Chemotherapy remains one of the major tools, along with surgery, radiotherapy, and more recently targeted therapy, in the war against cancer. There have appeared a plethora of highly potent cytotoxic drugs but the poor discriminability between cancerous and healthy cells of these agents limits their broader application in clinical settings. Therapeutic antibodies have emerged as an important class of biological anticancer agents, thanks to their ability in specific binding to tumor-associated antigens. While this important class of biologics can be used as single agents for the treatment of cancer through antibody-dependent cell cytotoxicity (ADCC), their therapeutical efficacy is often limited. Antitumor antibody drug conjugates (ADCs) combine the target-specificity of monoclonal antibody (mAb) and the highly active cell-killing drugs, taking advantages of the best characteristics out of both components. Thus, insufficiency of most naked mAbs in cancer therapy has been circumvented by arming the immunoglobulin with cytotoxic drugs. Here mAbs are used as vehicles to transport potent payloads to tumor cells. ADCs contain three main components: antibody, linker and cytotoxics (also frequently referred as payload). Antibodies can recognize and specifically bind to the tumor-specific antigens, leading to an antibody-assisted internalization, and payload release. While ADC has demonstrated tremendous success, a number of practical challenges limit the broader applications of this new class of anticancer therapy, including inefficient cellular uptake, low cytotoxicity, and off-target effects. This review article aims to cover recent advances in optimizing linkers with increased stability in circulation while allowing efficient payload release within tumor cells. We also attempt to provide some practical strategies in resolving the current challenges in this attractive research area, particularly to those new to the field.
Aminobenzoates ; pharmacology ; therapeutic use ; Animals ; Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Antineoplastic Agents ; pharmacology ; therapeutic use ; Cell Survival ; drug effects ; Cytotoxins ; pharmacology ; therapeutic use ; Drug Design ; Humans ; Immunoconjugates ; chemistry ; pharmacology ; therapeutic use ; Maytansine ; pharmacology ; therapeutic use ; Neoplasms ; drug therapy ; pathology ; Oligopeptides ; pharmacology ; therapeutic use

Vascular disrupting agents (VDAs) have presented a new kind of anti-cancer drug in recent years. VDAs take advantage of the weakness of established tumor endothelial cells and their supporting structures. In contrast to anti-angiogenic therapy, which inhibits the outgrowth of new blood vessels, vascular targeting treatments selectively attack the existing tumor vasculature. Here we summarized the anti-tumor activities, mechanisms and clinical applications of small molecule VDAs.
Angiogenesis Inhibitors ; chemistry ; pharmacology ; therapeutic use ; Animals ; Antineoplastic Agents ; chemistry ; pharmacology ; therapeutic use ; Bibenzyls ; chemistry ; pharmacology ; therapeutic use ; Diphosphates ; chemistry ; pharmacology ; therapeutic use ; Endothelial Cells ; drug effects ; Humans ; Molecular Structure ; Neoplasms ; drug therapy ; pathology ; Neovascularization, Pathologic ; Oligopeptides ; chemistry ; pharmacology ; therapeutic use ; Organophosphorus Compounds ; chemistry ; pharmacology ; therapeutic use ; Serine ; analogs & derivatives ; chemistry ; pharmacology ; therapeutic use ; Stilbenes ; chemistry ; pharmacology ; therapeutic use ; Tubulin Modulators ; chemistry ; pharmacology ; therapeutic use ; Xanthones ; chemistry ; pharmacology ; therapeutic use

OBJECTIVEThe aim of this study is to observe the effect of combined amiodarone and antiarrhythmic peptide (AAP10) use on the incidence of induced ventricular arrhythmias in healed myocardial infarction (MI) rabbits.

METHODSTwenty Japanese rabbits underwent thoracotomy without coronary artery ligation (Sham, group A), the middle left circumflex branch were ligated to induce MI in 180 Japanese rabbits. Eight weeks after operation, 124 rabbits survived MI operation and were divided into four groups: control group (group B, n = 31), amiodarone group (group C, n = 31), AAP10 group (group D, n = 31) and amiodarone plus AAP10 group (group E, n = 31). The A and B and D groups were treated with saline 2 ml/d, the C and E groups were treated with 2 ml saline containing amiodarone 100 mg×kg(-1)×d(-1). All rabbits were examined by echocardiogram at 12 weeks after operation, then anesthetized by sodium barbital, the left wedge ventricular preparations were cannulated and artery perfused by Tyrode's solution in vitro in the absence (Group A, B and C) and presence of AAP10 (500 nmol/L, Group D and E). The volume electrocardiogram, QT Interval, QRS interval, effective refractory period (ERP), the T-peak to T-end interval (T(p-e)), and ventricular tachycardia episodes induced by programmed stimulation were recorded. The T(p-e)/QT ratio was calculated. After perfusion, gap junctions protein connexin 43 (Cx43) expression was detected by Western blot and immunofluorescence.

RESULTSThe incidence of induced ventricular tachycardia episodes of group A, B, C, D, E was 0, 62.5%, 26.9%, 40.0%, 22.2% respectively. The incidence of induced ventricular tachycardia episodes of group E was less than group B. The T(p-e)/QT ratio in group B, C, D were greater than in group A. The T(p-e)/QT ratio of group E was less than group B. The myocardial Cx43 in the group B was down-regulated and disorganized compared to group A, up-regulated in group C and E compared to group B, up-regulated in group E compared to group D. The Cx43 in the heart of group D and E were well organized than in group B and C.

CONCLUSIONSThe artery perfused rabbits wedge preparations with healed myocardial infarction with high incidence of induced ventricular tachycardia episodes are good platform for ventricular arrhythmias research. Combined amiodarone and AAP10 use could decrease the T(p-e)/QT ratio and the incidence of induced ventricular tachycardia episodes. Amiodarone and AAP10 have synergistic effects on upregulating Cx43 and preventing ventricular arrhythmias in this rabbit model of healed myocardial infarction.

Amiodarone ; pharmacology ; therapeutic use ; Animals ; Anti-Arrhythmia Agents ; pharmacology ; therapeutic use ; Arrhythmias, Cardiac ; etiology ; Connexin 43 ; metabolism ; Male ; Myocardial Infarction ; drug therapy ; metabolism ; physiopathology ; Oligopeptides ; pharmacology ; therapeutic use ; Rabbits ; Treatment Outcome

In this study, we examined the therapeutic effects of an immune-stimulating peptide, WKYMVm, in ulcerative colitis. The administration of WKYMVm to dextran sodium sulfate (DSS)-treated mice reversed decreases in body weight, bleeding score and stool score in addition to reversing DSS-induced mucosa destruction and shortened colon. The WKYMVm-induced therapeutic effect against ulcerative colitis was strongly inhibited by a formyl peptide receptor (FPR) 2 antagonist, WRWWWW, indicating the crucial role of FPR2 in this effect. Mechanistically, WKYMVm effectively decreases intestinal permeability by stimulating colon epithelial cell proliferation. WKYMVm also strongly decreases interleukin-23 and transforming growth factor-beta production in the colon of DSS-treated mice. We suggest that the potent immune-modulating peptide WKYMVm and its receptor FPR2 may be useful in the development of efficient therapeutic agents against chronic intestinal inflammatory diseases.
Adjuvants, Immunologic/pharmacology/*therapeutic use ; Animals ; Caco-2 Cells ; Cell Proliferation ; Colitis, Ulcerative/*drug therapy/metabolism ; Colon/pathology ; Humans ; Interleukin-23/genetics/metabolism ; Intestinal Mucosa/drug effects/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Oligopeptides/pharmacology/*therapeutic use ; Permeability ; Receptors, Formyl Peptide/antagonists & inhibitors ; Transforming Growth Factor beta/genetics/metabolism