Animal experiments remain essential to understand the fundamental mechanisms underpinning malignancy and to discover improved methods to prevent, diagnose and treat cancer. Excellent standards of animal care are fully consistent with the conduct of high quality cancer research. Here we provide updated guidelines on the welfare and use of animals in cancer research. All experiments should incorporate the 3Rs: replacement, reduction and refinement. Focusing on animal welfare, we present recommendations on all aspects of cancer research, including: study design, statistics and pilot studies; choice of tumour models (e.g., genetically engineered, orthotopic and metastatic); therapy (including drugs and radiation); imaging (covering techniques, anaesthesia and restraint); humane endpoints (including tumour burden and site); and publication of best practice.

The vascular system plays a role of key importance during tumour growth and metastasis formation. In addition, the effectiveness of almost all therapeutic modalities, including drug therapy and radiotherapy, is influenced by the micro-architecture and the gradients of essential nutrients around each vessel. This underlines the importance of the vascular architecture, its origin and effectiveness as a nutrient delivery system. The knowledge that tumour vasculature is abnormal has led to concepts such as angiogenic attack and vascular targeting (Folkman, 1976;Denekamp, 1984;Bicknell, 1994;Folkman and D'Amore, 1996). This, in turn, has led to many more studies of tumour vasculature and primary as well as secondary angiogenesis. However, even though our knowledge of the mechanisms underlying angiogenesis has increased dramatically in the past 25 years, few quantitative data are available on the vascular network architecture and pattern formation in tumours.The fact that the tumour vascularity differs in many aspects from the vasculature of normal organs and tissues was already recognized in the last century (Virchow, 1863; Thiersch, 1865). Thomlinson and Gray (1955) indicated the importance of intervessel spacing because of the threefold increase in radioresistance that accompanies reduction of pO 2 concentrations below critical level. The important question as to whether the vascular architecture of an individual tumour is tumour type-specific has been controversial (Warren, 1979;Vaupel and Gabbert, 1986.) This is due, at least in part, to the methodologies used. Most reports confine themselves to qualitative observations and comparisons of gross vascular patterns in host and tumour, or to blood vessel density, length and diameter measurements, which in turn vary with the staining and counting techniques (Davidson et al, 1994;Endrich and Vaupel, 1998). Recently, morphometric analyses have been introduced in which the features of tumour cells (proliferation rate, oxygenation, angiogenic growth factor production) have been mapped by sequential staining of the same section, allowing the influence of the vascular assay on clinically relevant aspects of cell populations to be mapped. Vascular and metabolic profiles (VAMP) have illustrated marked differences between different types of tumour of the same general histology, for brain tumours and those from the head and neck region. Less et al (1991) introduced the first suitable approach for determining branching patterns and vessel dimensions in corrosion casts of mammary carcinomas. They established a quantitative classification scheme which takes account of the unique features of tumour microvascular network topology. However, it should be recognized that measurements were made on planar twodimensional (2D) projected images of three-dimensional (3D) specimens. All attempts to determine distances in corrosion casts geometrically after 2D projection inevitably include a considerable error. Measurements of vascular parameters such as intercapillary distance and vessel se...

(Teicher et al., 1981). Even more recently, the profound effects that hypoxia can have on the actions of cytokines, including interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-a) and interferon (IFN), have been described (Aune and Pogue, 1989;Ishizaka et al., 1992;Sampson and Chaplin, 1994).It has been known for many years that radiobiologicaly hypoxic cells exist in experimental rodent and xenografted human tumours. The recent availability of the Eppendorf Po2 histograph has enabled the demonstration of hypoxic regions in primary human tumours (Vaupel et al., 1991;Hockel et al., 1993). Despite our knowledge of the existence of hypoxic cells in tumours and the undoubted importance of hypoxia to therapeutic response, relatively little attention has been focused on how hyponia arises within a solid tumour mass. Knowledge as to how hypoxic cells occur has important impi;cations for the approaches that can be used to improve the oxygenation status of cells and ultimately therapeutic response. Moreover, in order to mimic more closely in vitro the nutritional and physiological status of hypoxic cells in vivo, knowledge of how they occur and how long they remain hypoxic represents important information.On a theoretical basis, hypoxic cells can result from two distinct processes: firstly from diffusion limitations in a system with a constant blood flow and oxygen delivery capacity; cell division and oxygen ultilisation by those cells closest to the blood vessel result in a gradual decline in the oxygenation and nutritional status of cells further away.

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Purpose: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents.Experimental Design: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors.Results: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m 2 , then expanded cohorts to 15.4 mg/m 2 in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drugrelated dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m 2 or higher. Conclusions:The maximum tolerated dose was 8.5 mg/m 2 but escalation to 14 mg/m 2 was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m 2 and maximum tumor perfusion reductions were seen at doses of 11 mg/m 2 or higher, the recommended phase II dose is from 11 to 14 mg/m 2 .

A novel oxygen sensor which does not rely on electrochemical reduction has been used to measure the oxygenation of the murine sarcoma F in a comparative study with an existing polarographic electrode that is available commercially. The prototype luminescence sensor yielded an oxygen distribution comparable with readings made using a pO2 histograph. The percentage of regions detected that had a pO2 less than 5 mm Hg was 79 and 75 using the Eppendorf pO2 histograph and the luminescence fiber optic sensor, respectively. These values were compatible with a measured radiobiologically hypoxic fraction of 67% in this tumor. The polarographic method detected more regions with a pO2 of 2.5 mm Hg or less (69%) compared with the optical sensor (50%) (P < 0.05). This could reflect differences in the oxygen use of the sensing devices. This initial assessment indicates the potential of a fiber-optic-based oxygen-monitoring system. Such a system should have several advantages including monitoring temporal oxygen changes in a given microregion and use with NMR procedures.

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