Synthesis of Novel Unsaturated Alkyl Ethers of Racemic Deoxyisopodophyllotoxin as Cytotoxic Agents

A series of isopentenyl-derived unsaturated alkyl ethers 19-31 of racemic deoxyisopodophyllotoxin were designed and synthesized. For comparison, compound 32 with a benzyl group at the same position was also prepared. The cytotoxicities of the synthetic compounds have been screened for six human tumor cell lines such as KB, BEL-7404, A549, Hela, PC-3 and CNE. The results showed that two of them exhibited significant cytotoxicities with their IC50 values on selected cell lines at μmol/L scale.

The safety parameters of the study on intraductal cytotoxic agent delivery to the breast before mastectomy

Background： Intraductal administration of cytotoxic agents has been shown to inhibit the development of breast cancer in animal models. The object of this study was to demonstrate the safety of intraductal delivery cytotoxic agents in patients prior to mastectomy. This method is hopeful to be developed as a chemoprevention approach in patients with pre-malignant or non-invasive ductal lesions to prevent breast cancer which will be further developed.Methods： Two drugs, pegylated liposomal doxorubicin（PLD） and carboplatin were administered at three dose levels（PLD： 10, 20, 50 mg and carboplatin 60, 120, 300 mg）. There were five subjects in each group with 15 subjects treated with each drug once. Venous blood samples were obtained for pharmacokinetic analysis. The breast was removed surgically 2-5 days post administration and the treated ducts were marked to enable identification on pathological evaluation. Results： Intraductal administration was generally well-tolerated with mild, transient breast discomfort. In the carboplatin arm, three women at the 300 mg dose experienced mild nausea and vomiting. In the PLD arm most women had mild erythema and swelling of the breast over the 72 hours following the drug administration. Patients receiving the 50 mg dose experienced local erythema until the time of surgery. Pharmacokinetic analysis showed that carboplatin rapidly entered systemic circulation with an early peak time（T max -30 min） with a corresponding plasma ultrafiltrate area under the curve（AUC） consistent with the Calvert Formula using estimated glomerular filtration rate（GFR）. Total plasma doxorubicin had delayed peak concentration times（T max 48 hours） with a linear dose response and peak concentrations substantially lower than expected from equivalent intravenous injection dosing. No doxorubicinol metabolite was detected in the plasma. Conclusions： This study demonstrates that cytotoxic drugs can be safely administered into breast ducts with minimal toxicity.

Nephrotoxicity in cancer treatment:An overview

Anticancer drug nephrotoxicity is an important and increasing adverse drug event that limits the efficacy of cancer treatment.The kidney is an important elimination pathway for many antineoplastic drugs and their metabolites,which occurs by glomerular filtration and tubular secretion.Chemotherapeutic agents,both conventional cytotoxic agents and molecularly targeted agents,can affect any segment of the nephron including its microvasculature,leading to many clinical manifestations such as proteinuria,hypertension,electrolyte disturbances,glomerulopathy,acute and chronic interstitial nephritis,acute kidney injury and at times chronic kidney disease.The clinician should be alert to recognize several factors that may maximize renal dysfunction and contribute to the increased incidence of nephrotoxicity associated with these drugs,such as intravascular volume depletion,the associated use of nonchemotherapeutic nephrotoxic drugs(analgesics,antibiotics,proton pump inhibitors,and bonetargeted therapies),radiographic ionic contrast media or radiation therapy,urinary tract obstruction,and intrinsic renal disease.Identification of patients at higher risk for nephrotoxicity may allow the prevention or at least reduction in the development and severity of this adverse effect.Therefore,the aim of this brief review is to provide currently available evidences on oncologic drug-related nephrotoxicity.

Nanoemulsion for delivery of anticancer drugs

Cancer refers to a collection of diseases that have abnormal cell growth as their hallmark.This inability of cytotoxic agents to distinguish between rapidly dividing healthy cells and rapidly multiplying cancerous cells produces the most notorious adverse effects of cytotoxic anticancer agents.As an essential tool in nanotechnology,nanoemulsions have therapeutic and clinical applications.Currently,nanoemulsions are considered to be one of the most feasible nano-carriers for delivering lipophilic antineoplastic agents with targeted delivery.In addition to solving water-solubilization issues,these formulations deliver specific targeting to cancer cells and might even be developed to overcome multi-drug resistance.Nanoemulsions overcome the problems associated with conventional drug delivery systems,such as low bioavailability and noncompliance.A review of nanoemulsion in cancer therapeutics is presented here to shed light on the current position of this technology.

Synthesis and in vitro biological evaluation of novel 2-aminoimidazolone derivatives as anti-tumor agents

Novel 2-aminoimidazolone derivatives were synthesized.Most compounds displayed strong anticancer activities against human carcinoma cells in vitro.Compounds 8a,8b and 8j exhibited optimal activity superior to 5-FU in most cancer cells tested.Especially,the lC_（50）s of 8b（12.6-21.5μmol/L） against five tumor cells were 1 -4 fold less than those of 5-FU（18.4-56.1μmol/L） in vitro.Furthermore,comp以ound 8b could induce SMMC-7721 cell apoptosis in a dose-dependent manner.Therefore,our novel findings may provide a new framework for the design of new 2-aminoimidazolone derivatives for the treatment of cancer.

Recent advances of antibody drug conjugates for clinical applications

Antibody drug conjugates(ADCs)normally compose of a humanized antibody and small molecular drug via a chemical linker.After decades of preclinical and clinical studies,a series of ADCs have been widely used for treating specific tumor types in the clinic such as brentuximab vedotin(Adcetris?)for relapsed Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma,gemtuzumab ozogamicin(Mylotarg?)for acute myeloid leukemia,ado-trastuzumab emtansine(Kadcyla?)for HER2-positive metastatic breast cancer,inotuzumab ozogamicin(Besponsa?)and most recently polatuzumab vedotin-piiq(Polivy?)for B cell malignancies.More than eighty ADCs have been investigated in different clinical stages from approximately six hundred clinical trials to date.This review summarizes the key elements of ADCs and highlights recent advances of ADCs,as well as important lessons learned from clinical data,and future directions.