内源性过氧亚硝基阴离子在博莱霉素A5诱发大鼠肺损伤和肺纤维化中的作用

目的：观察内源性过氧亚硝基阴离子(ONOO^-)在博莱霉素A5诱发大鼠肺损伤和肺纤维化中的作用．方法：通过测定出肺血脂质过氧化物水平和观察肺组织学变化(包括用偏振光显微镜观察天狼猩红染色的I、Ⅲ型胶原的变化)来判断肺损伤和肺纤维化;用硝基酪氨酸的免疫组化判断过氧亚硝基阴离子的表达．结果：气管内给予博莱霉素A5第14天观察到(1)出肺血脂质过氧化物含量升高;肺泡壁增厚,肺间质巨噬细胞浸润,且其邻近有成纤维细胞及增多的I、Ⅲ型胶原．(2)肺泡上皮细胞和肺间质细胞内ONOO^-高表达．(3)诱导型一氧化氮合酶(iNOS)抑制剂氨基胍减轻上述变化．结论：内源性ONOO^-介导BLM-A5的肺毒性作用;氨基胍对肺损伤和肺纤维化的治疗部分是通过减少内源性ONOO^-的形成实现的．     

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。     

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.     

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.     

A new experimental trial using repeated heating every 24 hours for local hyperthermic therapy with bleomycinin vivo

This report presents the effect of repeated heating every 24 hrs using bleomycin (BLM) which, although seemingly contrary to the usual agreement that hyperthermia should be carried out with a long interval due to thermotolerance, holds many possibilities. FM3A cells on the foot pad of C3H mouse were immersed in a heated water bath at 43 and 44°C for 30 min. The effect of repeated heating was appreciated by an improved growth curve and 50 day survival compared to mice which received heating twice with a 96-hr interval. Repeated heating every 24 hrs 5 times with BLM suppressed tumor growth significantly as compared to heating twice with a 96-hr interval without BLM. The longest survival time was obtained by the repeated heating with BLM among all protocols. There is therefore a good possibility that more effective results could be obtained clinically by repeated heating over a short period.     

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.     

PB方案在宫颈癌介入化疗中的应用

目的 探讨顺铂＋博莱霉素（PB）治疗方案在宫颈癌介入化疗中的应用效果。方法 采用P B方案,对64例ⅠB～ⅡB期宫颈癌病人术前均行双侧子宫动脉介入化疗栓塞术,观察化疗前后宫颈肿瘤体积变化及化疗后反应,评价介入化疗的效果。比较介入化疗后手术病人（观察组）与直接手术病人（对照组）术中情况及切除组织病理情况,评价介入化疗的近期疗效。长期随访病人,评价介入化疗的远期效果。结果 PB方案病人介入化疗的有效率为87.5%,缓解率为96.9%,34.4%的病人出现了发热反应,未见其他明显不良反应。观察组和对照组手术时间和术中出血量比较差异有显著性（t=9 0.99、9 1.02,P〈0.05）;两组术后盆腔淋巴结转移、脉管浸润、宫旁浸润及阴道切缘受累方面比较差异均有显著性（V2=5.037、7.246,P〈0.05）;观察组5年生存率及2、5年复发率与对照组比较,差异有显著性（V2=4 5.85～7.246,P〈0.05）。结论 PB介入化疗方案有效、低毒,对ⅠB～ⅡB期宫颈癌具有较好的疗效。PB方案是值得推广的介入化疗方案。