A drug for improved radiosensitization in radiotherapy.
A drug for improved radiosensitization in radiotherapy.
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一种用于改善放射治疗中放射增敏性的药物。
DOI：
10.1038/bjc.1980.213
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发表时间：
1980-07
影响因子：
8.8
通讯作者：
Lee, M E
中科院分区：
文献类型：
--
作者：
Dische, S;Fowler, J F;Saunders, M I;Stratford, M R;Anderson, P;Minchinton, A I;Lee, M E
乏氧肿瘤细胞对放射治疗的抵抗力可能是局部失败的常见原因，因为有充分的证据表明，乏氧细胞存在于几乎所有接受治疗的人类肿瘤中。在已经引入的克服该问题的方法中，化学放射增敏剂是最近开发的（亚当斯等人，1976年）。由于它们在放射治疗中具有广泛应用的潜力，因此引起了人们的极大兴趣（Lancet，1978）。1973年，第一种为此目的进行临床试验的药物是甲硝唑，随后不久，1974年，米索咪唑（Ro 07 - 582，MISO）在实验室研究中成为一种更有效的药物（Fowler等人，1976年）。目前，欧洲、美国、加拿大、南非、澳大利亚、新西兰和日本正在进行这种化合物的临床试验。在测试MISO的早期阶段，随着剂量的增加，该药物被证明是神经毒性的，产生脑病和周围神经病（Dische等人，1977年）。目前普遍接受在不少于17天的时间内给予12 g/m2的剂量限值。在这种剂量限制下，大多数周围神经病变病例是轻度和一过性的，但仍有约30%的发病率，偶尔有更严重的毒性病例（Dische et al.，1979年）。该剂量可使缺氧细胞的敏化达到1 - 3 - 1 - 6倍（Fowler等人，1976），但这必须与2 - 5 - 3的因子相一致，这是使致敏性恢复到氧化细胞水平所需的。尽管如此，目前的一些试验仍有望显示出使用该药物的益处。目前正在努力开发可能导致更大放射增敏作用的新化合物。已证明放射增敏硝基咪唑的亲脂性与神经毒性之间存在直接关系（Conroy，1980）。使用亲脂性相对较低的药物可获得较高的肿瘤/脑浓度比（Brown & Lee，1980）。另一种方法是开发在血浆中具有较短半衰期的化合物，因为在临床和动物研究中已经显示，血浆浓度的时间曲线下面积可以直接与神经毒性的发生率相关（Dische等人，1979年）。静脉途径被认为是潜在的上级途径，特别是使用一些亲脂性较低的化合物（白色等人，（1980年）;但这将减少临床应用，因为静脉制剂给药涉及的实际问题，特别是当患者在持续4 - 6周的疗程中可能接受20 - 30次放射治疗时。去甲基米索咪唑（Roche实验药物Ro 05 - 9963，DESMISO）是MISO的第一代谢物，并且在施用MISO后在血浆和尿液中检测到它（Flockhart等人，1978年a）。作为放射增敏剂，
THE RESISTANCE of hypoxic tumour cells to radiotherapy may be a common cause of local failure, for there is good evidence that hypoxic cells exist in nearly all human tumours which are treated. Among the methods which have been introduced to overcomethis problem, the chemical radiosensitizers are the most recently developed (Adams et al., 1976). There is considerable interestin them for they havegreat potential for wide use in radiotherapy (Lancet, 1978). The first drug to be tested clinically for this purpose was metronidazole in 1973, shortly followedin 1974 by misonidazole (Ro 07-582, MISO) a much more effective drug in laboratory studies (Fowler et al., 1976). Now many clinical trials are under way with this compound in Europe, the United States, Canada, South Africa, Australia, New Zealand and Japan. In the early stages of testing MISO, as the dosewas increased, the drug proved to be neurotoxic, producing encephalo-pathy and peripheral neuropathy (Dische et al., 1977). A dose limit of 12 g/m2 to be given over a period of not less than 17 days has now been generally accepted. With this dose limitation, most cases of peripheral neuropathy are mild and tran-sient, but there is still an incidence of-30%, and an occasional case of more severe toxicity (Dische et al., 1979). The dose may achieve a sensitizationof hypoxic cells by a factor of 1-3-1-6 (Fowler et al., 1976) but this must be com-pared with a factor of 2-5-3 which is required to bring sensitization back to the level of that of oxic cells. Nevertheless there is an expectation that some of the current trials will show benefit with the use of the drug.A considerable effort is currently being made to develop new compounds which may lead to greater radiosensitization. A direct relationship has been demonstrated between the lipophilicity of radiosensitizing nitroimidazoles and neurotoxicity (Conroy, 1980). High tumour/brain con-centration ratios have been obtained with drugs of relatively low lipophilicity (Brown & Lee, 1980). The alternative approach is to develop a compound with a shorter half-life in the plasma, for it has been shown in clinical as well as in animal studies that the area under the time curve of plasma concentration can be directly related to theincidence of neurotoxicity (Dische et al., 1979). The iv route has been considered asa potentially superior one, particularly with the use of some of the less lipophilic compounds (White et al., 1980); but this will reduce clinical use because of the practical problems involved with the administration of iv preparations, particularly when a patient may receive 20-30 radiation treatmentsin a courselasting 4-6 weeks. Desmethylmisonidazole (the Roche ex-perimental drug Ro 05-9963, DESMISO) is the first metabolite of MISO, and it has been detected in the plasma and urine after MISO has been administered (Flockhart et al., 1978a). As a radiosensitizer it