To estimate the antitumor activity of 9-aminocamptothecin (9-AC) in patients with recurrent platinum-"resistant" ovarian cancer; and to determine the natur e and degree of toxicity of 9-AC in this cohort of ...To estimate the antitumor activity of 9-aminocamptothecin (9-AC) in patients with recurrent platinum-"resistant" ovarian cancer; and to determine the natur e and degree of toxicity of 9-AC in this cohort of patients. A multicenter phas e II study was conducted by the Gynecologic Oncology Group (GOG). Patients were to receive 9-AC (colloidal dispersion) 25 μg/m2/h (600 μg/m2/day) IV over 120 h (5 days) beginning days 1 and 8. Dose adjustment was permitted for toxicity. This schedule was repeated every 21 days until disease progression or unacceptab le adverse events. Hematopoietic growth factor support was used as necessary. Fr om January 1999 to December 2000, 29 member institutions of the GOG enrolled 58 patients. Two patients received no therapy; thus, 56 (97%) were evaluable. Medi an age was 61 (range: 33-81) years. A median of four (range: 1-32) courses of 9-AC was administered. The most frequent grade 3 or 4 toxicities were neutropen ia in 46%, leukopenia in 37%, gastrointestinal in 29%, anemia in 25%, and th rombocytopenia in 21%. There was one possible treatment-related death. There w ere four (7%) complete and four (7%) partial responses, for an overall respons e rate of 14%. Eighteen (32%) patients had stable disease, 22 (39%)-progress ed, and response could not be assessed in 8 (14%). The 9-AC at this dose and s chedule showed limited activity comparable to that seen with other agents in pla tinum-resistant ovarian or primary peritoneal cancer.展开更多
There is an urgent need for new agents with activity inplatinum -and taxane -resistant epi thelial ovarian can-cer.Exatecan mesylate is a novel top oisomerase I inhibitor with potent activity against ovaria n cancer i...There is an urgent need for new agents with activity inplatinum -and taxane -resistant epi thelial ovarian can-cer.Exatecan mesylate is a novel top oisomerase I inhibitor with potent activity against ovaria n cancer in vitro.A multicentre phase IIA study was cond ucted in patients with platinum -and taxaneresistant epit helial ovarian cancer.Fifty -seven patients with bidimensionally measurable o-varian cancer,previously exposed t o platinum and taxanes,whose disease had relapsed within 6months of platinum -containing chemotherapy were randomised to one of two intravenous schedules of exatecan m esylate;0.3mg /m 2 daily for 5days every 3weeks(Arm A )or 2.1mg /m 2 weekly for 3weeks out of 4(Arm B ).There were no re-sponses in the weekly arm and a radiological response rate of 5.3%(95%CI 0.3-21.8%)in the daily arm.Principal toxicities were myelosup pression and emesis.Grade 3/4neutropenia occurred in 29%of patients inArm A and 6%patients in Arm B.Seventyone percent of pa-tients in Arm A required red cell tran sfusions while on treatment.Exatecan is well tolerated in this poor prognosis group of patients but only has modest single agent activity when administered in a daily regimen.展开更多
Preclinical and clinical data have d emonstrated the impor-tance of schedule in optimizing the c ytotoxic potential of topotecan,one of the most active age nts in ovarian cancer.The availability of oral topotecan p er...Preclinical and clinical data have d emonstrated the impor-tance of schedule in optimizing the c ytotoxic potential of topotecan,one of the most active age nts in ovarian cancer.The availability of oral topotecan p ermits the exploration of the clinical utility of prolonged tr eatment programs em-ploying this drug.Patients with pla tinum /taxane resistant ovarian and primary peritoneal cancers were treated with oral topotecan at an initial fixed dose of 1.5mg /day for 5days,followed by a 2-day break,with treatment contin-ued on this schedule until disease pr ogression or unac-ceptable toxicities.Seven patient s(median age 61)were entered into this phase 2trial before further enrollment was discontinued due to the development of excessive side ef-fects(grade 3:fatigue(n =3);emesis(n =1),throm-bocytopenia with bleeding(n =1).Two additional patients noted grade 2fatigue.Four patients experienced reductionsin hemoglobin concentrations >4.0g /dl from baseline during treatment,with two patients requiring red cell transfusions and two receiving recombinant erythropoietin.Three patients developed grade 3neu tropenia,while there were no episodes of≥grade 2diarrhea.Three patients exhibited biological evidence of an anti -neoplastic effect of therapy(>50%declines in serum CA -125levels).Despite the strong theoretical appeal(as well as limited biological evidence of activity in p latinum /taxane -re-fractory disease)associatedwith prolonging exposur e of cy-cling ovarian cancer cells to topote can,the specific oral regimen employed in this trial was associated with excessive bone marrow suppression,especiall y treatment -induced anemia,resulting in an unacceptabl e incidence of severe fatigue.展开更多
Objective： To investigate whether the change of drug resistance degree could be evaluated by apoptotic rate in ovarian cancer cell lines. Methods： Human epithelia ovarian cancer cell line A2780 and its platinum （DD...Objective： To investigate whether the change of drug resistance degree could be evaluated by apoptotic rate in ovarian cancer cell lines. Methods： Human epithelia ovarian cancer cell line A2780 and its platinum （DDP） resistance cell line AD4 were used. They were divided into 4 groups respectively （A2780-DDP group, A2780-DDP＋VRM group, AD4-DDP group and AD4-DDP＋VRM group）. 3-（4, 5- dimethylthiazol-2-yl）-2, 5-diphenyl-2H-tetrazolium bromide （MTT） was used to measure the multiple of drug resistance. The expression of drug-resistance genes （mdrl, TopoⅡα and GSTπ） was detected by using reverse transcription polymerase chain reaction （RT-PCR）. Semi-quantity assay was proceed by rate the of multidrug resistance genes to G3 PDH gene. Apoptosis was measured by DNA gel electrophoresis and flow cytometry respectively. The advantages and disadvantage of evaluating drug-resistance with these three methods were analyzed. Results： The 50% inhibition concentration （IC50） of A2780 and AD4 was 19.2 μg/mL and 66 μg/mL respectively, and the resistance fold of the AD4 was 3.4. Some drug-resistance genes could be detected by RT-PCR in A2780 and AD4 cell lines. The expression of mdrl was only （0.09±0.03）×10^-2 ： 1 and （0.10±0.02） × 10^-2：1 respectively （rate to G3 PDH gene） with the difference being not significant between them. The expression of TopoⅡα in the A2780 cells was （2.60±0.12）×10^-2：1 and （0.11±0.03）× 10^-2：1 in the AD4 cells respectively with the difference between them being significant. On the contrary, the expression of GSTπ in A2780 cells was lower than in AD4 cells, and the ratio was （0.11±0.03）×10^-2：1 and （3.13±0.14）×10^-2：1 respectively with tile difference being significant between them. There was no significant difference among the genes expression after the drugs were given for 6 h, 12 h and 24 h. couldn＇t reflect the change of drug-resistance timely. DNA gel electrophoresis used to detect apoptosis was only a qualitative analysis. Different drug resistance degrees may be detected by flow cytometry as early as few hours after drugs were given, which realized the earlier and quantities detection of drug resistance. Conclusion： Detection of apoptosis with flow cytometry may not be affected by the variety of drug-resistance genes, suggested this was a general, quantitative and objective method to reflect drug resistance.展开更多
文摘To estimate the antitumor activity of 9-aminocamptothecin (9-AC) in patients with recurrent platinum-"resistant" ovarian cancer; and to determine the natur e and degree of toxicity of 9-AC in this cohort of patients. A multicenter phas e II study was conducted by the Gynecologic Oncology Group (GOG). Patients were to receive 9-AC (colloidal dispersion) 25 μg/m2/h (600 μg/m2/day) IV over 120 h (5 days) beginning days 1 and 8. Dose adjustment was permitted for toxicity. This schedule was repeated every 21 days until disease progression or unacceptab le adverse events. Hematopoietic growth factor support was used as necessary. Fr om January 1999 to December 2000, 29 member institutions of the GOG enrolled 58 patients. Two patients received no therapy; thus, 56 (97%) were evaluable. Medi an age was 61 (range: 33-81) years. A median of four (range: 1-32) courses of 9-AC was administered. The most frequent grade 3 or 4 toxicities were neutropen ia in 46%, leukopenia in 37%, gastrointestinal in 29%, anemia in 25%, and th rombocytopenia in 21%. There was one possible treatment-related death. There w ere four (7%) complete and four (7%) partial responses, for an overall respons e rate of 14%. Eighteen (32%) patients had stable disease, 22 (39%)-progress ed, and response could not be assessed in 8 (14%). The 9-AC at this dose and s chedule showed limited activity comparable to that seen with other agents in pla tinum-resistant ovarian or primary peritoneal cancer.
文摘There is an urgent need for new agents with activity inplatinum -and taxane -resistant epi thelial ovarian can-cer.Exatecan mesylate is a novel top oisomerase I inhibitor with potent activity against ovaria n cancer in vitro.A multicentre phase IIA study was cond ucted in patients with platinum -and taxaneresistant epit helial ovarian cancer.Fifty -seven patients with bidimensionally measurable o-varian cancer,previously exposed t o platinum and taxanes,whose disease had relapsed within 6months of platinum -containing chemotherapy were randomised to one of two intravenous schedules of exatecan m esylate;0.3mg /m 2 daily for 5days every 3weeks(Arm A )or 2.1mg /m 2 weekly for 3weeks out of 4(Arm B ).There were no re-sponses in the weekly arm and a radiological response rate of 5.3%(95%CI 0.3-21.8%)in the daily arm.Principal toxicities were myelosup pression and emesis.Grade 3/4neutropenia occurred in 29%of patients inArm A and 6%patients in Arm B.Seventyone percent of pa-tients in Arm A required red cell tran sfusions while on treatment.Exatecan is well tolerated in this poor prognosis group of patients but only has modest single agent activity when administered in a daily regimen.
文摘Preclinical and clinical data have d emonstrated the impor-tance of schedule in optimizing the c ytotoxic potential of topotecan,one of the most active age nts in ovarian cancer.The availability of oral topotecan p ermits the exploration of the clinical utility of prolonged tr eatment programs em-ploying this drug.Patients with pla tinum /taxane resistant ovarian and primary peritoneal cancers were treated with oral topotecan at an initial fixed dose of 1.5mg /day for 5days,followed by a 2-day break,with treatment contin-ued on this schedule until disease pr ogression or unac-ceptable toxicities.Seven patient s(median age 61)were entered into this phase 2trial before further enrollment was discontinued due to the development of excessive side ef-fects(grade 3:fatigue(n =3);emesis(n =1),throm-bocytopenia with bleeding(n =1).Two additional patients noted grade 2fatigue.Four patients experienced reductionsin hemoglobin concentrations >4.0g /dl from baseline during treatment,with two patients requiring red cell transfusions and two receiving recombinant erythropoietin.Three patients developed grade 3neu tropenia,while there were no episodes of≥grade 2diarrhea.Three patients exhibited biological evidence of an anti -neoplastic effect of therapy(>50%declines in serum CA -125levels).Despite the strong theoretical appeal(as well as limited biological evidence of activity in p latinum /taxane -re-fractory disease)associatedwith prolonging exposur e of cy-cling ovarian cancer cells to topote can,the specific oral regimen employed in this trial was associated with excessive bone marrow suppression,especiall y treatment -induced anemia,resulting in an unacceptabl e incidence of severe fatigue.
基金This work was supported by a grant from National Natural Sciences Foundation of China (No. 30070786).
文摘Objective： To investigate whether the change of drug resistance degree could be evaluated by apoptotic rate in ovarian cancer cell lines. Methods： Human epithelia ovarian cancer cell line A2780 and its platinum （DDP） resistance cell line AD4 were used. They were divided into 4 groups respectively （A2780-DDP group, A2780-DDP＋VRM group, AD4-DDP group and AD4-DDP＋VRM group）. 3-（4, 5- dimethylthiazol-2-yl）-2, 5-diphenyl-2H-tetrazolium bromide （MTT） was used to measure the multiple of drug resistance. The expression of drug-resistance genes （mdrl, TopoⅡα and GSTπ） was detected by using reverse transcription polymerase chain reaction （RT-PCR）. Semi-quantity assay was proceed by rate the of multidrug resistance genes to G3 PDH gene. Apoptosis was measured by DNA gel electrophoresis and flow cytometry respectively. The advantages and disadvantage of evaluating drug-resistance with these three methods were analyzed. Results： The 50% inhibition concentration （IC50） of A2780 and AD4 was 19.2 μg/mL and 66 μg/mL respectively, and the resistance fold of the AD4 was 3.4. Some drug-resistance genes could be detected by RT-PCR in A2780 and AD4 cell lines. The expression of mdrl was only （0.09±0.03）×10^-2 ： 1 and （0.10±0.02） × 10^-2：1 respectively （rate to G3 PDH gene） with the difference being not significant between them. The expression of TopoⅡα in the A2780 cells was （2.60±0.12）×10^-2：1 and （0.11±0.03）× 10^-2：1 in the AD4 cells respectively with the difference between them being significant. On the contrary, the expression of GSTπ in A2780 cells was lower than in AD4 cells, and the ratio was （0.11±0.03）×10^-2：1 and （3.13±0.14）×10^-2：1 respectively with tile difference being significant between them. There was no significant difference among the genes expression after the drugs were given for 6 h, 12 h and 24 h. couldn＇t reflect the change of drug-resistance timely. DNA gel electrophoresis used to detect apoptosis was only a qualitative analysis. Different drug resistance degrees may be detected by flow cytometry as early as few hours after drugs were given, which realized the earlier and quantities detection of drug resistance. Conclusion： Detection of apoptosis with flow cytometry may not be affected by the variety of drug-resistance genes, suggested this was a general, quantitative and objective method to reflect drug resistance.
