Amifostine (Ethyol), an inorganic thiophosphate, is a selective broad-spectrum cytoprotector of normal tissues that provides cytoprotection against ionizing radiation and chemotherapeutic agents, thus preserving the efficacy of radiotherapy and chemotherapy. This review summarizes the preclinical data and clinical experience with amifostine, and provides insight into future clinical directions. Amifostine, an inactive pro-drug, is transformed to an active thiol after dephosphorylation by alkaline phosphatase found in the normal endothelium. The absence of alkaline phosphatase in the tumoral endothelium and stromal components, and the hypovascularity and acidity of the tumor environment, may explain its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. Intravenous administration of amifostine 740-900 mg/m(2) before chemotherapy and 250-350 mg/m(2) before each radiotherapy fraction are widely used regimens. The US Food and Drug Administration has approved the use of amifostine as a cytoprotector for cisplatin chemotherapy and for radiation-induced xerostomia. Ongoing trials are being conducted to determine the efficacy of amifostine in reducing radiation-induced mucositis and other toxicities. Novel schedules and routes of administration are under investigation, and may further simplify the use of amifostine and considerably broaden its applications.

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The prognostic significance of intratumoral angiogenesis was investigated in 62 patients with stage I-III carcinomas of the gallbladder treated with simple cholecystectomy. Microvessel density (MVD) was assessed immunohistochemically, using the alkaline phosphatase/anti-alkaline phosphatase method and the monoclonal antibody CD31. The mean MVD was 30.5 vessels per x 200 optical field. Using the thirty-third and the sixty-sixth percentile, the patients were grouped into three MVD categories: low (MVD 9-18; 20 patients), medium (MVD 19-31; 20 patients), and high (MVD 32-86; 22 patients). A high MVD was more frequent in well-differentiated adenocarcinomas compared with moderately and poorly differentiated tumors (p = 0.04), but there was no statistically significant association between MVD and T stage, or patients' age or sex. Multivariate analysis, including MVD, T stage, and histologic grade, showed that MVD was a significant independent prognostic factor in carcinomas of the gallbladder (p = 0.001, t ratio 3.3). It is believed that the assessment of intratumoral angiogenesis in patients with operable gallbladder carcinomas may be useful in predicting prognosis and, perhaps, in decision making for postoperative adjuvant treatment.

Suummary Several in vitro studies stress a potentially important role of interleukin 4 (IL-4) and the related gp200-MR6 molecule in the immunological response to cancer and in tumour proliferation. In the present study, we assessed the expression of gp200-MR6 in primary breast cacrinomas using the MR6 monoclonal antibody. Results were correlated with tumour parameters (T-,N-stage, histology, grade, oestrogen and epidermal growth factor (EGF) receptors), and the impact on survival was assessed. Twenty-four out of 110 cases (22%) were positive for gp200-MR6, 62 out of 110 (56%) expressed weak staining and 24 out of 114 (22%) did not stain. The normal breast epithelia were invariably stained for gp200-MR6 showing that downregulation or loss of this molecule occurred during the evolution of breast cancer. Gp200-MR6 loss was independent from differentiation, nodal positivity and oestrogen receptor levels as well as patients' age. Loss of the gp200-MR6 molecule was more frequent in lobular cases (P=0.03). The overall survival was better, although not reaching statistical significance, in patients with positive gp200-MR6 expression (92% alive at 5 years compared with 70% for those with weak or no expression, P=0.1). The local relapse-free survival was independent of gp200-MR6 status. It is concluded that loss of gp200-MR6 may be one of the mechanisms through which breast cancer cells escape immune surveillance, resulting in an increased metastatic potential and poorer outcome. Evidence of down-regulation of the gp200-MR6 molecule has implications for IL-4-linked toxin therapy and, as IL-4 is an inhibitor of breast epithelial growth, may represent loss of a tumoursuppression mechanism.