Vascular disrupting agents: a new class of drug in cancer therapy.

AIMS: To provide a comprehensive overview of the current state of development of a novel class of anti-cancer drugs, the vascular disrupting agents (VDAs), previously known as vascular targeting agents (VTAs). MATERIALS AND METHODS: A comprehensive review, analysis and commentary of the published medical literature on VDAs was performed. RESULTS: Tumour vascular targeting therapy exploits known differences between normal and tumour blood vessels. VDAs target the preexisting vessels of tumours (cf anti-angiogenics), and cause vascular shutdown leading to tumour cell death and rapid haemorrhagic necrosis within hours. It is becoming clear that VDAs have overlapping activity with anti-angiogenic drugs, which prevent the formation of new blood vessels. There are two types of VDA. First, biological or ligand-directed VDAs use antibodies, peptides or growth factors to target toxins or pro-coagulants to the tumour endothelium. In contrast, small molecule VDAs work either as tubulin-binding agents or through induction of local cytokine production. VDAs can kill tumour cells resistant to conventional chemotherapy and radiotherapy, and work best on cells in the poorly perfused hypoxic core of tumours, leaving a viable rim of well-perfused tumour tissue at the periphery, which rapidly regrows. Consequently, responses of tumours to VDAs given as single agents have been poor; however, combination therapy with cytotoxic chemotherapy, external-beam radiotherapy, and radioimmunotherapy, which target the peripheral tumour cells, has produced some excellent responses in animal tumours. VDAs are generally well tolerated with different side-effect profiles to current oncological therapies. Dynamic magnetic resonance imaging is most frequently used to obtain a pharmacodynamic end point to determine whether the VDA is acting on its intended target. CONCLUSIONS: VDAs are a promising new class of drug, which offer the attractive possibility of inducing responses in all tumour types with combination therapy.

Cardiac complications of radiation therapy.

AIMS: To present an overview of cardiac complications arising from radiation therapy. MATERIALS AND METHODS: Medline the (February 2004) and Embase (1974 to February 2004) searches of the medical literature relating to the cardiac complications of radiotherapy were conducted. RESULTS: Radiation damage may affect the pericardium, myocardium or coronary vasculature, and consists of fibrotic or small vessel damage. Cardiac complications are a particular problem with radiation treatments to the mediastinum and breast, especially when greater than 65% of the heart is irradiated. Most of the literature relates to the treatment of Hodgkin's disease, as patients with this disease tend to be young and live long enough to manifest late cardiac complications. Pericarditis, angina, myocardial infarction and arrhythmias are the most frequent causes of morbidity, with myocardial infarction being the most common fatal complication. The incidence of ischaemic heart disease does not increase rapidly until 10 years from treatment. CONCLUSIONS: Much of the evidence relates to the use of outdated radiation therapy equipment and techniques. Today's patients almost certainly have a lower risk of cardiac complications. Cardiac complications are probably under-reported, as they occur long after cured patients have been discharged from follow-up.

Perforated diverticulitis following extra-abdominal surgery.

The peritonitis of perforated diverticular disease is a life-threatening condition. We report three cases where it occurred following unrelated extra-abdominal surgery and where surgical intervention proved to be the correct course of management. All cases were treated with a Hartmann's procedure; this is probably the safest option for purulent peritonitis in patients who are a high operative risk and have recently undergone major surgery.