Objective.:Doxorubicin has reported activity in advanced and recurrent cervical cancer but hematologic toxicity has limited its use in some combinations. To determine the level of activity and potential for use in fut...Objective.:Doxorubicin has reported activity in advanced and recurrent cervical cancer but hematologic toxicity has limited its use in some combinations. To determine the level of activity and potential for use in future combinations,a phase II trial of pegylated liposomal doxorubicin as second-line therapy in advanced and recurrent cervical cancer was performed. Methods.:Eligible patients had squamous cell carcinoma of the cervix,measurable disease,one prior chemotherapy regimen which did not include an anthracycline,absolute neutrophil count (ANC) > 1500/μl,platelet count > 100,000/μl,and adequate hepatic function. Pegylated liposomal doxorubicin 40 mg/m2 was administered intravenously over 1 h every 4 weeks. Results.:Twenty-seven patients were entered on this study. All patients were evaluable for toxicity and 26 were evaluable for response. A median of 2 courses of therapy (range 1-10)-was given. No grade 4 toxicities were noted. Three patients (11.1%) had partial responses. Conclusion.:Liposomal doxorubicin has limited activity,at the dose and schedule employed in previously-treated cervical cancer.展开更多
Objective: To evaluate the effect of doxorubicin and its pegylated liposomal formulation(Doxil, Caelyx) on in vitro susceptibility of promastigote and amastigote stages of Leishmania major. Methods: Throughout in vitr...Objective: To evaluate the effect of doxorubicin and its pegylated liposomal formulation(Doxil, Caelyx) on in vitro susceptibility of promastigote and amastigote stages of Leishmania major. Methods: Throughout in vitro assays the IC50 was calculated in the promastigotes and amastigotes forms in J774 macrophage cell line. Also as cytotoxicity in J774 cell line macrophages. Results: Doxorubicin and Doxil showed the same activity against promastigote form with IC50 values of 10.49 μg/m L and 9.63 μg/m L, respectively. Similarly, the amastigote stage was susceptible at concentration of at least 1 μg/m L when compared to positive control(P<0.000 1). Also, cytotoxicity assay against macrophage revealed no toxicity on the host cells at IC50 concentrations. Conclusions: Our findings demonstrated the efficacy of both doxorubicin and its pegylated liposomal formulation on Leishmania major at low concentrations. Further researches are needed for evaluating the safety of drugs in animal model particularly as topical formulation.展开更多
Objective. The aim of this study is to evaluate the effect of oral de xamethaso ne in attenuating palmar-plantar erythrodysesthesias (PPE) in Doxil-treated patients for gynecologic malignancies. Methods. An IRB-appr...Objective. The aim of this study is to evaluate the effect of oral de xamethaso ne in attenuating palmar-plantar erythrodysesthesias (PPE) in Doxil-treated patients for gynecologic malignancies. Methods. An IRB-approved prospective cas e study was conducted in patients with recurrent gynecologic malignancies who we re treated with Doxil(50 mg/m2) on a 28-day cycle. Patients experiencing grad es Ⅱ-ⅣPPE were delayed until resolution then retreated without dose reduction and with a tapering oral dexamethasone regimen (8 mg BID days -1 to 4; 4 mg BI D day 5; 4 mg day 6). Standard treatment for grades Ⅱ-ⅣPPE in those not recei ving dexamethasone was weekly dose delay until resolution of symptoms up to 2 we eks. If resolution occurred within 3 weeks of delay, a 25%dose reduction was ma de. Persistent grades Ⅲ/ⅣPPE resulted in withdrawal of Doxil. Results. Twent y-three patients (ovarian-16, uterine-7) were treated between January 1998 an d December 2000. The median number of cycles administered was 5 (range 1-20). N ine patients (39%) developed grades Ⅱ-ⅣPPE.All nine patients receivedmore th an five cycles of Doxil. The median time to PPE was 3 cycles (range 2-5). Six out of nine PPE patients received scheduled dose dexamethasone. All six had com plete or near complete resolution of PPE and all continued treatment without sub sequent dose modification. All three of the nine PPE patients not receiving dexa methasone required treatment delays and were dose reduced. Conclusion. Oral dexa methasone is effective in attenuating or eliminating Doxil-induced PPE. The u se of the dexamethasone regimen prevents treatment delay and dose reduction.展开更多
Poly(ethylene glycol)-modified(PEGylated)liposomal doxorubicin(Doxil),a clinically used long-circulating liposomal delivery system of doxorubicin for the treatment of various malignancies,is bottlenecked by its therap...Poly(ethylene glycol)-modified(PEGylated)liposomal doxorubicin(Doxil),a clinically used long-circulating liposomal delivery system of doxorubicin for the treatment of various malignancies,is bottlenecked by its therapeutic outcome due to insufficient tumor penetration,suboptimal drug release within the tumor microenvironment,and non-selective toxicities to normal cells.To address these limitations,we developed poly(2-(N-oxide-N,Ndiethylamino)ethyl methacrylate)-b-poly(ε-caprolactone)(OPDEAPCL)-functionalized Doxil(OP-Doxil)via a one-step engineering strategy using amphiphilic block copolymer,OPDEA-PCL.The decoration of OPDEA-PCL endowed Doxil with enhanced tumor penetration,cellular uptake,and pH-responsive drug release.Furthermore,OP-Doxil facilitated both nuclear and mitochondrial co-localization,thereby promoting tumor cell apoptosis while minimizing cytotoxicity to normal cells,realizing tumor-cell selective killing due to the distinct cellular uptake and pH-responsive doxorubicin(DOX)release between tumor cells and normal cells.In the orthotopic hepatocellular carcinoma model,a single injection of OP-Doxil showcased potent anti-tumor activity,achieving a tumor inhibition rate of 97.2%,compared to 68.4%in the Doxil-treated group.Additionally,OP-Doxil spared fibroblasts in the tumor microenvironment,while downregulating WNT16B expression and preventing tumor metastasis,with reduced cardiotoxicity.OP-Doxil also effectively inhibited lung metastasis and cancer embolus formation in the 4T1 breast cancer model.These results highlighted OP-Doxil as a safe,efficient,and clinically translatable therapeutic strategy for primary and metastatic tumors.展开更多
文摘Objective.:Doxorubicin has reported activity in advanced and recurrent cervical cancer but hematologic toxicity has limited its use in some combinations. To determine the level of activity and potential for use in future combinations,a phase II trial of pegylated liposomal doxorubicin as second-line therapy in advanced and recurrent cervical cancer was performed. Methods.:Eligible patients had squamous cell carcinoma of the cervix,measurable disease,one prior chemotherapy regimen which did not include an anthracycline,absolute neutrophil count (ANC) > 1500/μl,platelet count > 100,000/μl,and adequate hepatic function. Pegylated liposomal doxorubicin 40 mg/m2 was administered intravenously over 1 h every 4 weeks. Results.:Twenty-seven patients were entered on this study. All patients were evaluable for toxicity and 26 were evaluable for response. A median of 2 courses of therapy (range 1-10)-was given. No grade 4 toxicities were noted. Three patients (11.1%) had partial responses. Conclusion.:Liposomal doxorubicin has limited activity,at the dose and schedule employed in previously-treated cervical cancer.
基金financially supported by Vice Chancellors for Research and Technology of Mazandaran University of Medical Sciences(project number:1919)
文摘Objective: To evaluate the effect of doxorubicin and its pegylated liposomal formulation(Doxil, Caelyx) on in vitro susceptibility of promastigote and amastigote stages of Leishmania major. Methods: Throughout in vitro assays the IC50 was calculated in the promastigotes and amastigotes forms in J774 macrophage cell line. Also as cytotoxicity in J774 cell line macrophages. Results: Doxorubicin and Doxil showed the same activity against promastigote form with IC50 values of 10.49 μg/m L and 9.63 μg/m L, respectively. Similarly, the amastigote stage was susceptible at concentration of at least 1 μg/m L when compared to positive control(P<0.000 1). Also, cytotoxicity assay against macrophage revealed no toxicity on the host cells at IC50 concentrations. Conclusions: Our findings demonstrated the efficacy of both doxorubicin and its pegylated liposomal formulation on Leishmania major at low concentrations. Further researches are needed for evaluating the safety of drugs in animal model particularly as topical formulation.
文摘Objective. The aim of this study is to evaluate the effect of oral de xamethaso ne in attenuating palmar-plantar erythrodysesthesias (PPE) in Doxil-treated patients for gynecologic malignancies. Methods. An IRB-approved prospective cas e study was conducted in patients with recurrent gynecologic malignancies who we re treated with Doxil(50 mg/m2) on a 28-day cycle. Patients experiencing grad es Ⅱ-ⅣPPE were delayed until resolution then retreated without dose reduction and with a tapering oral dexamethasone regimen (8 mg BID days -1 to 4; 4 mg BI D day 5; 4 mg day 6). Standard treatment for grades Ⅱ-ⅣPPE in those not recei ving dexamethasone was weekly dose delay until resolution of symptoms up to 2 we eks. If resolution occurred within 3 weeks of delay, a 25%dose reduction was ma de. Persistent grades Ⅲ/ⅣPPE resulted in withdrawal of Doxil. Results. Twent y-three patients (ovarian-16, uterine-7) were treated between January 1998 an d December 2000. The median number of cycles administered was 5 (range 1-20). N ine patients (39%) developed grades Ⅱ-ⅣPPE.All nine patients receivedmore th an five cycles of Doxil. The median time to PPE was 3 cycles (range 2-5). Six out of nine PPE patients received scheduled dose dexamethasone. All six had com plete or near complete resolution of PPE and all continued treatment without sub sequent dose modification. All three of the nine PPE patients not receiving dexa methasone required treatment delays and were dose reduced. Conclusion. Oral dexa methasone is effective in attenuating or eliminating Doxil-induced PPE. The u se of the dexamethasone regimen prevents treatment delay and dose reduction.
基金supported by the National Natural Science Foundation of China(No.52273153)the National Key Research and Development Program of China(No.2021YFA1201200)+4 种基金Zhejiang Provincial Medical Health Technology Project(No.2025KY111)the Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project(No.2026ZL0101)the Construction Fund of Key Medical Disciplines of Hangzhou(No.2025HZZD07)the Zhejiang Key Research Program(No.2020C01123)Hangzhou Joint Fund of Zhejiang Provincial Natural Science Foundation(No.LHZQN25H300002).
文摘Poly(ethylene glycol)-modified(PEGylated)liposomal doxorubicin(Doxil),a clinically used long-circulating liposomal delivery system of doxorubicin for the treatment of various malignancies,is bottlenecked by its therapeutic outcome due to insufficient tumor penetration,suboptimal drug release within the tumor microenvironment,and non-selective toxicities to normal cells.To address these limitations,we developed poly(2-(N-oxide-N,Ndiethylamino)ethyl methacrylate)-b-poly(ε-caprolactone)(OPDEAPCL)-functionalized Doxil(OP-Doxil)via a one-step engineering strategy using amphiphilic block copolymer,OPDEA-PCL.The decoration of OPDEA-PCL endowed Doxil with enhanced tumor penetration,cellular uptake,and pH-responsive drug release.Furthermore,OP-Doxil facilitated both nuclear and mitochondrial co-localization,thereby promoting tumor cell apoptosis while minimizing cytotoxicity to normal cells,realizing tumor-cell selective killing due to the distinct cellular uptake and pH-responsive doxorubicin(DOX)release between tumor cells and normal cells.In the orthotopic hepatocellular carcinoma model,a single injection of OP-Doxil showcased potent anti-tumor activity,achieving a tumor inhibition rate of 97.2%,compared to 68.4%in the Doxil-treated group.Additionally,OP-Doxil spared fibroblasts in the tumor microenvironment,while downregulating WNT16B expression and preventing tumor metastasis,with reduced cardiotoxicity.OP-Doxil also effectively inhibited lung metastasis and cancer embolus formation in the 4T1 breast cancer model.These results highlighted OP-Doxil as a safe,efficient,and clinically translatable therapeutic strategy for primary and metastatic tumors.
