隐匿型脂质体阿霉素治疗乳腺癌的临床研究

阿霉素是细胞毒素类抗肿瘤药物,临床应用受到药物相关副作用的限制.羟甲基聚乙二醇(PEG)脂质体包裹的阿霉素的结构是空间稳定性的,不易与血浆蛋白结合,因此称为隐匿型脂质体阿霉素,具有血液浓度高、血浆循环时间长、心脏毒性低、肿瘤靶向性的特征.PEG脂质体阿霉素更易于耐受,心脏毒性及其他副反应较传统阿霉素少,但在生存时间,有效率方面,与传统阿霉素无明显差异.与其他药物联合应用是否能增加有效率,延长生存时间,还需要进一步证实.     

脂质体阿霉素药理研究进展

阿霉素是临床常用的抗恶性肿瘤药,但由于毒性反应较为严重,其临床应用受到限制。近年研究显示,采用脂质体载运阿霉素可减轻阿霉素的毒性作用,而抗肿瘤作用并不减弱。在动物肝转移肿瘤模型上还观察到了抗肿瘤作用的增强。目前,对脂质体阿霉素的临床试验正在进行中。     

聚乙二醇脂质体阿霉素的研究进展

阿霉素抗瘤谱广，但毒性大，临床应用受到限制。脂质体阿霉素不够稳定，而且脂质体不易进入肿瘤。聚乙二醇包裹的脂质体阿霉素（ＰＬＤ）性质稳定，在血循环中停留时间长，血浆清除率低，分布容积小。ＰＬＤ增加了阿霉素在肿瘤内的分布，提高了抗肿瘤活性，同时减少了对机体的毒性。     

常用化疗药物的脂质体剂型

脂质体作为抗癌药物的载体,能增加癌细胞对药物的摄取量,减少用药剂量,提高疗效,减少药物不良反应,因此受到了广泛的关注.目前多种化疗药物如紫杉醇、阿霉素、长春新碱、铂类等脂质体剂型已相继产生,并应用于临床.     

脂质体阿霉素在肿瘤热化疗中的研究进展

体内外研究表明，脂质体阿霉素在肿瘤热化疗研究方面，联合热疗疗效明显优于单独热疗或单药脂质体阿霉素治疗，其作用机制可能是热疗直接引起阿霉素从脂质体中释放，增加加热区域肿瘤组织的微循环渗透压，从而增加了肿瘤细胞对药物的生物利用度，发挥协同增加抗肿瘤作用。临床研究表明，联合热化疗在难治性或复发的卵巢癌、晚期乳腺癌、恶性软组织肉瘤及肝癌等晚期恶性肿瘤疗效较好。     

mTOR抑制剂联合阿霉素在肝癌细胞株对化疗药物协同增敏中的作用研究

目的 初步探讨mTOR抑制剂Temsirolimus联合阿霉素对肝癌细胞的抗肿瘤作用机制及化疗增敏作用.方法 体外培养肝癌细胞,取增殖期细胞进行实验,用MTT法检测单用Temsirolimus、阿霉素以及两者联合应用时对肿瘤细胞生长的影响,用流式细胞术检测细胞凋亡情况.结果 在体外肝癌细胞株PLC/PRF/5、BEL7402、HuH7中,与单独用药相比,Temsirolimus联合阿霉素提高了细胞增殖抑制率及凋亡率.Temsirolimus联合阿霉素的抗肿瘤作用高于将阿霉素浓度增加1倍时的抗肿瘤作用.结论 联合应用mTOR抑制剂及阿霉素可以提高抗肿瘤作用,前者对化疗药物有一定的增敏效应,两者联合可以通过减少阿霉素的剂量来减轻不良反应,同时不降低药物效能,有临床应用的前景.     

脂质体阿霉素热化疗对食管癌细胞的毒性实验研究

目的了解脂质体阿霉素体外不同温度热化疗对食管癌细胞株的细胞毒性作用。方法以体外培养食管癌细胞株EC9706为靶细胞,以游离阿霉素作为阳性对照,未加药物组作为阴性对照,采用WST-1法测定阿霉素和脂质体阿霉素对EC9706的半数抑制浓度(IC50)。再使用此IC50时药物的浓度,在37℃、41℃、43℃下水浴加温1 h进行热化疗,同样使用WST-1法测定其细胞杀伤率。结果阿霉素、脂质体阿霉素对食管癌细胞株EC9706的IC50分别为19.064 μg/ml、51.359 μg/ml(含阿霉素的量为5.707 μg/ml)。在37℃条件下,阿霉素与脂质体阿霉素对EC9706细胞株的杀伤率分别为(49.29±2.14)%、(49.39±6.07)%（P>0.05）。在41℃条件下,单纯加热、阿霉素、脂质体阿霉素对EC9706的杀伤率分别为(25.25±2.52)%、(64.80±5.01)%、(76.39±3.42)%,两种药物加热条件下的细胞杀伤作用均较单纯加热组高(P<0.01),且脂质体阿霉素较阿霉素的细胞毒作用提高了11.59% (P<001)。在43℃条件下,虽脂质体阿霉素的杀伤作用(79.05 ± 3.09)%较阿霉素(71.89±2.30)%提高了716% (P<0.05),但与该药在41℃条件下的杀伤作用比较仅提高2.66%,且差异没有统计学意义(P>0.05)。结论食管癌细胞株EC9706对阿霉素和脂质体阿霉素都很敏感。在热化疗作用上,阿霉素和脂质体阿霉素对食管癌细胞较单纯热疗具有更强的杀伤作用;在37℃条件下,脂质体阿霉素对细胞的杀伤作用与阿霉素相当,在41℃和43℃条件下脂质体阿霉素对细胞的杀伤作用强于阿霉素,但脂质体阿霉素在43℃与41℃对细胞的杀伤作用相当,两种药物联合热疗都具有协同增敏作用。     

脂质体阿霉素对人喉癌HEP-2细胞株的影响

[目的]研究脂质体阿霉素对人喉癌HEP-2细胞株的作用特点。[方法]以MTT法分别测定脂质体阿霉素组与游离阿霉素组分别作用于HEP-2细胞株72h后的细胞增殖抑制率并比较两组的半数抑制浓度（IC50）;通过流式细胞仪（FCM）检测两组药物分别作用于HEP-2细胞株72h后对其细胞周期的影响：采用荧光分光光度法分别测定脂质体阿霉素和游离阿霉素分别作用于HEP-2细胞株1、3、6h后实验细胞内的药物浓度。[结果]脂质体阿霉素对HEP-2细胞株的IC50是游离阿霉素的1,4倍。脂质体阿霉素组与游离阿霉素组分别采用0．016μg/ml、0．06μg／ml的浓度作用于HEP-2细胞株72h后．均使HEP-2细胞株停滞于G2/M期．且脂质体阿霉素G2/M期百分率高于游离阿霉素。荧光分光光度法结果显示：脂质体阿霉素组内药物浓度在1、3、6h后均分别大于游离阿霉素组,且6h后脂质体阿霉素作用于HEP-2细胞株内的阿霉素浓度是游离阿霉素的4倍。[结论]与游离阿霉素相比．脂质体阿霉素对人喉癌HEP-2细胞株具有较好的增殖抑制作用,并且阻滞HEP[2细胞株于G2/M．其可能机制是与脂质体阿霉素增加细胞内阿霉素浓度有关。     

MRK-16修饰阿霉素免疫脂质体逆转肺癌细胞多药耐药研究

目的：研究MRK-16修饰阿霉素免疫脂质体与阿霉素脂质体对非小细胞肺癌多药耐药的逆转作用。方法：25％的戊二醛偶联MRK-16于阿霉素脂质体，制备MRK-16修饰阿霉素免疫脂质体；以MTS测定细胞存活率，检测SPC—A1／TAX的耐阿霉素指数；以阿霉素脂质体与MRK-16修饰阿霉素免疫脂质体作用于SPC—A1／TAX，设阿霉素组对照；研究两者对SPC—A1／TAX的体外细胞毒与多药耐药逆转作用；流式细胞仪检测用药后2．4、6小时后细胞内药物浓度。结果：免疫脂质体细胞杀伤率（48h）达67．7％，其多药耐药逆转指数达7．45；脂质体对细胞的杀伤率49．2％，逆转指数4．28；流式细胞仪检测细胞内药物浓度，6小时后阿霉素免疫脂质体组细胞内药物浓度是阿霉素组的18．34倍，脂质体组是阿霉素的10．1倍。结论：MRK-16修饰阿霉素免疫脂质体、阿霉素脂质体在体外对非小细胞肺癌多药耐药具有-定的逆转作用。     

蒽环类抗肿瘤药物研究进展

蒽环类抗肿瘤药物在结构上具有蒽并一个六元环为基础带有侧链和一氨基糖的化合物,在体内、外都具有抗肿瘤作用。第一代蒽环类抗生素柔红霉素和第二代的阿霉素在60年代已进入临床应用,并取得了较好的治疗效果。但由于其对骨髓的抑制,尤其是心脏毒性,限制了剂量提高和临床治疗效果。因此,试图通过改变其化学结构以去除或降低毒性特别是心脏毒性,就成为近年来药理学家研究的重点课题之一。到目前为止,已有十多种蒽环类抗肿瘤药物陆续进入临床试用(表1)图1。其中表阿霉素 (EDR)、去甲氧基柔红霉素(DMDR)及结构相似的米托蒽醒已进入临床试用显现较为突出的结果。本文将主要结合UICC蒽环类抗癌药物圆桌讨论会内容,综述这几种药物近年来的研究进展。 一、表阿霉素(EDR或E—ADM) EDR是由阿霉素(ADM)半合成的衍生物,由氨基糖4位的顺式OH基变成了反式而与ADM相区别,主     

Liposomal nanomedicines in the treatment of prostate cancer

Prostate cancer is the most common cancer type and the second leading cause of death from cancer in males. In most cases, no curative treatment options are available for metastatic castration-resistant prostate cancer as these tumors are highly resistant to chemotherapy. Targeted drug delivery, using liposomal drug delivery systems, is an attractive approach to enhance the efficacy of anticancer drugs and prevent side effects, thereby potentially increasing the therapeutic index. In most preclinical prostate cancer studies, passive liposomal targeting of anticancer drugs (caused by enhanced permeability and retention of the therapeutic compound) leads to an increased antitumor efficacy and decreased side effects compared to non-targeted drugs. As a result, the total effective dose of anticancer drugs can be substantially decreased. Active (ligand-mediated) liposomal targeting of tumor cells and/or tumor-associated stromal cells display beneficial effects, but only limited preclinical studies were reported. To date, clinical studies in prostate carcinoma have been performed with liposomal doxorubicin only. These studies showed that long-circulating, PEGylated, liposomal doxorubicin generally outperforms conventional short-circulating liposomal doxorubicin, stressing the importance of passive tumor targeting for this drug in prostate carcinoma. In this review, we provide an overview of the (pre)clinical studies that focus on liposomal drug delivery in prostate carcinoma.     

The anthrapyrazoles: a new class of compounds with clinical activity in breast cancer.

The anthrapyrazoles are DNA-binding anticancer agents with broad spectrum preclinical activity and reduced potential for free radical generation compared with doxorubicin. In early clinical trials, the dose-limiting toxicity has been leukopenia, other side effects being minor, and promising antitumor activity has been shown, especially in breast cancer. It remains to be confirmed that the anthrapyrazoles are less cardiotoxic than doxorubicin, but it is clear that these drugs are showing real promise, appear significantly less toxic than doxorubicin, and seem to represent a genuine therapeutic advance.     

Pirarubicin (THP-adriamycin)

Pirarubicin (THP-adriamycin or THP-doxorubicin) was found during a search of new anthracycline antibiotics among 4'-O-substituted compounds having less toxicities than other anthracycline anticancer drugs in 1979 by Umezawa et al. In its preclinical studies, this compound possessed almost similar antitumor efficacies to doxorubicin, but was effective against doxorubicin-resistant P388 and other murine tumor cell lines. This compound was rapidly incorporated into tumor cells, inhibiting DNA polymerase alpha and subsequently DNA synthesis. Inhibition of RNA synthesis was also noted. In the clinical studies, clinical responses were established against head and neck cancer, breast cancer, urogenital cancers, ovarian cancer, uterine cancer, acute leukemia, and malignant lymphoma, showing a wide antitumor spectrum clinically. Among the side effects, cardiac toxicity, alopecia and disturbance of the digestive organs were mild. From these results, THP-adriamycin seems to be a useful clinical drug for human solid tumors.     

Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors

Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration‐dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors.     

A comparison of mitoxantrone and doxorubicin in breast cancer

Ninety patients with breast cancer refractory to cyclophosphamide/fluorouracil/methotrexate (CMF) have been randomized in their treatment, receiving either doxorubicin or mitoxantrone. Seventy-nine have received two full courses of therapy. Twelve of the 40 (30%) who initially received doxorubicin responded, whereas eight of the 47 (17%) who received mitoxantrone responded. These rates are not statistically different. The degree of myelosuppression was equivalent. Patients who received mitoxantrone had less nausea, vomiting, alopecia, and fatigue. Controllable clinical congestive heart failure developed in seven patients, and four others had a deterioration of noninvasive measures of cardiac function without clinical failure. One patient with clinical heart failure developing received only doxorubicin and one, only mitoxantrone, whereas the others received both agents. The duration of remission and time lapsed before disease progression were almost identical for the two regimens. This study included a crossover design. Two of 22 (10%) patients receiving doxorubicin and five of 24 (21%) receiving mitoxantrone as secondary therapy responded. This suggests that there is not absolute cross-resistance between these agents. We conclude that the efficacy of these two drugs is comparable in patients refractory to CMF, though the nonhematologic side effects of mitoxantrone are less.     

Chemotherapy and total body hyperthermia

Combination therapies of anti-tumor drugs such as doxorubicin, cis-platinum and bleomycin or its analogues and extracorporeally induced total-body hyperthermia (THT) were performed against various advanced solid tumors. Fifty-nine patients were treated with combination chemotherapy including doxorubicin and THT. The overall response rate was 41.4%. However, against colo-rectal and stomach cancer, the response rate was only 25% (2/8) and 28.5% (2/7) respectively. Twelve patients were treated with chemotherapy including cis-platinum and THT and the response rate was 57.1% (4/7). Three patients (malignant lymphoma, nasopharyngeal cancer and maxillary sinus cancer) were treated with THT in combination with cis-platinum, peplomycin and doxorubicin. Two cases were evaluable and recognized as complete responses. In these studies, no new side effect of the drugs appeared and thus, advantageous combination chemotherapy with doxorubicin, cis-platinum and bleomycin analogues and hyperthermia for the treatment of advanced cancer is implied.     

The cardio-protecting agent and topoisomerase II catalytic inhibitor sobuzoxane enhances doxorubicin-DNA adduct mediated cytotoxicity

Purpose The importance of understanding the mechanism of action of anticancer agents is sometimes overlooked in the pursuit of new and therapeutically advantageous compounds. Doxorubicin has long been identified as an inhibitor of the DNA-decatenating enzyme topoisomerase II, this being believed to be the major mechanism of action of this drug. However, the complex nature of cytotoxicity induced by doxorubicin suggests that more than one mechanism of action is responsible for cell kill. Investigation into various other cellular effects has shown that doxorubicin can, in the presence of formaldehyde, form doxorubicin-DNA adducts, resulting in enhanced cell death. Methods We have used six catalytic inhibitors of topoisomerase II (aclarubicin, merbarone, suramin, staurosporine, maleimide and sobuzoxane) to investigate the role of topoisomerase II mediated cell effects in doxorubicin-DNA adduct inducing treatments. Adduct levels were determined by scintillation counting of [¹⁴C]doxorubicin-DNA lesions and DNA damage responses by Comet analysis and flow cytometry (apoptosis). Results Here we show that sobuzoxane inhibits topoisomerase II but in the presence of doxorubicin also enhances the production of doxorubicin-DNA adducts resulting in an enhanced cytotoxic response. We show that the formation of doxorubicin-DNA adducts is mediated by formaldehyde released from sobuzoxane when it is metabolised. Conclusions Sobuzoxane has also been shown to decrease the normally dose limiting cardiotoxicity commonly exhibited with clinical use of doxorubicin. The potential combination of doxorubicin and sobuzoxane in cancer chemotherapy has two advantages. First, the mechanism of doxorubicin toxicity is shifted away from topoisomerase II inhibition and towards drug-DNA adduct formation which may allow for a lower drug dose to be used and circumvent some drug resistance problems. Second, the addition of a cardioprotecting agent will counteract the commonly dose limiting side effect of cardiac damage resulting from doxorubicin treatment. The importance of the potentiation of cell kill of doxorubicin and sobuzoxane provides a rationalisation of a mechanistic-based combination of anticancer drugs for an improved clinical outcome.     

Indomethacin and SC236 enhance the cytotoxicity of doxorubicin in human hepatocellular carcinoma cells via inhibiting P-glycoprotein and MRP1 expression

Doxorubicin is a chemotherapeutic drug widely used for the treatment of hepatocellular carcinoma but its efficacy is restricted by multidrug resistance. Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2-selective inhibitors exhibit anti-cancer properties as well as abilities to overcome drug resistance. In the present study, indomethacin (a NSAID) and SC236 (a COX-2-selective inhibitor) enhanced the cytotoxicity of doxorubicin in the hepatocellular carcinoma cell line HepG2 and its drug-resistant sub-line R-HepG2. Both drugs increased the intracellular accumulation and retention of doxorubicin in vitro. The effects were not reversed by prostaglandin E(2), implicating a COX-independent mechanism. Indomethacin and SC236 partially reversed the increase in expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) induced by doxorubicin in R-HepG2 cells. In conclusion, indomethacin and SC236 increased the intracellular accumulation and retention of doxorubicin and thus its cytotoxicity in HepG2 and drug-resistant HepG2 cells. These effects, mediated through decrease in P-gp and MRP1 expression and/or direct inhibition of P-gp activity, may improve multidrug resistant-cancer chemotherapy.     

Adjuvant and neoadjuvant combination chemotherapy for osteogenic sarcoma

PURPOSE OF REVIEW: The most recent developments regarding chemotherapy treatment of osteogenic sarcoma are reviewed, with special emphasis on prospective clinical trials and evaluations of late effects of chemotherapy. RECENT FINDINGS: In recent years, clinical research has essentially focused on possible refinements of the classic four-drug (methotrexate, cisplatin, doxorubicin and ifosfamide) therapy rather than investigating new drugs. It has been demonstrated that dose-intensification does not improve prognosis. Many investigators have evaluated late chemotherapy-related side effects, particularly in terms of cardiac, renal and auditive toxicity, risk of infertility and of second tumors. Recent findings recommend further studies to define the role of the immunostimulating agent muramyl tripeptide-phosphatidilethanolamine in osteosarcoma. Preclinical and phase II studies suggest an activity of mammalian target of rapamycin (mTOR) inhibitors in osteosarcoma, which also deserves further clinical studies. SUMMARY: At present, patients with nonmetastatic osteosarcoma of the extremity aged less than 40 years have an expected 5-year survival rate of 70% with a chemotherapy regimen based on methotrexate, cisplatin, doxorubicin and ifosfamide. Further improvement cannot be achieved by dose intensification of treatment and new strategies are required. Prolonged follow-up is mandatory due to the risk of late effects, second tumors and late relapse from osteosarcoma.     

Antitumor activities of ME 2303 on human gastrointestinal cancer xenografted to nude mice

The antitumor activity of ME 2303 was evaluated on 3 human stomach and 3 colon cancers xenografted to nude mice, which were established in our laboratory. The activity was compared with that of doxorubicin in terms of the inhibition of tumor growth and the histopathological changes. The dosage of ME 2303 was 35 or 50 mg/kg and that of doxorubicin was 5 mg/kg. Both drugs were administered intravenously 4 times at 5-day intervals. Thirty-five mg/kg of ME 2303 was effectively inhibited tumor growth against 3 lines, with marked efficacy against 2 lines. On the other hand, 50 mg/kg of ME 2303 was also effective against 4 lines tested (2 each of gastric and colorectal cancers), with marked efficacy against 3. In all, ME 2303 was more effective than doxorubicin except one of stomach cancer. The histopathological findings also revealed that 35 mg/kg of ME 2303 was equal or slightly superior to doxorubicin in efficacy. The side effects of ME 2303 such as weight loss were as mild as those with doxorubicin, except in the female mice administered 30 mg/kg of ME 2303 and no other adverse effect was observed. ME 2303 seems promising for clinical application in human since the increased efficacy in nude mice human xenograft might be found after more adequate modification of the dosage and administration schedule.