP Pro 16软件,以包封率为指标优化脂质体(ELE/CTX@LIP)工艺参数;通过体外细胞增殖抑制活性和体外细胞摄取,筛选最佳阳离子材料种类、含量与配比,在此基础上制备双靶向阳离子脂质体并表征其形态、粒径稳定性等,验证其对RG2胶质瘤细胞的细胞周期和细胞凋亡的影响。结果:ELE/CTX抗胶质瘤活性结果显示ELE/CTX分别对C6、RG2细胞具有更强的细胞增殖抑制活性;体外细胞增殖抑制活性和体外细胞摄取结果显示阳离子材料用量为总含量的0.10%;T7、精氨酸-甘氨酸-天冬氨酸三肽序列(cRGD)与磷脂最佳配比为1∶1∶50。T7/cRGD-ELE/CTX@CLIP[1,2-二油酰氧基-3-二甲基氨基丙烷(DlinMC3-DMA)]、T7/cRGD-ELE/CTX@CLIP[二肉豆蔻酰甘油-聚乙二醇2000(DMG-PEG2000)]呈现多层次球状纳米结构,粒径分别为146.0 nm和111.3 nm,血清稳定性良好;体外细胞增殖抑制结果显示,与单靶向脂质体或双靶向非阳离子脂质体比较,T7/cRGD-ELE/CTX@CLIP在体外对胶质瘤细胞具有更高的细胞增殖抑制活性;T7/cRGD-ELE/CTX@CLIP影响胶质瘤细胞凋亡及周期,结果显示,ELE/CTX联用能通过脂质体载体能更加有效的激活细胞凋亡通道抑制胶质瘤细胞增殖,且使用T7/cRGD短肽及阳离子修饰后,增强了细胞凋亡诱导能力,ELE/CTX能有效将胶质瘤细胞周期阻滞于G2/M期,且经T7/cRGD靶向修饰后,效果增强。结论:ELE可以增强CTX抗胶�展开更多
Prostate cancer is the most common non-cutaneous malignancy for men. The skeleton is the most common metastatic site but, following an improvement in survival, metastases in uncommon sites are being found more frequen...Prostate cancer is the most common non-cutaneous malignancy for men. The skeleton is the most common metastatic site but, following an improvement in survival, metastases in uncommon sites are being found more frequently in clinical practice, especially brain metastases. Despite the new drugs now available for metastatic castration resistant prostate cancer, no clinical evidence exists about their effectiveness on brain metastases. We describe the clinical history of 3 patients treated with cabazitaxel plus whole brain radiotherapy. These case reports demonstrate that cabazitaxel is highly active and well tolerated in brain metastases.展开更多
Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substan...Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.展开更多
Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer （mCRPC）. The past year and a half has been marked by un...Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer （mCRPC）. The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents （sipuleuceI-T, cabazitaxel and abiraterone） with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.展开更多
Brain metastasis is a common and serious complication of breast cancer,which is commonly associated with poor survival and prognosis.In particular,the treatment of brain metastasis from triplenegative breast cancer(BM...Brain metastasis is a common and serious complication of breast cancer,which is commonly associated with poor survival and prognosis.In particular,the treatment of brain metastasis from triplenegative breast cancer(BM-TNBC)has to face the distinct therapeutic challenges from tumor heterogeneity,circulating tumor cells(CTCs),blood-brain barrier(BBB)and blood-tumor barrier(BTB),which is in unmet clinical needs.Herein,combining with the advantages of synthetic and natural targeting moieties,we develop a“Y-shaped”peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC.Inherited from the activated platelet,the hybrid liposomes still retain the native affinity toward CTCs.Further,the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo.The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions,and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug.Overall,this work provides a promising prospect for the comprehensive treatment of BMTNBC,which could be generalized to other cell types or used in imaging platforms in the future.展开更多
Background:To evaluate the effectiveness and safety of cabazitaxel in castration-resistant prostate cancer patients aged>80 years,we performed a retrospective study on a sample of patients from 11 Italian cancer ce...Background:To evaluate the effectiveness and safety of cabazitaxel in castration-resistant prostate cancer patients aged>80 years,we performed a retrospective study on a sample of patients from 11 Italian cancer centers.Materials and methods:Fifty-seven patients aged>80 years were treated with cabazitaxel after previous failure with docetaxel;39 completed a comprehensive geriatric assessment questionnaire(34 fit and 5 vulnerable)and 8 patients(14%)had an Eastern Cooperative Oncology Group performance status(PS)>2,while most had a PS of 0-1(86%).Cabazitaxel was administered at a dose of 25 mg/m^(2)in 30(52%)patients and 20 mg/m^(2)or adapted schedules in 27(48%)patients.These schedules were adopted mainly in patients>85 years(75%),with a PS>2(87.5%),and those classified as vulnerable(100%).Results:The duration of treatment was 4.8 months and was comparable in all subgroups;disease control rate was reported in 36 patients(63%);prostate-specific antigen response was recorded in 18 patients(31.5%).Median overall survival was 13.1 months regardless of age(<85/>85 years),but overall survival was reduced in vulnerable(7.2 months)and PS>2 patients(6.8 months).The most frequently documented grade 3-4 toxicities were neutropenia(14%)and diarrhea(10.5%).Six patients(10.5%)dropped out due to severe toxicity.Conclusions:Octogenarian patients can be treated with cabazitaxel with reduced doses or alternative schedules that are associated with less toxicity and fewer treatment interruptions.Comprehensive geriatric assessment could facilitate more appropriate patient selection.展开更多
文摘Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.
文摘Cabazitaxel is a second-generation taxane with promising anti-tumor activity and is approved for treating hormone-refractory metastatic prostate cancer previously treated with docetaxel. Although first-generation taxanes （i.e. paclitaxel and docetaxel） have sparked broad interest in a variety of drug delivery vehicles, fewer have yet been developed for cabazitaxel. This review summarizes several clinical-stage approaches for taxane formulation and recent efforts to develop novel cabazitaxel delivery systems.
基金supported by the National Key R&D Program of China(No.2017YFE0102200)the Natural Science Foundation of China(81373348 and 81573365)Basic Public Welfare Re-search Project of Zhejiang Province,China(LGF18H300004)
文摘The potential side effects of cabazitaxel(CBZ)in the field of cancer treatment have become a great limitation to its further clinical application.Liposomal delivery is a well-established approach to increase the therapeutic index of hydrophobic drugs.In this study,a PEGmodified liposome was developed for efficiently encapsulating CBZ,thus enhancing its specific tumor inhibition effect and reducing the systemic toxicity.It was found that the loading efficiency of CBZ into the liposome could be improved with the increase of lipophilic materials,as it could be over 80%under the weight ratio of 20:1(total lipid:CBZ).The diameter of CBZ loaded liposome(CBZ@Lipo)was^100 nm.And the liposome suspending in aqueous medium was stable at 4°C for at least one month,according to the change of its size distribution.The killing ability of CBZ@Lipo to cancer cells was significantly lower comparing to that of CBZ solution,which could be attributed to the slow release of CBZ from the liposomes.However,CBZ@Lipo could induce an obvious apoptosis of the cancer cells at low concentration.Furthermore,CBZ@Lipo exhibited an expressively enhanced tumor growth inhibition effect comparing to CBZ solution.More importantly,CBZ@Lipo showed an obviously higher biosafety proved by lower hemolysis probability,stable body weight of mice during the whole experiment and no obvious lesion in histology analysis.Our work provided a useful reference of the formulation of CBZ,which had potential for greater clinical application.
基金supported by the National Natural Science Foundation of China(82373808)Chongqing Natural Science Foundation(cstc2021jcyj-bshX0125)+1 种基金Fundamental Research Funds for the Central Universities(SWURC2020001)the project for Chongqing University Innovation Research Group,Chongqing Education Committee(CXQT20006).
文摘Objective:In this study,we aim to enhance the anti-prostate cancer efficacy of cabazitaxel(CTX)and reduce its immunosuppression and systemic toxicity by developing CTX-loaded liposomes modified with ginsenoside Rk1(Rk1/CTX-Lip).Methods:Physical and chemical properties of Rk1/CTX-Lip were investigated.We evaluated the biological functions of Rk1/CTXLip,both in vitro and in vivo.A subcutaneous prostate cancer(RM-1)-bearing mouse model was established to study the efficacy of Rk1/CTX-Lip inhibition in tumors.Simultaneously,a Candida albicans infection model was established in tumor-bearing mice to study the infection-relieving efficacy of Rk1/CTX-Lip.Finally,biocompatibility and in vivo safety of Rk1/CTX-Lip were evaluated.Results:We successfully prepared Rk1/CTX-Lip,achieving high CTX encapsulation efficiency(97.24±0.75)%and physical stability.Rk1/CTX-Lip demonstrated evasion of macrophage phagocytosis,effective tumor tissue targeting,and a significant reduction(>50%)in average tumor volume compared with Chol/CTX-Lip.Moreover,it relieved the concurrent infection burden and effectively regulated immune organs and cells,demonstrating superior biocompatibility.Conclusion:Rk1/CTX-Lip presents a promising new therapy for prostate cancer and holds potential for relieving concurrent fungal infections in cancer patients with low immunity.
基金supported by National Natural Science Foundation of China(No.82173766,82104109)Natural Science Foundation of Liaoning Province(2022-BS158)+1 种基金Liaoning Province Applied Basic Research Program(No.2022JH2/101300097)National Key R&D Program of China(No.2022YFE0111600).
文摘The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.
文摘目的:探究榄香烯(ELE)增强卡巴他赛(CTX)抗胶质瘤疗效,制备一种共载ELE/CTX的双靶向阳离子脂质体(LIP)用于胶质瘤的治疗研究,并达到增加药效、减少不良反应的作用,经体外药效学试验揭露其优势及作用机制。方法:采用高速剪切法联合探头超声法制备脂质体ELE/CTX@LIP,并采用纳米粒径电位仪对其粒径及电位进行表征,采用高效液相色谱法(HPLC)测定ELE/CTX包封率及载药量;采用细胞增殖与活性检测法(CCK-8)检测ELE/CTX体外细胞增殖抑制活性;通过JMP Pro 16软件,以包封率为指标优化脂质体(ELE/CTX@LIP)工艺参数;通过体外细胞增殖抑制活性和体外细胞摄取,筛选最佳阳离子材料种类、含量与配比,在此基础上制备双靶向阳离子脂质体并表征其形态、粒径稳定性等,验证其对RG2胶质瘤细胞的细胞周期和细胞凋亡的影响。结果:ELE/CTX抗胶质瘤活性结果显示ELE/CTX分别对C6、RG2细胞具有更强的细胞增殖抑制活性;体外细胞增殖抑制活性和体外细胞摄取结果显示阳离子材料用量为总含量的0.10%;T7、精氨酸-甘氨酸-天冬氨酸三肽序列(cRGD)与磷脂最佳配比为1∶1∶50。T7/cRGD-ELE/CTX@CLIP[1,2-二油酰氧基-3-二甲基氨基丙烷(DlinMC3-DMA)]、T7/cRGD-ELE/CTX@CLIP[二肉豆蔻酰甘油-聚乙二醇2000(DMG-PEG2000)]呈现多层次球状纳米结构,粒径分别为146.0 nm和111.3 nm,血清稳定性良好;体外细胞增殖抑制结果显示,与单靶向脂质体或双靶向非阳离子脂质体比较,T7/cRGD-ELE/CTX@CLIP在体外对胶质瘤细胞具有更高的细胞增殖抑制活性;T7/cRGD-ELE/CTX@CLIP影响胶质瘤细胞凋亡及周期,结果显示,ELE/CTX联用能通过脂质体载体能更加有效的激活细胞凋亡通道抑制胶质瘤细胞增殖,且使用T7/cRGD短肽及阳离子修饰后,增强了细胞凋亡诱导能力,ELE/CTX能有效将胶质瘤细胞周期阻滞于G2/M期,且经T7/cRGD靶向修饰后,效果增强。结论:ELE可以增强CTX抗胶�
文摘Prostate cancer is the most common non-cutaneous malignancy for men. The skeleton is the most common metastatic site but, following an improvement in survival, metastases in uncommon sites are being found more frequently in clinical practice, especially brain metastases. Despite the new drugs now available for metastatic castration resistant prostate cancer, no clinical evidence exists about their effectiveness on brain metastases. We describe the clinical history of 3 patients treated with cabazitaxel plus whole brain radiotherapy. These case reports demonstrate that cabazitaxel is highly active and well tolerated in brain metastases.
基金supported by funds from the National Institutes of Health (1R15CA143701)St.John's University Research Seed Grant(579-1110-7002) to Dr.Zhe-Sheng Chen.Drs.Suneet ShuklaSuresh V.Ambudkar were supported by the Intramural Research Program,Center for Cancer Research, National Cancer Institute,National Institutes of Health
文摘Introduction:ATP-binding cassette subfamily B member 1(ABCB1) and subfamily C member 10(ABCCIO) proteins are efflux transporters that couple the energy derived from ATP hydrolysis to the translocation of toxic substances and chemotherapeutic drugs out of cells.Cabazitaxel is a novel taxane that differs from paclitaxel by its lower affinity for ATP-binding cassette(ABC) transporters.Methods:We determined the effects of cabazitaxel,a novel tubulin-binding taxane,and paclitaxel on paclitaxelresistant,ABCB1-overexpressing KB-C2 and LLC-MDR1-WT cells and paclitaxel-resistant,ABCC10-overexpressing HEK293/ABCC10 cells by calculating the degree of drug resistance and measuring ATPase activity of the ABCB1 transporter.Results:Decreased resistance to cabazitaxel compared with paclitaxel was observed in KB-C2,LLC-MDR1-WT,and HEK293/ABCC10 cells.Moreover,cabazitaxel had low efficacy,whereas paclitaxel had high efficacy in stimulating the ATPase activity of ABCB1,indicating a direct interaction of both drugs with the transporter.Conclusion:ABCB1 and ABCC10 are not primary resistance factors for cabazitaxel compared with paclitaxel,suggesting that cabazitaxel may have a low affinity for these efflux transporters.
文摘Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer （mCRPC）. The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents （sipuleuceI-T, cabazitaxel and abiraterone） with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.
基金supported by Shanghai Education Commission Major Project(No.2017-01-07-00-07-E00052,China)National Natural Science Foundation of China(Nos.81773657,81690263,and 81903547,China)Shanghai Sailing Program(No.20YF1404500,China)。
文摘Brain metastasis is a common and serious complication of breast cancer,which is commonly associated with poor survival and prognosis.In particular,the treatment of brain metastasis from triplenegative breast cancer(BM-TNBC)has to face the distinct therapeutic challenges from tumor heterogeneity,circulating tumor cells(CTCs),blood-brain barrier(BBB)and blood-tumor barrier(BTB),which is in unmet clinical needs.Herein,combining with the advantages of synthetic and natural targeting moieties,we develop a“Y-shaped”peptide pVAP-decorated platelet-hybrid liposome drug delivery system to address the all-stage targeted drug delivery for the whole progression of BM-TNBC.Inherited from the activated platelet,the hybrid liposomes still retain the native affinity toward CTCs.Further,the peptide-mediated targeting to breast cancer cells and transport across BBB/BTB are demonstrated in vitro and in vivo.The resultant delivery platform significantly improves the drug accumulation both in orthotopic breast tumors and brain metastatic lesions,and eventually exhibits an outperformance in the inhibition of BM-TNBC compared with the free drug.Overall,this work provides a promising prospect for the comprehensive treatment of BMTNBC,which could be generalized to other cell types or used in imaging platforms in the future.
文摘Background:To evaluate the effectiveness and safety of cabazitaxel in castration-resistant prostate cancer patients aged>80 years,we performed a retrospective study on a sample of patients from 11 Italian cancer centers.Materials and methods:Fifty-seven patients aged>80 years were treated with cabazitaxel after previous failure with docetaxel;39 completed a comprehensive geriatric assessment questionnaire(34 fit and 5 vulnerable)and 8 patients(14%)had an Eastern Cooperative Oncology Group performance status(PS)>2,while most had a PS of 0-1(86%).Cabazitaxel was administered at a dose of 25 mg/m^(2)in 30(52%)patients and 20 mg/m^(2)or adapted schedules in 27(48%)patients.These schedules were adopted mainly in patients>85 years(75%),with a PS>2(87.5%),and those classified as vulnerable(100%).Results:The duration of treatment was 4.8 months and was comparable in all subgroups;disease control rate was reported in 36 patients(63%);prostate-specific antigen response was recorded in 18 patients(31.5%).Median overall survival was 13.1 months regardless of age(<85/>85 years),but overall survival was reduced in vulnerable(7.2 months)and PS>2 patients(6.8 months).The most frequently documented grade 3-4 toxicities were neutropenia(14%)and diarrhea(10.5%).Six patients(10.5%)dropped out due to severe toxicity.Conclusions:Octogenarian patients can be treated with cabazitaxel with reduced doses or alternative schedules that are associated with less toxicity and fewer treatment interruptions.Comprehensive geriatric assessment could facilitate more appropriate patient selection.
基金supported by the National Institutes of Health of the US(DP5OD017898 and R01EB017270)the National Science Foundation of the US(1555220)+1 种基金the National Natural Science Foundation of China(32071384)the National Key Research and Development Program of China(2021YFC2102300)。
