采用含博来霉素ABVD方案治疗霍奇金淋巴瘤合并肺结核致患者死亡1例

目的ABVD化疗方案中博来霉素治疗指数较低,本文报道1例死亡病例供临床参考,旨在提示临床谨慎应用。方法报道1名74岁的中国男性患者因发热、咳嗽入院,经诊断为经典霍奇金淋巴瘤合并肺结核。采用ABVD化疗方案,第1天给予多柔比星35mg,长春地辛4mg,达卡巴嗪500mg,博来霉素15mg。结果患者给予博来霉素20min后,体温突然升至41℃并伴有呼吸困难、多汗、昏迷症状,血压下降至108／58mmHg,患者最后死于多器官功能衰竭。结论对于合并肺结核的老年霍奇金病患者特别是年龄〉70岁者,应该谨慎选择含有博来霉素的化疗方案。并且在充分给予预防用药后,首先使用1mg的博来霉素进行预实验,如果没有不良反应发生才能全剂量给药。     

Fibroblast growth factor 2 decreases bleomycin‐induced pulmonary fibrosis and inhibits fibroblast collagen production and myofibroblast differentiation

Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin‐induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double‐transgenic (DTG) mice with doxycycline‐inducible overexpression of human FGF2 (SPC‐rtTA;TRE‐hFGF2) or single‐transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild‐type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline‐induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1‐induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad‐dependent gene expression, FGF2 inhibited TGFβ1‐induced stress fiber formation and serum response factor‐dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin‐induced pulmonary fibrosis in vivo and reverses TGFβ1‐induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Crystal structure of DNA-bound Co(III) bleomycin B2: Insights on intercalation and minor groove binding

Bleomycins constitute a widely studied class of complex DNA cleaving natural products that are used to treat various cancers. Since their first isolation, the bleomycins have provided a paradigm for the development and discovery of additional DNA-cleaving chemotherapeutic agents. The bleomycins consist of a disaccharide-modified metal-binding domain connected to a bithiazole/C-terminal tail via a methylvalerate-Thr linker and induce DNA damage after oxygen activation through site-selective cleavage of duplex DNA at 5'-GT/C sites. Here, we present crystal structures of two different 5'-GT containing oligonucleotides in both the presence and absence of bound Co(III).bleomycin B(2). Several findings from our studies impact the current view of bleomycin binding to DNA. First, we report that the bithiazole intercalates in two distinct modes and can do so independently of well ordered minor groove binding of the metal binding/disaccharide domains. Second, the Co(III)-coordinating equatorial ligands in our structure include the imidazole, histidine amide, pyrimidine N1, and the secondary amine of the beta aminoalanine, whereas the primary amine acts as an axial ligand. Third, minor groove binding of Co(III).bleomycin involves direct hydrogen bonding interactions of the metal binding domain and disaccharide with the DNA. Finally, modeling of a hydroperoxide ligand coordinated to Co(III) suggests that it is ideally positioned for initiation of C4'-H abstraction.     

DDP-BLM方案用于口腔癌的诱导化疗的初步评估

目的探讨顺铂(DDP)和博莱霉素(BLM)短周期联合运用对口腔鳞癌的术前或放疗前诱导化疗的临床疗效。方法9例口腔鳞癌术前或放疗前采用"DDP+BLM联合诱导化疗"DDP100mg/㎡1d,BLM15mg/㎡4d。结果诱导化疗结束后2天,6例(66.7%)肿瘤体积缩小,其中按国际疗效通用标准有效率达44.4%。结论 DDP+BLM短周期联合诱导化疗取得一定的临床效果,毒性小,实用性强。     

新型内皮素受体拮抗剂ETP-508对实验性大鼠肺纤维化的干预作用

目的：研究新型内皮素受体拮抗剂ETP-508对实验性大鼠肺纤维化的干预作用,并探讨其机制．方法：实验分为4组：博莱霉素组、ETP-508组、地塞米松组和正常对照组．博莱霉素组、ETP-508组和地塞米松组均给以博莱霉素（5mg／kg）气管内注射复制大鼠肺纤维化模型,正常对照组给以气管内注射等量生理盐水替代．ETP-508组和地塞米松组造模开始后次日又分别给以腹腔注射ETP-508（100μg／kg）和地塞米松（1mg／kg）,隔日1次．博莱霉素组和正常对照组以等量生理盐水替代．造模后第28日处死所有大鼠,测定肺组织ET-1和羟脯氨酸含量,并进行组织病理学观察．结果：博莱霉素组肺组织内羟脯氨酸明显高于正常对照组,病理为肺纤维化改变．博莱霉素组的ET-1水平高于正常对照组和地塞米松组,差异有统计学意义（P〈0．01）;ETP-508组ET-1水平均高于上述各组,与博莱霉素组（P〈0．05）,正常对照组和地塞米松组比较（P〈0．01）有统计学意义;地塞米松组与正常对照组比较,无统计学意义（P〉0．05）．结论：ETP-508对肺纤维化的形成有一定的干预作用,其机制可能通过拮抗ET-1与内皮素受体结合的作用有关．     

三七总皂甙对实验性肺纤维化大鼠病理变化和转化生长因子-β1表达的影响

目的研究博莱霉素（BLM）所致大鼠肺纤维化的病理形态学变化和三七总皂甙（PNS）的干预作用及其机制。方法通过气管内注入BLM复制动物肺纤维化模型,于造模后第2天各治疗组开始每天给药,于给药后第7,14,28天分别随机处死一批大鼠,取肺组织行HE染色,用免疫组织化学方法检测肺组织中TGF-β1的表达,并测定肺组织中羟脯氨酸（HYP）含量。结果PNS能抑制实验性肺纤维化大鼠肺组织中胶原沉积及TGF-β1的异常升高,减轻其肺部的病理损害。结论PNS对BLM诱导产生的肺纤维化有一定的抑制作用。     

Antitumour effect of electrochemotherapy with bleomycin on human prostate cancer xenograft

OBJECTIVE

To investigate the antitumour effect of electroporation (EP), a drug delivery system that has been shown to be effective synergistically with antitumour drugs, with bleomycin on the growth of prostate cancer xenografts in nude mice.

MATERIALS AND METHODS

PC‐3 cells were implanted subcutaneously into nude mice. After determination of the optimal conditions of electric pulse voltage and bleomycin dose, tumour growth in mice treated with EP plus bleomycin was compared with that in mice receiving EP alone, bleomycin alone or no treatment. In all four groups, apoptosis in the tumours was assessed.

RESULTS

There was a significant reduction in tumour growth in mice that received EP with bleomycin. Apoptotic cells in tumours at 24 h after treatment with EP plus bleomycin showed a significant difference compared with the other three groups, but not at 12 h after treatment.

CONCLUSIONS

These results indicate the possibility that EP with bleomycin could be effective as an ablation therapy for prostate cancer, especially androgen‐independent cancer.     

G-CSF is not necessary to maintain over 99% dose-intensity with ABVD in the treatment of Hodgkin lymphoma: low toxicity and excellent outcomes in a 10-year analysis

Dose-intensity of chemotherapy is important in the treatment of Hodgkin lymphoma (HL) and granulocyte-colony stimulating factor (G-CSF) is commonly used to maintain it. We reviewed all newly diagnosed HL patients who were treated at our institution between 1996 and 2005. Fifty-nine patients received adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy with no dose reductions, treatment delays, and without G-CSF, regardless of absolute neutrophil count (ANC). The median ANC on all ABVD treatment days (n = 658) was 0.925 x 10(9)/l, and was <0.5 x 10(9)/l on 26% of treatment days. Median normalised ABVD dose-intensity was 99.1% (range, 93-100%) and median cycle duration was 28.2 d. Incidence of bleomycin lung toxicity was 1.6%, 0.44% treatments were complicated by febrile neutropenia, and no secondary malignancies have occurred (median follow-up 48 months; range, 11-130 months). Five-year event-free (EFS) and overall survival (OS) were 92.9% and 97.4% respectively. Furthermore, the 5-year EFS and OS (87.4% and 94.1% respectively) for advanced stage patients compared favourably with a similar ABVD patient group who received routine prophylactic G-CSF (n = 23) with EFS 80.0% and OS 91.3% (P = 0.46 and 0.67 respectively). Our experience suggests that ABVD may be safely and effectively administered at >99% dose-intensity without G-CSF support, regardless of the ANC.     

Complete resolution of recalcitrant periungual/subungual wart with recovery of normal nail following “prick” method of administration of bleomycin 1%

We report a case of 14 year old girl with recalcitrant subungual wart which responded dramatically to bleomycin with normal nail regrowth.