Lee Tat Khuen, Stupans Ieva
Center for Pharmaceutical Research, School of Pharmaceutical Molecular and Biomedical Sciences, University of South Australia, SA, 5000, Australia.
J Pharm Pharmacol. 2002 Nov;54(11):1435-45. doi: 10.1211/00223570254.
Clinical and experimental studies of the acute and late effects of radiation on cells have enhanced our knowledge of radiotherapy and have led to the optimisation of radiation treatment schedules and to more precise modes of radiation delivery. However, as both normal and cancerous tissues have similar response to radiation exposure, radiation-induced injury on normal tissues may present either during, or after the completion of, the radiotherapy treatment. Studies on both NSAIDs and prostaglandins have indeed shown some evidence of radioprotection. Both have the potential to increase the survival of cells but by entirely different mechanisms. Studies of cell kinetics reveal that cells in the mitotic (M) and late G2 phases of the cell cycle are generally most sensitive to radiation compared with cells in the early S and G1/G0 phases. Furthermore, radiation leads to a mitotic delay in the cell cycle. Thus, chemical agents that either limit the proportion of cells in the M and G2 phases of the cell cycle or enhance rapid cell growth could in principle be exploited for their potential use as radioprotectors to normal tissue during irradiation. NSAIDs have been shown to exert anti-cancer effects by causing cell-cycle arrest, shifting cells towards a quiescence state (G0/G1). The same mechanism of action was observed in radioprotection of normal tissues. An increase in arachidonic acid concentrations after exposure to NSAIDs also leads to the production of an apoptosis-inducer ceramide. NSAIDs also elevate the level of superoxide dismutase in cells. Activation of heat shock proteins by NSAIDs increases cell survival by alteration of cytokine expression. A role for NSAIDs with respect to inhibition of cellular proliferation possibly by an anti-angiogenesis mechanism has also been suggested. Several in-vivo studies have provided evidence suggesting that NSAIDs may protect normal tissues from radiation injury. Prostaglandins do not regulate the cell cycle, but they do have a variety of effects on cell growth and differentiation. PGE(2) mediates angiogenesis, increasing the supply of oxygen and nutrients, essential for cellular survival and growth. Accordingly, PGE(2) at sufficiently high plasma concentrations enhances cellular survival by inhibiting pro-inflammatory cytokines such as TNF-alpha and IL-1beta. Thus, PGE(2) acts as a modulator, rather than a mediator, of inflammation. Prospective studies have suggested the potential use of misoprostol, a PGE(1) analogue, before irradiation, in prevention of radiation-induced side effects. The current understanding of the pharmacology of NSAIDs and prostaglandins shows great potential to minimise the adverse effects of radiotherapy on normal tissue.
关于辐射对细胞的急性和晚期影响的临床及实验研究增进了我们对放射治疗的了解，并促使放射治疗方案得到优化，以及放射治疗模式更加精确。然而，由于正常组织和癌组织对辐射暴露的反应相似，正常组织的辐射损伤可能在放射治疗期间或治疗完成后出现。对非甾体抗炎药（NSAIDs）和前列腺素的研究确实显示了一些放射防护的证据。两者都有提高细胞存活率的潜力，但作用机制完全不同。细胞动力学研究表明，与处于细胞周期早期S期和G1/G0期的细胞相比，处于有丝分裂（M）期和G2晚期的细胞通常对辐射最为敏感。此外，辐射会导致细胞周期中的有丝分裂延迟。因此，原则上，那些能够限制处于细胞周期M期和G2期细胞比例或促进细胞快速生长的化学试剂，有可能被用作辐射期间对正常组织的放射防护剂。已表明NSAIDs通过引起细胞周期停滞，使细胞向静止状态（G0/G1）转变来发挥抗癌作用。在正常组织的放射防护中也观察到了相同的作用机制。暴露于NSAIDs后花生四烯酸浓度的增加也会导致凋亡诱导剂神经酰胺的产生。NSAIDs还能提高细胞中超氧化物歧化酶的水平。NSAIDs对热休克蛋白的激活通过改变细胞因子表达提高细胞存活率。也有人提出NSAIDs可能通过抗血管生成机制抑制细胞增殖。一些体内研究提供的证据表明，NSAIDs可能保护正常组织免受辐射损伤。前列腺素不调节细胞周期，但它们对细胞生长和分化有多种作用。前列腺素E2（PGE(2)）介导血管生成，增加对细胞存活和生长至关重要的氧气和营养物质的供应。因此，血浆浓度足够高时，PGE(2)通过抑制促炎细胞因子如肿瘤坏死因子-α（TNF-alpha）和白细胞介素-1β（IL-1beta）来提高细胞存活率。因此，PGE(2)作为炎症的调节剂而非介质发挥作用。前瞻性研究表明，在放疗前使用米索前列醇（一种PGE(1)类似物）预防辐射引起的副作用具有潜在用途。目前对NSAIDs和前列腺素药理学的理解显示出将放射治疗对正常组织的不良影响降至最低的巨大潜力。
