米非司酮逆转人乳腺癌细胞MCF-7/ADR耐多柔比星机制的探讨

目的 探讨米非司酮对乳腺癌耐药细胞株MCF-7/ADR的逆转耐药作用.方法 以亲本乳腺癌细胞MCF-7和耐多柔比星(阿霉素)乳腺癌细胞MCF-7/ADR为研究对象,分别应用MIF进行干预后,流式细胞仪检测MIF作用前后瘤细胞P-gp的表达、细胞内阿霉素蓄积量的变化以及细胞周期的分布.结果 (1)10 μmol/L MIF作用72小时后,MCF-7/ADR细胞P-gp表达率[(23.21±1.80)％]明显高于MCF-7细胞[(19.37±2.37)％,P＜0.05].(2)5 μmol/L ADR处理后,MCF-7/ADR细胞内ADR蓄积量为(47.13±4.11)％,低于MCF-7细胞[(60.24±2.61)％,P＜0.05].(3) 10 μmol/L MIF联合5 μmol/L ADR处理细胞,MCF-7/ADR和MCF-7细胞内ADR的蓄积量分别为(82.72±2.42)％及(88.63±2.75)％ (P ＞0.05);但均较单用ADR时升高(均P＜0.01).(4) MIF作用前,MCF-7/ADR细胞G0/G1期比例[(77.21±3.10)％]高于MCF-7细胞G0/G1期比例[(59.05±2.16)％,P＜0.05];MCF-7/ADR细胞S期比例明显低于MCF-7细胞(P＜0.05).经10 μmol/L MIF作用后,MCF-7细胞G0/G1期比例(75.28±2.53)％较MIF作用前明显升高(P＜0.05);S期比例则较MIF作用前显著降低(P＜0.05);MCF-7/ADR细胞G0/G1期比例和S期比例分别为(80.13±2.72)％及(13.52±1.03)％,与MIF作用前比较差异均无统计学意义(均P＞0.05);两种瘤细胞的G2/M期比例与MIF作用无关(P＞0.05).结论 (1)MIF可以逆转MCF-7/ADR的耐药性,其作用机制与降低细胞P-gp含量、增加细胞内ADR蓄积量有关.(2) 10 μmol/L浓度的MIF对MCF-7/ADR细胞周期分布影响不大.     

（125）I联合ADM对乳腺癌MCF-7细胞增殖、凋亡的影响

目的研究放射性粒子125I联合化疗药物多柔比星（阿霉素,ADM）对乳腺癌MCF-7细胞增殖、凋亡的影响。方法按2×2析因设计将乳腺癌敏感株MCF-7细胞随机分成A、B、C、D 4组,A组：空白对照组;B组：单纯125I粒子组;C组：单纯ADM组;D组：125I粒子＋ADM组。采用流式细胞术检测各组干预后的细胞周期分布及细胞凋亡率。结果 （1）单纯125I粒子近距离低剂量率持续照射后将MCF-7细胞阻滞于G2~M期1。25I联合ADM将MCF-7细胞周期主要集中在G0~G1期,同时伴有较大比例的细胞凋亡。（2）各组细胞的早期凋亡率分别为：A组（0.99±0.05）%、B组（19.22±4.92）%、C组（16.57±4.73）%、D组（3.16±1.08）%;各组晚期凋亡及坏死率为：A组（0.32±0.18）%、B组（3.16±1.39）%、C组（3.24±0.75）%、D组（28.99±7.96）%,D组晚期凋亡及死亡率明显提高。结论 125I放射性粒子能有效诱导乳腺癌细胞凋亡,与化疗药物ADM联合作用除诱导细胞凋亡,还可导致大量细胞死亡,具有协同、增效的作用。     

Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group

ICON3 trial results have suggested that CAP and carboplatin-taxol regimens as first-line treatment of advanced ovarian cancer (AOC) yield similar survival. We explored the impact of increased dose of cyclophosphamide in a modified CAP regimen on the disease-free survival (DFS) and overall survival (OS) of AOC patients. From February 1994 to June 1997, 164 patients were randomised to receive six cycles every 3 weeks of either standard CEP (S) combining cyclophosphamide (C), 500 mg m(-2), epirubicin (E) 50 mg m(-2), and cisplatin (P) 75 mg m(-2) or intensive CEP (I) with E and P at the same doses, but with (C) 1800 mg m(-2) and filgrastim 5 mug kg(-1) per day x 10 days. Response was evaluated at second-look surgery. Patient characteristics were well balanced. Except for grade 3-4 neutropaenia (S: 54%, I: 38% of cycles), Arm1 presented a significantly more important toxicity: infection requiring antibiotics, grade 3-4 thrombocytopaenia, anaemia, nausea-vomiting, diarrhoea, mucositis. Median follow-up was 84 months. DFS (15.9 vs 14.8 months) and OS (33 vs 30 months) were not significantly different between S and I (P>0.05). Increasing cyclophosphamide dose by more than 3 times with filgrastim support in the modified CAP regimen CEP induces more toxicity but not better efficacy in AOC.     

Randomized study for the treatment of adult advanced Hodgkin's disease: Epirubicin,vinblastine, bleomycin,and dacarbazine (EVBD) versus mitoxantrone,vinblastine, bleomycin,and dacarbazine (MVBD)

Seventy patients with previously untreated advanced Hodgkin's disease and without bulky disease were entered in a prospective randomized clinical trial comparing epirubicin in combination with vinblastine, bleomycin, and dacarbazine (EVBD) with a regimen containing mitoxantrone, vinblastine, bleomycin, and dacarbazine (MVBD). Both groups were comparable for the variables of age, sex, stage, and presence of B symptoms and histology. Thirty-one (88%) of EVBD-treated patients achieved a pathologically documented complete remission (CR) compared to the 24 cases (68%) of the MVBD-treated group. After a median follow-up of 36 months, duration of CR is better in the EVBD-treated patients with an actuarial 5-year duration of CR of 80%, statistically different to the MVBD group: 53% (P < 0.01). Both regimens ahowed the same gastrointestinal toxicity, but the patients treated with the MVBD regimen shown most and severe hematological and cardiac toxicities. Also, biochemical alterations in hepatic test were observed in these patients. The alternative use of epirubicin in combination chemotherapy appears to be as effective in advanced Hodgkin's disease without bulky disease, with reduced clinical toxicity. Mitoxantrone containing regimen was not found to have an equivalent efficacy and clinical toxicity was most frequent and severe. We feld that mitoxantrone could be consider a second-line drug in the treatment of advanced Hodgkin's disease. © 1994 Wiley-Liss, Inc.     

Twelve-year follow up of a randomized prospective trial comparing bacillus Calmette-Guerin and epirubicin as adjuvant therapy in superficial bladder cancer

AIM: To compare bacillus Calmette-Guerin (BCG) with epirubicin in adjuvant therapy of superficial bladder transitional cell carcinoma, with respect to recurrence, progression and survival. Prognostic factors are also evaluated. METHODS: Between October 1991 and September 1999, all patients harboring superficial bladder cancers (Ta or T1) with any of the relevant criteria (stage>a, grade>1, size>1 cm, multiple or recurrent tumors), after complete transurethral resection were randomized to receive either 81 mg Connaught strain BCG or 50 mg epirubicin. Patients with recurrences were eligible to crossover, even repeatedly, until progression. Recurrence, progression and survival were analyzed in relation to initial treatment, patient characteristics and tumor characteristics. RESULTS: There were 209 patients included in the study, 149 men and 60 women. The mean age was 69.9 years (range, 24-92). The BCG group consisted of 102 patients and the epirubicin group contained 107 patients. Final analysis was made at a median follow up of 23, 47 and 61 months for recurrence, progression and survival, respectively. The 10-year Kaplan-Meier estimates for recurrence-free, progression-free and disease-specific survival were 61%, 78% and 80%, respectively, for the BCG group. The corresponding figures were 32%, 74% and 92%, respectively, for the epirubicin group. Time to recurrence differed significantly between two treatment groups (P=0.0004). Multiplicity increased the risk of recurrence, while grading influenced recurrence, progression and disease specific survival. CONCLUSIONS: Bacillus Calmette-Guerin prolonged time to recurrence when compared with epirubicin. Grading was shown to be a universal prognostic factor for recurrence, progression and disease specific survival.     

Drug eruption due to intravesical instillations of both epirubicin and mitomycin C

We present the first patient to develop drug eruption due to intravesical instillations of both epirubicin and mitomycin C. A 58-year-old-man underwent transurethral resection (TUR) for superficial bladder carcinoma followed by instillations of intravesical chemotherapy. Immediately after TUR, the first instillation of epirubicin was performed. Two days after the first instillation, the patient developed generalized erythema of the face, trunk, upper and lower limbs. Two days after the second instillation, the patient developed severe generalized erythema and was diagnosed as having drug eruption due to intravesical instillations of epirubicin by the dermatologist. Instead of epirubicin, mitomycin C was instilled 2 weeks postoperatively. Two days after the first instillation of mitomycin C, the patient again developed severe generalized erythema and was diagnosed as having drug eruption due to intravesical instillation of mitomycin C. Drug eruption after the first instillation of epirubicin might have been due to drug toxicity of the agent. However, drug eruptions after the second instillation of epirubicin and the first instillation of mitomycin C might have been due to allergic reactions to the drugs. The patient has not received any further intravesical chemotherapy and has not demonstrated any such a drug eruption again.     

Identifying Risk Factors for Anthracycline Chemotherapy-induced Phlebitis in Women with Breast Cancer: An Observational Study

AimsAnthracycline chemotherapy administered via a peripheral cannula results in severe anthracycline chemotherapy-induced phlebitis (ACIP) in about 20–30% of patients. Administering chemotherapy via a central venous catheter (CVC) prevents ACIP. However, CVCs are associated with an increased risk of thrombosis and sepsis. Our aim was to identify risk factors associated with severe ACIP and to provide evidence about the individual risk of developing symptoms.Materials and methodsA prospective observational study of 263 women with breast cancer receiving peripheral administration of anthracycline chemotherapy at a UK cancer centre was conducted between May 2016 and January 2018. Data were collected at baseline and every 3 weeks following each chemotherapy treatment, using both healthcare professional- and participant-reported symptom assessments.ResultsAfter three cycles of chemotherapy, 27% of participants experienced severe ACIP. Factors associated with symptom severity were identified as: arm used for chemotherapy administration, epirubicin dose, age, pre-existing hypertension, comorbidity, ethnic group and pain during chemotherapy administration. The sequence of arm used for chemotherapy administration was the single most significant factor (P < 0.001). When alternating arms were used no other risk factor was influential. Where alternating arms were not used, younger age and higher dose were associated with higher-grade symptoms, with age being more influential than dose. The cumulative effect of increasing symptom severity with repeated cycles was also identified (P < 0.001).ConclusionIt is recommended that a CVC is not routinely required for women with breast cancer who have not undergone an axillary node clearance and receive chemotherapy in alternate arms. The need for a CVC for women who are planned to receive all anthracycline chemotherapy cycles in the same arm should be assessed in the light of peripheral venous access assessment and the key risk factors of age, dose and number of cycles.     

Greater antitumor efficacy of paclitaxel administered before epirubicin in a mouse mammary carcinoma

Combined treatment with paclitaxel and anthracyclines is increasingly being tested in clinical practice. Epirubicin is in general administered before paclitaxel. We have investigated, using a murine mammary adenocarcinoma, whether the efficacy and toxicity of this combination is influenced by treatment sequence, different time intervals and dose intensity. The tumor was transplanted into the right hind foot of C3D2F1 female mice. Paclitaxel was administered i.p. in doses ranging from 15 mg/kg to 75 mg/kg and epirubicin (i.p. or i.v.) in doses from 9 mg/kg to 30 mg/kg. The hepatic and peritoneal toxicity observed with epirubicin administration increased in combined treatments (stronger with i.p. than i.v. epirubicin administrations) and was dose-dependent. When paclitaxel and epirubicin were administered simultaneously or paclitaxel was given 24 h before epirubicin, the same tumor growth delays were obtained in all groups. A smaller effect was observed when paclitaxel was administered 24 h after epirubicin. Increasing the epirubicin or paclitaxel dose led to higher tumor growth delays but also an increased toxicity. In conclusion, in this experimental model, the administration of 45 mg/kg paclitaxel before 15 mg/kg epirubicin was very effective and the increased toxicity can be limited by introducing an interval of 24 h between drug administrations. These results should be considered when designing clinical trials. Received: 22 September 1997 / Accepted: 23 December 1997     

Epirubicin and cytosine arabinoside for the induction therapy of childhood acute nonlymphocytic leukemia.

Epirubicin, a new anthracycline, was used in combination with cytosine arabinoside for the induction therapy of de novo acute nonlymphocytic leukemia in childhood. The treatment consisted of epirubicin 20 mg/m2/day for 3 days and cytosine arabinoside 100 mg/m2/day for 7 days. The treatment could be repeated every 3 weeks. Remission induction rate was 80% (20/25). Moreover, in 13 patients, the remissions were obtained after a single course. In general, the side effects of epirubicin and cytosine arabinoside were tolerable. However, the main causes of all the three deaths were infections. Our study suggests that epirubicin is acceptable and effective for the induction therapy for de novo acute nonlymphocytic leukemia in childhood.