Bioreductive activation of quinones: A mixed blessing

Quinones can be metabolized by various routes: substitution or reductive addition with nucleophilic compounds (mainly glutathione and protein thiol groups), one-electron reduction (mainly by NADPH: cytochrome P-450 reductase) and two-electron reduction (by D,T-diaphorase). During reduction semiquinone radicals and hydroquinones are formed, which can transfer electrons to molecular oxygen, resulting in the formation of reactive oxygen intermediates and back-formation of the parent quinone (redox cycling). Reaction of semiquinones and reactive oxygen intermediates with DNA and other macromolecules can lead to acute cytotoxicity and/or to mutagenicity and carcinogenicity. The enhanced DNA-alkylating properties of certain hydroquinones are exploited in the bioreductive alkylating quinones. Acute cytotoxicity of quinones appears to be related to glutathione depletion and to interaction with mitochondria and subsequent disturbance of cellular energy homoeostasis and calcium homoeostasis. These effects can to a certain extent be predicted from the electron-withdrawing and electron-donating effects of the substituents on the quinone nucleus of the molecule. Prediction of cytostatic potential remains much more complicated, because reduction of the quinones and the reactivity of the reduction products with DNA are modulated by the prevailing oxygen tension and by the prevalence of reducing enzymes in tumour cells.This article is based on a lecture given at the 16th LOF Symposium, 27 October 1989, Utrecht, the Netherlands.     

Loading anticancer drugs into HDL as well as LDL has little affect on properties of complexes and enhances cytotoxicity to human carcinoma cells

Low density lipoprotein (LDL) has been found to represent a suitable carrier for cytotoxic drugs that may target them to cancer. This study investigated whether very low density lipoprotein (VLDL), LDL and high density lipoprotein (HDL) can be used to effectively incorporate four cytotoxic drugs, 5-fluorouracil (5-FU), 5-iododeoxyuridine (IUdR), doxorubicin (Dox) and vindesine; characterized the complexes; and examined the effect of incorporation on drug cytotoxicity against HeLa cervical and MCF-7 breast carcinoma cells. Significant drug loading was achieved into all three classes of lipoproteins, consistent with the sizes and hydrophobicity of the drugs. The relative loading efficiency was found to be vindesine>IUdR>Dox>5-FU for all three classes of lipoproteins. As shown by electron microscopy (EM), drug incorporation did not affect the size or morphology of the lipoproteins. Differential scanning calorimetry (DSC) showed that drug loading did not significantly change the thermal transition temperature of core lipids in the lipoproteins. The transition enthalpy was changed only for LDL–Dox and LDL–vindesine. The drugs remained stable in the lipoproteins as determined by high performance liquid chromatography (HPLC). EM, DSC and HPLC data suggest that drugs were incorporated into lipoproteins without disrupting their integrity and drugs remained in their stable forms inside lipoproteins. Compared with free drugs in cytotoxicity assays, the IC₅₀ values of LDL– and HDL–drug complexes were significantly lower (2.4- to 8.6-fold for LDL complexes and 2.5- to 23-fold for HDL complexes). All free or lipoprotein-bound drug formulations were comparably more cytotoxic against MCF-7 than HeLa cells. Upregulating the lipoprotein receptors enhanced, and downregulating them inhibited, the cytotoxicity, indicating the mechanistic involvement of lipoprotein receptor pathways. Complexes of all four drugs with VLDL, in contrast to LDL and HDL, had the same cytotoxicity as the four corresponding free drugs. Our results suggest that further studies are required of the potential of HDL to be a cancer targeting drug carrier.     

临床肿瘤用药的统计分析

[目的]了解肿瘤用药的消费现状及发展趋势，为临床合理用药提供依据。[方法]对本院1996年-2002年抗肿瘤药、生物反应调节剂和升白细胞药的用药情况进行统计分析，以药品的年消耗金额作统计。[结果]抗肿瘤药、生物反应调节剂和升白细胞药分别占全部药品年消耗总金额的24．24％～33．73％、15．80％～23．33％和5．86％～9．11％。[结论]抗肿瘤药、生物反应调节剂和升白细胞药是用于肿瘤治疗的主要药品，尤其是抗肿瘤天然药物有着广阔的应用前景。     

抗癌生物活性肽对人乳腺癌nm231细胞的增殖抑制作用

 目的 探讨抗癌生物活性肽（ACBP）对人乳腺癌 nm231细胞的作用及其机制。 方法 nm231 细胞经不同浓度（0.05、0.10、0.20、 0.25 µg/ml）ACBP 作用 72 h，以噻唑蓝（MTT）法测定细胞增殖活性。以 0.25 µg/ml 的 ACBP 分别作用于 nm231 细胞 4、6、24、48、72 h，行光镜和透射电镜（作用 48 h 细胞）观察。应用 DNA 凝胶电泳和磷脂结合蛋白 V（Annexin V，AV）/碘化丙啶（PI）双标记染色流式细胞术等方法，观察 0.25 µg/ml 的 ACBP 作用不同时间对nm231 细胞凋亡发生及作用 48 h 对细胞周期的影响。以上各项检测均设以 RPMI 1640 培养液取代 ACBP 的对照组。 结果 浓度为 0.1 µg/ml 的 ACBP 即对 nm231 细胞的增殖有明显抑制作用，抑制率为 10.3%，抑制作用具有浓度依赖性，ACBP 浓度为 0.25 µg/ml 时抑制率达 35.1%。光镜观察显示，经 0.25 µg/ml 的 ACBP 作用 24 h，细胞出现凋亡特征；作用 48 h，光镜及电镜下均可见大量的典型凋亡细胞。DNA 凝胶电泳显示，经 0.25 µg/ml 的ACBP 作用 24 h 的细胞出现 DNA 断裂；作用 48 h 的细胞出现典型的梯形电泳图谱。流式细胞术分析显示，ACBP 作用后AV（+）/ PI（－）细胞和 AV（+）/ PI（+）细胞比例均随培养时间延长而增大；作用 48 h 的 nm231细胞 G0/1 期细胞比例高于对照组（P < 0.01），而细胞增殖指数低于对照组（P < 0.01）。 结论 ACBP 可抑制 nm231 细胞的增殖，其机制与抑制nm231 细胞的 DNA 合成和诱导细胞凋亡相关。     

三组不同的联合化疗方案治疗晚期胃腺癌病例的比较

目的 比较三组不同的联合化疗方案对晚期胃癌的疗效和毒性。方法 对ECF方案,FAMTx方案,FAM方案治疗的77例晚期胃腺癌病例的临床资料统计分析。结果 ECF组有效率为61．5％（16／26）,其中完全缓解2例;FAMTx组有效率为52％（13／25）,其中完全缓解1例;FAM组有效率为34．2％（9／26）。毒副作用主要为骨髓抑制,肾功能不全,脱发及粘膜炎。结论 ECF及FAMTx方案为治疗晚期胃腺癌的较为安全而有效的治疗方案。     

多西他赛+卡铂联合曲妥珠单抗方案对早期人表皮生长因子受体2阳性乳腺癌的新辅助治疗效果

目的探讨多西他赛+卡铂联合曲妥珠单抗(TCH)方案对早期人表皮生长因子受体2(HER2)阳性乳腺癌的新辅助治疗效果。方法回顾性分析2013年1月至2018年12月北京大学第一医院乳腺疾病中心经治的522例早期HER2阳性乳腺癌患者的临床资料,占同期收治早期浸润性乳腺癌患者的21.80%(522/2 394)。其中113例接受TCH方案进行新辅助治疗,年龄[M(QR)]52(13)岁(范围:23~69岁)。记录TCH方案新辅助治疗后病理完全缓解(pCR,ypT0N0M0期)的例数,采用Miller-Payne标准进行病理学评价。采用Kaplan-Meier法计算无病生存率和总体生存率,采用Log-rank检验比较组间生存差异。结果接受曲妥珠单抗规范治疗患者(294例)的无病生存率优于未规范治疗患者(177例)(84.4%比72.4%,χ²=4.095,P=0.046)。发生3~4级不良反应的患者占全部患者的15.9%(18/113),包括3~4级中性粒细胞减少12例,腹泻6例。31例患者获得pCR(ypT0N0M0),pCR率为27.4%(31/113)。pCR患者与非pCR患者的无病生存率和总体生存率无差异(91.8%比85.0%,92.5%比90.5%,P值均>0.05)。病理学评价为G4~5的患者无病生存率优于G1~3患者(89.6%比81.5%,χ²=5.340,P=0.021),而总体生存率的差异无统计学意义(91.4%比89.1%,χ²=1.008,P=0.315)。结论早期HER2阳性乳腺癌采用TCH方案行新辅助治疗的效果较好,新辅助治疗后病理学评价为G4~5的患者的无病生存率更高。     

新抗肿瘤化合物8-氯腺苷代谢物在大鼠体内的药代动力学研究

目的 :全面了解一次静注 8 氯腺苷后其代谢产物在大鼠体内药代动力学的规律及特点 ,为临床实验提供理论依据。方法 :给大鼠单次静注 4种剂量 8 氯腺苷后 ,应用HPLC方法测定在体液和组织中 8 氯腺苷代谢产物8 氯肌苷和 8 氯嘌呤的含量。结果 :8 氯腺苷在大鼠体内迅速转化为代谢产物 8 氯肌苷和 8 氯嘌呤。代谢产物之一 8 氯嘌呤半衰期 (t1/2 )有随用药剂量的增加而延长的趋势 ,为 10 .15～ 32 .84min。药时曲线下面积 (areaunderthecurve ,AUC)在 8 氯腺苷剂量增加至 15 0mg·kg-1时不成比例地增高 ,呈非线性动力学消除的特点。另一代谢产物 8 氯肌苷的t1/2 约为 10 0min ,在剂量增加至 10 0mg·kg-1时 ,其AUC不成比例地增加 ,呈非线性动力学消除的特点。除脂肪、脑、睾丸组织外 ,8 氯肌苷和 8 氯嘌呤在体内分布广泛 ,其中肝、肾等代谢和排泄器官的含量较高。药物主要以代谢物形式从尿及胆汁中排泄 ,排泄量占总给药量的 39.81%。结论 :静注 8 氯腺苷后 8 氯嘌呤在大鼠血中迅速生成 ,消除也比较迅速 ,8 氯肌苷在大鼠血中出现较晚 ,消除也比较缓慢 ,两种代谢物在用药剂量 2 5～ 10 0mg·kg-1范围内呈线性动力学消除 ,当剂量增加至 10 0～ 15 0mg·kg-1有非线性动力学消除的趋势。两代谢物广泛分布于各组织     

Economic study of neutropenia induced by myelotoxic chemotherapy

This article describes the economic and social impact of nutropenia induced by myelotoxic chemotherapy in patients with cancer during the period 1 January–31 December 1991. Neutropenia is a life-threatening complication of chemotherapy in patients with cancer. The episodes of (ever and infections originating from neutropenia require hospitalization of the patient until the granulocyte levels are restored. The calculation of the economic cost was based on the following parameters: length of stay in hospital, analytical tests performed on the patient, type and cost of drug therapy administered, blood transfusions performed, health assistance received, cost of isolation and absence from work. The overall economic cost of neutropenia in patients with cancer reached 329,775 pesetas ($2,893). Cost of the health-care staff was the largest budget item in relation to the total health resources estimated.     

Cancer risk assessment for health care workers occupationally exposed to cyclophosphamide

In the present study a cancer risk assessment of occupational exposure to cyclophosphamide (CP), a genotoxic carcinogenic antineoplastic agent, was carried out following two approaches based on (1) data from an animal study and (2) data on primary and secondary tumors in CP-treated patients. Data on the urinary excretion of CP in health care workers were used to estimate the uptake of CP, which ranged from 3.6 to 18 g/day. Based on data from an animal study, cancer risks were calculated for a health care worker with a body weight of 70 kg and a working period of 40 years, 200 days a year (linear extrapolation). The lifetime risks (70 years) of urinary bladder cancer in men and leukemias in men and women were found to be nearly the same and ranged from 95 to 600 per million. Based on the patient studies, cancer risks were calculated by multiplication of the 10-year cumulative incidence per gram of CP in patients by the estimated mean total uptake in health care workers over 10 years, 200 days a year. The risk of leukemias in women over 10 years ranged from 17 to 100 per million using the secondary tumor data (linear extrapolation). Comparable results were obtained for the risk of urinary bladder tumors and leukemias in men and women when primary tumor data were used. Thus, on an annual basis, cancer risks obtained from both the animal and the patient study were nearly the same and ranged from about 1.4 to 10 per million. In The Netherlands it is proposed that, for workers, a cancer risk per compound of one extra cancer case per million a year should be striven for (target risk) and that no risk higher than 100 per million a year (prohibitory risk) should be tolerated. From the animal and the patient study it appears that the target risk is exceeded but that the risk is still below the prohibitory risk.