Resistant mechanisms of anthracyclines — pirarubicin might partly break through the P-glycoprotein-mediated drug-resistance of human breast cancer tissues

Juliano and Ling initially reported the expression of a 170 kDa glycoprotein in the membrane of Chinese hamster ovarian cells in 1976, and named this glycoprotein P-glycoprotein (P-gp) based on its predicted role of causing "permeability" of the cell membrane. After much research on anthracycline-resistance, this P-gp was finally characterized as a multidrug-resistant protein coded by the mdr1 gene. Multidrug resistance associated protein (MRP) was initially cloned from H69AR, a human small cell-lung carcinoma cell line which is resistant to doxorubicin (DXR) but does not express P-gp. MRP also excretes substrates through the cell membrane using energy from ATP catabolism. The substrate of MRP is conjugated with glutathione before active efflux from cell membrane. Recently, membrane transporter proteins were re-categorized as members of "ATP-Binding Cassette transporter"(ABC-transporter) superfamily, as shown at http://www.med.rug.nl/mdl/humanabc.htm and http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html. A total of ABC transporters have been defined, and MDR1 and multidrug resistance associated protein 1 (MRP1) were reclassified as ABCB1 and ABCC1, respectively. Their associated superfamilies include 11 and 13 other protein, in addition to ABCB and ABCC, respectively. Lung resistance-related protein (LRP) is not a member of the superfamily of ABC transporter proteins, because it shows nuclear membrane expression and transports substrate between nucleus and cytoplasm. LRP was initially cloned from a non-small cell lung carcinoma cell line, SW1573/2R120 which is resistant to DXR, vincristine, etoposide and gramicidin D and does not express P-gp. The mechanisms of resistance remains unclear, and why some resistant cell lines express P-gp and others express MRP and/or LRP is likewise unclear.     

Pharmacology of N-benzyladriamycin-14-valerate in the rat

Purpose: N-Benzyladriamycin-14-valerate (AD 198) is a semisynthetic anthracycline analogue superior to doxorubicin (DOX) both in vitro and in experimental rodent tumor models, and with differing mechanistic properties from those of the parental antibiotic agent. In the present study, we examined the metabolic fate and hematotoxicity of AD 198 in rats, with a view to determining whether some of the therapeutic properties observed for this drug might be due to a DOX prodrug effect. Methods: Samples of plasma, bile and urine were obtained at various times following intravenous (i.v.) [¹⁴C]–AD 198 administration to rats and were analyzed by reversed-phase HPLC with flow–fluorescence detection and complementary liquid scintillography. In other animals, red blood cell and white blood cell (WBC) counts were determined for blood obtained by retrobulbar sampling on selected days from groups of animals receiving either AD 198 or DOX at several dose levels, as well as from vehicle controls. Results: Following a single iv dose of [¹⁴C]-AD 198 (5 mg/kg; equivalent to the optimal murine antitumor dose) in anesthetized rats, a triphasic plasma decay pattern for parental drug was evident with extremely rapid α and β phases followed by a very long terminal elimination phase. Principal plasma products included N–benzyladriamycin (AD 288) and N–benzyladriamycinol (AD 298) together with very low levels of DOX and doxorubicinol (DOXOL). Analysis of bile from anesthetized and conscious animals receiving AD 198 revealed DOX to be the principal biliary fluorescent species together with low levels of AD 288, AD 298 and DOXOL; no parental drug was seen. By contrast, AD 288 was the principal urinary product, together with low levels of AD 298 and DOX; again, no parental drug was evident. Dose recovery (8 h) in the respective bile and urine of anesthetized rats was 12.4% and 13.2% based upon total fluorescence versus 1% and 15.3% of the administered radiolabel. In conscious animals, 13.4% of drug fluorescence was recovered in the bile (48 h), while in urine 16.6% and 77.1% of drug fluorescence and radiolabel, respectively, were eliminated over 72 h. The discrepancy between recovery of drug fluorescence and ¹⁴C was due to the production of nonfluorescent hippuric acid (benzoylglycine) and N–benzyl daunosamine as a consequence of hepatic and renal drug metabolism. In the separate hematotoxicity studies, AD 198 (24.6 mg/kg i.v.; equivalent to the murine LD₅₀ dose), produced a 45% reduction (nadir day 3–5) in WBC count, with recovery by day 10. By contrast, DOX (10 mg/kg i.v.; equivalent to the mouse highest nonlethal dose) produced an 80% decline in WBC with only partial recovery by day 17. Conclusions: By virtue of the low systemic DOX levels and low hematotoxicity observed in rats receiving AD 198, the in vivo therapeutic superiority of AD 198 cannot be attributed to substantial intracellular DOX generation. The conclusion that the therapeutic superiority of AD 198 compared to DOX results from the mechanistic differences between these two drugs is further supported by recent observations on their biochemical differences with regard to protein kinase C and topoisomerase II inhibition. Received: 26 January 1998 / Accepted: 5 August 1998     

Uptake and Intracellular Distribution of Amrubicin, a Novel 9-Amino-anthracycline, and Its Active Metabolite Amrubicinol in P388 Murine Leukemia Cells

Amrubicin, a 9-aminoanthracycline anti-cancer drug, and its C-13 hydroxyl metabolite amrubicinol, were examined for growth-inhibitory activity as well as cellular uptake and distribution in P388 murine leukemia cells and doxorubicin-resistant P388 cells. Also discussed are the differences in the mechanisms of action among amrubicin, amrubicinol and doxorubicin in terms of their cellular pharmacokinetic character. In P388 cells, amrubicinol was about 80 times as potent as amrubicin, and about 2 times more potent than doxorubicin in a 1-h drug exposure growth-inhibition test. A clear cross-resistance was observed to both amrubicin and amrubicinol in doxorubicin-resistant P388 cells, though the resistance index was lower for amrubicin. The intracellular concentration of amrubicinol was about 6 times and 2 times higher than those of amrubicin and doxorubicin, respectively. Compared to doxorubicin, amrubicin and amrubicinol were released rapidly after removal of the drugs from the medium. A clear correlation was found between the growth-inhibiting activity and the cellular level of amrubicin and amrubicinol in P388 cells. About 10 to 20% of amrubicin or amrubicinol taken up by the cells was detected in the cell nuclear fraction, whereas 70 to 80% of doxorubicin was localized in this fraction. These results suggest that amrubicin and amrubicinol exert cytotoxic activity via a different mechanism from that of doxorubicin.     

去甲长春花碱为主方案治疗蒽环类药物耐药性晚期乳腺癌的疗效

目的：观察抗肿瘤新药去甲长春花碱（Navelbine,NVB）为主的联合方案化疗治疗蒽环类耐药的晚期乳腺癌的疗效。方法：1995年9月－1999年2月，以此法治疗晚期腺癌21例，其中，NVB＋ADM治疗9例，NVB＋DDP治疗8例，NVB＋MTI4例。全组化疗共54周期，中位数3周期（2－4周期）。结果：CR2例，PR8例，SD8例，PD3例，总有效率（CR＋PR）47．6％。全组中位缓解期5个月（2－17个月）。主要剂量限制毒性为骨髓抑制，以白细胞减少为主，Ⅱ－Ⅲ度白细胞减少发生率为90．5％。静脉炎发生率为14．3％（3／21）。结论：以NVB为主的联化化疗对蒽环类药物耐药的转移性乳腺癌有较好的疗效，且毒性可以耐受，可以考虑作为后续化疗方案。     

Improving the therapeutic index of anthracycline chemotherapy: Focus on liposomal doxorubicin (Myocet™)

Anthracyclines are valuable cytotoxic agents in cancer treatment. However, their usefulness is limited by cumulative dose-dependent cardiotoxicity that may manifest as life-threatening congestive heart failure. To avoid cardiotoxicity, the use of doxorubicin is typically capped at a safe cumulative dose. Liposomal formulations may reduce cardiac risks whilst maintaining anti-cancer efficacy.Efficacy and safety studies of non-pegylated liposomal doxorubicin (NPLD) in metastatic breast cancer (MBC) are reviewed, along with studies that examine efficacy and cardiac tolerability in combination with newer agents such as paclitaxel and trastuzumab. These show that cardiac safety of liposomal doxorubicin is similar to that of epirubicin in cumulative dose, but that the formulation, unlike epirubicin, has similar anti-cancer efficacy to doxorubicin at equimolar doses. Liposomal doxorubicin may have a better therapeutic index than non-liposomal anthracyclines. This justifies further studies in patients where cumulative cardiotoxicity is a concern, as does study of its use with other potentially cardiotoxic agents.     

HAD方案治疗成人急性非淋巴细胞白血病临床观察

成人急性非淋巴细胞白血病５０例，作者采用ＨＡＤ方案诱导化疗，缓解后以ＨＡＤ、ＥＡ、ＭＡ或再加ＡＡ方案巩固强化。结果完全缓解（ＣＲ）４３例，ＣＲ率８６．０％。初治３８例，ＣＲ３３例（８６．８％），复治１２例，ＣＲ１０例（８３．３％）。ＣＲ４３例中３３例（７６．７％）仅用１疗程即达ＣＲ。远期疗效仍在观察中。ＨＡＤ方案毒性低，能为患者接受。取得高缓解率的原因可能与高三尖杉酯碱和柔红霉素之间的协同作用有关     

Cardiotoxicity of cancer chemotherapy in clinical practice

Several anticancer agents are associated with significant cardiotoxicity. The list of cardiotoxic cancer therapeutic agents includes anthracyclines, trastuzumab, alkylating agents, antimetabolites, which have been in use for decades; and recently introduced anticancer therapies such as tyrosine kinase inhibitors, angiogenesis inhibitors, checkpoint inhibitors and proteasome inhibitors. Cardiac imaging using echocardiography, nuclear imaging techniques, and magnetic resonance (MR) imaging can help in the early detection of chemotherapy-related cardiotoxicity. This can prevent the morbidity and mortality resulting from the cardiotoxicity of these agents. Further research is needed to improve our understanding of the underlying mechanism of their cardiotoxicity and to develop newer preventive and therapeutic strategies for chemotherapy related cardiotoxicity.     

蒽环类药物心脏毒性机制及其监测进展

以阿霉素(多柔比星)、表阿霉素(表柔比星)和吡喃阿霉素(吡柔比星)为代表的蒽环类抗癌药作为最有效的化疗药之一,目前在临床上广泛应用于白血病、乳腺癌、肺癌、淋巴瘤等多种恶性肿瘤,具有抗瘤谱广、临床疗效高等显著特点,是多种化疗方案的核心药物。然而,剂量依赖性不可逆的心脏毒性严重限制了其使用。现就国内外近年对蒽环类药物心脏毒性的发病机制、监测等方面的进展予以综述。     

联合应用吉西他滨与顺铂对蒽环类与紫杉类耐药晚期乳腺癌患者的疗效观察

目的分析并评价联合应用吉西他滨与顺铂对耐蒽环类与紫杉类晚期乳腺癌患者的临床治疗效果及不良反应。方法对我院2007年11月-2011年6月收治的68例对蒽环类与紫杉类耐药的晚期乳腺癌患者给予1 000 mg/m2吉西他滨(第1、8天)、顺铂30 mg/m2(第1～3天),21 d为1个周期,2个周期后评价疗效。结果共治疗227个周期,平均为3.34个周期。全部可评价68例患者中,CR 2例(3.0%),PR 30例(44.1%),SD 24例(35.3%),PD 12例(17.6%),总有效率为47.1%。全部患者的中位疾病进展时间为6个月,中位生存期为12.6个月。不良反应主要包括骨髓抑制及胃肠道反应。结论联合应用吉西他滨与顺铂对耐蒽环类与紫杉类晚期乳腺癌患者疗效良好,不良反应轻微,是一种理想的治疗方案。