Radioprotection: the non-steroidal anti-inflammatory drugs (NSAIDs) and prostaglandins.
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.
Lee
Tat Khuen
TK
Center for Pharmaceutical Research, School of Pharmaceutical Molecular and Biomedical Sciences, University of South Australia, SA, 5000, Australia.
Stupans
Ieva
I
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002986:Clinical Trials as Topic; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004249:DNA Damage; D015777:Eicosanoids / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D011453:Prostaglandins / Q000096:biosynthesis* / Q000494:pharmacology; D011832:Radiation Injuries / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011878:Radiotherapy / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D011453:Prostaglandins; D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53