Nanocarriers for delivery of platinum anticancer drugs

Platinum based anticancer drugs have revolutionized cancer chemotherapy, and continue to be in widespread clinical use especially for management of tumors of the ovary, testes, and the head and neck. However, several dose limiting toxicities associated with platinum drug use, partial anti-tumor response in most patients, development of drug resistance, tumor relapse, and many other challenges have severely limited the patient quality of life. These limitations have motivated an extensive research effort towards development of new strategies for improving platinum therapy. Nanocarrier-based delivery of platinum compounds is one such area of intense research effort beginning to provide encouraging preclinical and clinical results and may allow the development of the next generation of platinum chemotherapy. This review highlights current understanding on the pharmacology and limitations of platinum compounds in clinical use, and provides a comprehensive analysis of various platinum–polymer complexes, micelles, dendrimers, liposomes and other nanoparticles currently under investigation for delivery of platinum drugs.     

头颈部恶性肿瘤住院病人2007-2009年用药分析

目的:调查上海交通大学医学院附属第九人民医院头颈部恶性肿瘤病人住院治疗的临床用药状况。方法:依据医院信息系统(HIS)的临床用药数据,对2007-2009年头颈部恶性肿瘤住院病人的用药频度和金额进行统计分析。结果:头颈部恶性肿瘤的治疗药物包括抗肿瘤药物和抗肿瘤辅助药物,金额构成比分别为21.2%和78.8%,化疗药物以平阳霉素、顺铂和奈达铂为主。营养药、生物反应调节剂和中成药等是主要的抗肿瘤辅助药物。营养药以注射用三磷酸腺苷辅酶胰岛素、丙氨谷氨酰胺注射液、人血白蛋白和整蛋白型肠内营养剂为主。生物反应调节剂以胸腺五肽和胸腺肽α1为主。结论:本院治疗头颈部恶性肿瘤的临床用药呈现多元化的特点。     

Pharmacogenomics in cancer therapy: is host genome variability important?

Pharmacogenomics aims to elucidate the genomic determinants of drug disposition and effect. Because cancer chemotherapy is relatively nonspecific and has narrow therapeutic indices, there is great potential for pharmacogenomics to improve treatment outcomes by either reducing toxicity or increasing efficacy. The diversity of therapeutic targets for anticancer drugs and the intensity of clinical pharmacology research in oncology have provided many examples of clinically relevant pharmacogenomic applications. Important elements that are discussed in this article include the association of genetic variability in the metabolism, intracellular transport and targets of anticancer drugs. In addition, we summarize where the field stands currently, and how information from the host and tumor might be integrated into decision making.     

Pathogenesis and treatment of human genital papillomavirus infections: a review

HPV infection of the genital tract is common and anogenital warts or condyloma acuminatum is increasing rapidly in incidence. In addition, certain HPV types are closely associated with genital tract malignancies. Although recent advances in molecular biology have led to an increased understanding of the organization and functions of the papillomavirus genome, the pathogenesis of HPV infections and host responses to these diseases remain poorly understood. Treatment of anogenital warts is difficult and no completely satisfactory treatment modality is currently available. Comparatively few therapeutic modalities have been thoroughly evaluated, although recent studies of intralesionally and parenterally administered interferons have demonstrated beneficial effects of interferon compared to placebo. Additional studies of treatment for condyloma acuminatum are needed and should include the use of biologic response modifiers such as interferons, as well as antiviral drugs, with or without conventional methods of local therapy.     

Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer

Human epidermal growth factor receptor-2 (HER2/erbB-2) is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival and differentiation via multiple signal transduction pathways. Amplification of the HER2 gene occurs in 20–25% of human breast cancers. This amplification event is an independent adverse prognostic factor as well as a predictive factor for increased response to doxorubicin-based combination chemotherapy, response to trastuzumab and decreased response to hormonal therapy. Methods for detecting protein overexpression or gene amplification in clinical tumor specimens include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) techniques, with the latter considered by some to be more accurate. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody which targets an epitope in the extracellular domain of the HER2 protein. Preclinical models demonstrated that this antibody has significant anti-tumor activity as a single agent and has synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancer that overexpress HER2 have shown that trastuzumab has clinical activity when used as first-, second- or third-line monotherapy, and improves survival when used as first-line therapy in combination with chemotherapy. Newer combinations with numerous chemotherapeutic drugs have also shown significant clinical activity in phase II studies. In all of these trials, trastuzumab was generally well-tolerated, but cardiac toxicity (particularly when the antibody was combined with anthracyclines) was an unexpected adverse effect. Although trastuzumab is currently usually administered on a weekly intravenous schedule, evidence suggests that a triple dose of the drug given once every three weeks has a pharmacokinetic profile expected to be equally efficacious. Neither the optimal schedule nor the optimal duration of trastuzumab therapy has yet been clearly defined in controlled clinical trials. Current clinical investigations of trastuzumab include its use in both the adjuvant and neoadjuvant settings as well as in combination with other chemotherapy drugs or new biologic targeted agents.     

An update on the systemic therapy of malignant salivary gland cancers: role of chemotherapy and molecular targeted agents

Salivary gland cancers are a rare malignancy accounting for less than 1% of all cancers and 3-6% of cancers of the head and neck region. The classification of salivary gland tumors is traditionally based on morphology and the different subtypes exhibit various clinical behaviors. The low grade and biologically indolent cell types include the adenoid cystic, acinic cell and adenocarcinoma while the salivary duct, squamous and mucoepidermoid are more active and high grade. The initial management of salivary gland malignancies is to assess resectability and possible adjuvant radiation therapy. Those with locoregional recurrence or metastatic disease are treated with systemic therapy. Numerous studies with small sample sizes have assessed the activity of different cytotoxic agents. Both single agent and combination chemotherapy have been used for the treatment of this disease. For these agents, the response rates are generally modest with objective response rates ranging from 15-50%. Duration of response is typically cited in the range of 6-9 months. Clinicopathological data have demonstrated correlations between poor clinical outcomes and the expression of molecular markers such as mutated p53 protein and vascular endothelial growth factor (VEGF) in salivary gland cancers. Recent studies have also evaluated the epidermal growth factor receptor family including erbB1/EGFR and erbB2/HER2 as potential therapeutic targets. While the prognostic significance of EGFR overexpression has not been well defined, overexpression of the HER2 oncoprotein has been associated with biological aggressiveness and poor prognosis in most series. Given the suboptimal response rates, duration of response, and toxicity of conventional chemotherapy, a better understanding of the biology of salivary gland malignancies will lead to improved prognostication and treatment. With the emergence of molecular targeted therapy, these tumors become an optimal candidate for trials of investigational drugs and established drugs for new indications.     

Ceramidases in hematological malignancies: senseless or neglected target?

Ceramidases are ubiquitous amidohydrolases that catalyze the cleavage of ceramides into sphingosine and fatty acids. This reaction exerts a cytoprotective role in physiological conditions, while altered ceramidase activities favour a number of human diseases. Among these diseases, several reports point to important roles of ceramidases, mainly the acid ceramidase, in the initiation and progression of cancer, and the response of tumors to radio- or chemotherapy. Multiple reports confirm the interest of acid ceramidase inhibitors as anticancer drugs, either alone or in combination with other therapies. Sphingolipid metabolism plays a role in hematological malignancies and appears as an interesting target for therapeutic intervention. Although the use of ceramidase inhibitors in chemotherapy of hematologic cancers has not been widely investigated, a number of indirect evidence suggest that inhibition of specific ceramidases could potentiate the effect of drugs in clinical use to treat hematologic malignancies and may afford strategies to combat relapses. The arsenal of ceramidase inhibitors so far available is wide and hopefully, upcoming research will assess the feasibility of this approach.     

Danusertib, an aurora kinase inhibitor

INTRODUCTION: Drugs that interfere with the normal progression of mitosis belong to the most successful cytotoxic agents currently used for anticancer treatment. Aurora kinases are serine/threonine kinases that function as key regulators of mitosis and are frequently overexpressed in human cancers. The use of several small molecule aurora kinase inhibitors as potential anticancer therapeutic is being investigated. Danusertib (formerly PHA-739358) is a small ATP competitive molecule that inhibits aurora A, B and C kinases. Interestingly, danusertib also inhibits several receptor tyrosine kinases such as Abl, Ret, FGFR-1 and TrkA. These tyrosine kinases are involved in the pathogenesis of a variety of malignancies and the observed multi-target inhibition may increase the antitumor activity resulting in extending the indication. Danusertib was one of the first aurora kinase inhibitors to enter the clinic and has been studied in Phase I and II trials. AREAS COVERED: This review provides an updated summary of preclinical and clinical experience with danusertib up to July 2011. EXPERT OPINION: Future studies with danusertib should focus on the possibility of combining this agent with other targeted anticancer agents, chemotherapy or radiotherapy. As a single agent, danusertib may show more promise in the treatment of leukemias than in solid tumors.     

Therapeutic potential of thiazolidinediones as anticancer agents

There has been great interest in the development of oncolytic viruses – viruses that selectively destroy tumour cells – as cancer therapeutics. Reovirus holds great promise as an anticancer therapy, not just because it is a wild type virus that inherently displays selective tumour cytotoxicity in cancers with active Ras signalling pathways but also because it results only in relatively benign infections with few minor symptoms. As many tumours have an activated Ras pathway, the potential for utilizing reovirus as an effective anticancer agent is substantial. The several challenges that need to be overcome in the development of oncolytic viruses as anticancer agents, including issues of systemic toxicity, tumour selectivity and immune response, are addressed in this review. Clinical studies with the objective of developing Reolysin (human reovirus serotype 3 Dearing) as a human cancer therapeutic are currently underway. The first human Phase I study with intravenous Reolysin has now been completed and further studies, including Phase I and II clinical trials using Reolysin alone and in combination with radiation or chemotherapy, delivered via local or systemic intravenous administration, have commenced.     

Critical aspects in rationale design of fluorouracil-based adjuvant therapies for the management of colon cancer

The strategic goal behind adjuvant therapy is to open novel avenues for colon cancer treatment by specifically inactivating pathways needed for the growth of tumor cells. 5-Fluorouracil (5-FU) therapy is a prominent conventional treatment for colon cancer that has been used for five decades. Among the rich diversity of chemotherapeutics, 5-FU has been extensively manipulated as an anticancer drug. The pharmacology of 5-FU has spawned myriad alternatives to achieve low-toxicity treatment for better colon cancer management. The existing highly toxic chemotherapeutic regimens, lack of new congeners with significant efficacy, and drug resistance to cancer cells have prompted scientists to manipulate conventional treatments. These factors make it imperative to rationalize the current 5-FU therapy in combination with synthetic or natural compounds by optimizing the dose with respect to pharmacokinetic and preclinical data. To attempt to tailor effective conventional 5-FU regimens, novel therapeutic perspectives associated with the 5-FU-based colon cancer chemotherapy currently available in clinical settings have been summarized. This review presents comprehensive summary of a dedicated literature search of databases (i.e., PUBMED, CAPLUS, and MEDLINE) for adjuvant approaches such as NSAIDs (COX-II inhibitors), natural compounds, viral vectors, novel agents/molecules, and various targeted therapies, in combination with 5-FU in developing treatment alternatives for colon cancer.     

The role of myelopoietic growth factors in managing cancer in the elderly

More than 50% of all malignancies are diagnosed in patients aged > 65 years and most cancer-related deaths occur in this population. Misconceptions about prognosis and treatment contribute to the undertreatment of elderly cancer patients and consequent poor outcomes. Although older patients have been excluded from cancer treatment trials in the past, response rates to chemotherapy in a variety of common cancers in otherwise healthy elderly patients are comparable to those attained in younger patients. Lower functional reserve in many organ systems alters the pharmacokinetics of chemotherapeutic drugs as well as the patient's response to treatment-induced toxicity. Except for myelosuppression and mucositis, otherwise fit elderly cancer patients are not at significantly enhanced risk of toxicity to chemotherapy. Severe neutropenia and related infection are encountered much more frequently during the treatment of elderly as compared with younger cancer patients. These lead to treatment delays, dose reductions and higher hospitalisation rates. Myelopoietic growth factor support reduces myelosuppression and the associated risk of severe infection, thereby allowing delivery of chemotherapy at full dose intensity. Beneficial responses to granulocyte colony-stimulating factor (G-CSF; filgrastim) in elderly patients have been found in aggressive non-Hodgkin's lymphoma with standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy and acute myeloid leukaemia (AML) during induction and consolidation chemotherapy. Granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim) has been found to reduce myelosuppression in elderly AML patients receiving induction but not consolidation chemotherapy. These prophylactic treatments produce significant cost benefits because of the reduced hospitalisation and antibiotic use associated with neutropenia. To maximise positive outcomes, elderly patients should be included in clinical trials of new cancer agents. Since myelosuppression is the main risk factor for elderly patients undergoing chemotherapy, optimisation of growth factor support and the development of more effective and safer myelopoietic agents may improve success rates and reduce adverse events. Such information will lead to better management of cancer in older patients.     

Recent strategies in the development of taxane anticancer drugs

Paclitaxel (Taxol^®, Bristol-Myers Squibb) and docetaxel (Taxtere^®, Rhône-Poulenc Rorer SA - now Aventis), complex polyoxygenated taxane diterpenoids bearing phenylisoserine moieties currently in extensive clinical use for the treatment of breast, ovarian and other cancers, are considered to be two of the most important drugs in cancer chemotherapy. However, low solubility, multi-drug resistance (MDR), dose-limiting toxicity as well as other adverse effects associated with these drugs present significant drawbacks. Accordingly, seeking the solutions to these problems of taxane anticancer drugs has been the main focus of both academic and industrial research activities for the period of 1997 - 1999. New taxoids (i.e., Taxol^®-like compounds) with various modifications at the baccatin skeleton and the phenylisoserine side chain have been developed, which possess improved potency, especially against cancers expressing P-glycoprotein (P-gp)-based MDR. A number of prodrugs of paclitaxel and taxoids have been designed and synthesised to tackle the solubility problem, mainly by attaching water-soluble subunit(s) to the C-2 and/or C-7 hydroxyl groups. Novel tumour-recognising taxoids and taxane-based MDR modulators have also been developed, showing considerable promise. Recently, the improvement in drug formulation and delivery of taxane anticancer agents has been receiving increasing attention.     

Use of anticancer agents in gynecological oncology during pregnancy: a systematic review of maternal pharmacokinetics and transplacental transfer

Introduction: Cancer affects one in a thousand pregnant women and gynecological cancers are one of the most frequent malignancies. Chemotherapy remains the cornerstone treatment for gynecological cancer. Although all chemotherapeutic agents can cross the placental barrier, the extent of placental transfer varies considerably. Furthermore, the significant physiological variations observed in pregnant women may have an impact on pharmacokinetic parameters. Given the complexity of predicting placental transfer, in vivo and ex vivo studies are essential in this context. In view of the paucity of data on chemotherapy during pregnancy, the objective of the present study was to summarize all the available data on the transplacental transfer of anticancer drugs used to treat gynecological cancers.

Areas covered: In order to evaluate the in vivo and ex vivo transplacental transfer of the anticancer drugs most frequently used in gynecological malignancies, we carried out a comprehensive review of the literature published from 1967 to 2015. Lastly, we summarized recent clinical guidelines on the treatment of gynecological cancers in pregnant patients.

Expert opinion: The preclinical and scarce clinical data must now be extrapolated to define the maternofetal toxicity/efficacy profile and thus guide the physicians to choose anticancer drugs more efficiently in this complex situation.     

Gemcitabine in non-small cell lung cancer

Incidence of small bowel adenocarcinoma is slowly but steadily increasing. As we gain more knowledge of the molecular basis of this disease, we may be able to approach it via using novel biologic or targeted therapies with or without traditional chemotherapy agents. In the meantime, early diagnosis is still best as it prompts early surgical resection and offers potential cure. The role of adjuvant and neoadjuvant therapy is currently being explored in clinical trials. Several clinical trials have suggested that first-line chemotherapy for patients with metastatic disease should consist of either 5-fluorouracil-leucovorin-oxalipatin or capecitabine-oxaliplatin, while 5-fluorouracil-leucovorin-irinotecan can be reserved for second-line treatment. However, we realize the limitations of these studies, given their small sample size and/or retrospective nature. Single-agent 5-fluorouracil/capecitabine should be considered in patients who are either intolerant to or experience significant side effects with oxaliplatin or irinotecan. We believe that cancers originating in the ampulla of Vater probably deserve a prospective randomized trial of cisplatin-gemcitabine, the current standard of therapy for advanced biliary malignancies.     

Targeting P-glycoprotein for effective oral anti-cancer chemotherapeutics

Oral anticancer drug treatment represents a significant change to current oncology practice. Support for oral anticancer treatment is driven by issues of pharmacoeconomics, accommodating the need for protracted drug administration for many emerging cytostatic therapies, response to patient preference and in improving patient quality of life. Much focus has concentrated on defining the cellular mechanisms underlying the pharmacokinetic limitations associated with the oral route of administration. However, the potential effects of oral anticancer drugs on gut associated host mediated immunity have been overlooked. Given that the immune system is central for tumour rejection, an assessment of the potential effects oral anticancer drugs may have at this level, and the impact of this on the treatment of gastrointestinal malignancy is of significant clinical importance. P-glycoprotein is a multidrug transporter that contributes to the reduced bioavailability of many orally administered medications. P-glycoprotein achieves this by virtue of its drug efflux capacity at the level of the gut epithelia. P-glycoprotein is also notorious for contributing to the multidrug resistance phenotype observed in many drug refractory human cancers. Likewise, this drug transporter serves a role in the cells of the immune system; particularly in dendritic cell maturation and function. This multifaceted involvement in drug disposition, cancer drug resistance and regulation of the immune response makes P-glycoprotein an attractive target for the optimization of oral anticancer drug treatment strategies. This review introduces and discusses for the first time the potential impact that oral anticancer drugs may have on P-glycoprotein expression and function and the potential consequences of this on dendritic cell function in relation to human cancer. This review also aims to foster a better understanding of the host mediated immunological mechanisms which may be potentially manipulated in cancer patients undergoing oral chemotherapy.     

Knowledge of epigenetic influence for prostate cancer therapy

Prostate cancer is one of the most prevalent cancers in men in many countries, increasing in frequency with age through the most advanced years. The standard treatment for newly diagnosed metastatic tumors is androgen ablation. However, advanced prostate cancer nevertheless often develops in many cases. Although hormonal manipulation and chemotherapy have uncertain value for advanced lesions, especially androgen-independent, recent studies of docetaxel-based chemotherapy in men with androgen-independent prostate cancer have shown a survival benefit. Intensive investigations have shown that aberrant epigenetic features. including aberrant DNA methylation, make an important contribution to carcinogenesis as well as genetic alterations. Hypermethylation of CpG islands in promoter regions can lead to silencing of tumor-suppressor genes, while hypomethylation of the genome leads to instability. This review attempts to provide up-to-date information regarding the significance of epigenetics for human prostate cancer, with aberrations offering dues to therapy and possibly also providing targets for anticancer drugs.     

NGR-based strategies for targeting delivery of chemotherapeutics to tumor vasculature

In the last decades, NGR-containing peptides have been proved useful for ligand-directed targeted delivery of various chemotherapeutic drugs to tumor vasculature. Aminopeptidase N (APN; CD13) has been demonstrated to be a key binding site for NGR peptides on tumor vasculature. For drug targeting, chemical means have been applied to couple NGR-peptides to small molecule drugs, such as cytokines, antiangiogenic compounds, viral particles, contrast agents, DNA complexes and other biologic response modifiers. Some products have shown impressive results in preclinical animal models, such as NGR-TNF which was currently tested in Phase III trials. In this article we will review the process of NGR-to-isoDGR transition and provide suggestions for the design of the diverse NGR peptide-chemotherapeutics conjugates.     

Apigenin in cancer therapy: Prevention of genomic instability and anticancer mechanisms

The incidence of cancer has been growing worldwide. Better survival rates following the administration of novel drugs and new combination therapies may concomitantly cause concern regarding the long-term adverse effects of cancer therapy, for example, second primary malignancies. Moreover, overcoming tumour resistance to anticancer agents has been long considered as a critical challenge in cancer research. Some low toxic adjuvants such as herb-derived molecules may be of interest for chemoprevention and overcoming the resistance of malignancies to cancer therapy. Apigenin is a plant-derived molecule with attractive properties for chemoprevention, for instance, promising anti-tumour effects, which may make it a desirable adjuvant to reduce genomic instability and the risks of second malignancies among normal tissues. Moreover, it may improve the efficiency of anticancer modalities. This paper aims to review various effects of apigenin in both normal tissues and malignancies. In addition, we explain how apigenin may have the ability to protect usual cells against the genotoxic repercussions following radiotherapy and chemotherapy. Furthermore, the inhibitory effects of apigenin on tumours will be discussed.     

Electroporation therapy of solid tumors

The curative effects of some chemotherapeutic drugs are impeded by their poor permeation through the cell membrane. This limitation can be overcome by a novel approach called electroporation therapy (EPT), electrochemotherapy (ECT), or electrical impulse chemotherapy (EIC). The method involves application of brief electrical pulses, which destabilize the cell membrane barrier, allowing intracellular access of chemotherapeutic drugs that otherwise would not be able to penetrate the cell membrane effectively. EPT makes it possible to lower the drug dose, thereby relieving the patient of adverse side effects associated with conventional chemotherapy. Even with the lower drug dose, EPT has shown significantly higher efficacy than has conventional chemotherapy. The method is currently being evaluated clinically for treating various cancer indications using the anticancer drugs bleomycin or cisplatin. This article provides a historical perspective and current insights into this new modality of cancer treatment, including basic physical, biological, and medical facts about EPT; computer-assisted development of electrical pulse generators and electrodes necessary to create effective electrical fields in the treatment area; results of cancer cell and tumor treatments in vitro, in animals, and in humans; safety aspects of EPT; potential combined delivery of chemotherapeutic drugs and biological agents to reduce or eliminate metastatic disease; and intracellular delivery of DNA by electroporation for cancer gene therapy.     

Vorinostat in cutaneous T-cell lymphoma

Histone deacetylase inhibitors (HDAC-Is) are a novel class of small molecules being evaluated in clinical trials for a number of different malignancies. HDAC-Is are able to induce differentiation, apoptosis and/or cell cycle arrest of malignant cells selectively. Vorinostat (Zolinza, Merck & Co., Whitehouse Station, NJ, USA) is the first HDAC-I approved by the U.S. Food and Drug Administration for treatment of the cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Vorinostat was active against solid tumors and hematologic malignancies as intravenous and oral preparations in phase I development. In two phase II trials, Vorinostat was safe and effective at an oral dose of 400 mg/day with an overall response rate of 30-31% in refractory advanced patients with CTCL including large cell transformation and Sezary syndrome. The most frequent side effects of vorinostat include gastrointestinal symptoms, fatigue and thrombocytopenia. Vorinostat, in combination with other agents such as radiation therapy and chemotherapy, can have synergistic or additive effects in a variety of cancers in clinical trials.