Horsman M R
Danish Cancer Society, Department of Experimental Clinical Oncology, Aarhus.
Acta Oncol. 1995;34(5):571-87. doi: 10.3109/02841869509094031.
Oxygen deficient hypoxic cells, which are resistant to sparsely ionising radiation, have now been identified in most animal and some human solid tumours and will influence the response of those tumours to radiation treatment. This hypoxia can be either chronic, arising from an oxygen diffusion limitation, or acute, resulting from transient stoppages in microregional blood flow. Although clinical attempts to overcome hypoxia have met with some success, the results have been far from satisfactory, and efforts are still being made to find better methods. Extensive experimental studies, especially in the last decade, have shown that nicotinamide and structurally related analogs can effectively sensitise murine tumours to both single and fractionated radiation treatments and that they do so in preference to the effects seen in mouse normal tissues. The earliest studies suggested that this enhancement of radiation damage was the result of an inhibition of the repair mechanisms, as was well documented in vitro. However, recent studies in mouse tumours have shown that the primary mode of action actually involves a reduction in tumour hypoxia. More specifically, these drugs prevent transient cessations in blood flow, thus inhibiting the development of acute hypoxia. This novel discovery led to the suggestion that the potential role of these agents as radiosensitizers would be when combined with treatments that overcame chronic hypoxia. The first attempt to demonstrate this combined nicotinamide with hyperthermia and found that the enhancement of radiation damage by both agents together was greater than that seen with each agent alone. Similar results were later seen for nicotinamide combined with a perfluorochemical emulsion, carbogen breathing, and pentoxifylline, and in all these studies the effects in tumours were always greater than those seen in appropriate normal tissues. Of all the analogs, it is nicotinamide itself which has been the most extensively studied as a radiosensitizer in vivo and the one that shows the greatest effect in animal tumours. It is also an agent that has been well established clinically for the treatment of a variety of disorders, with daily doses of up to 6 g being considered reasonably safe and associated with a low incidence of side effects. This human dose is equivalent to 100-200 mg/kg in mice and such doses will maximally sensitize murine tumours to radiation. These findings have now resulted in phase I/II clinical trials of nicotinamide, in combination with carbogen breathing, as a potential radiosensitizing treatment.
现已在大多数动物实体瘤和一些人类实体瘤中发现了对低剂量电离辐射具有抗性的缺氧细胞，这些细胞会影响肿瘤对放射治疗的反应。这种缺氧情况可能是慢性的，由氧扩散受限引起，也可能是急性的，由微区域血流的短暂停止导致。尽管临床上克服缺氧的尝试取得了一些成功，但结果远不尽人意，人们仍在努力寻找更好的方法。广泛的实验研究，尤其是在过去十年中，表明烟酰胺及其结构相关类似物能有效使小鼠肿瘤对单次和分次放射治疗敏感，而且它们对小鼠正常组织的影响较小。最早的研究表明，这种放射损伤的增强是由于修复机制受到抑制，这在体外已有充分记录。然而，最近对小鼠肿瘤的研究表明，其主要作用方式实际上是减少肿瘤缺氧。更具体地说，这些药物可防止血流短暂停止，从而抑制急性缺氧的发展。这一新颖发现表明，这些药物作为放射增敏剂的潜在作用在于与克服慢性缺氧的治疗方法联合使用。首次尝试将烟酰胺与热疗联合使用，发现两种药物共同作用时对放射损伤的增强作用大于单独使用每种药物时的作用。后来烟酰胺与全氟化学乳剂、卡波金呼吸法和己酮可可碱联合使用也得到了类似结果，在所有这些研究中，对肿瘤的影响总是大于对相应正常组织的影响。在所有类似物中，烟酰胺本身作为体内放射增敏剂的研究最为广泛，并且在动物肿瘤中显示出最大的效果。它也是一种在临床上已被广泛用于治疗多种疾病的药物，每日剂量高达6克被认为相当安全，且副作用发生率较低。这种人体剂量相当于小鼠中的100 - 200毫克/千克，这样的剂量能使小鼠肿瘤对辐射达到最大程度的敏感。这些发现现已导致烟酰胺与卡波金呼吸法联合作为潜在放射增敏治疗的I/II期临床试验。
